CA2121687A1

CA2121687A1 - Ionic beads useful for controlled release and adsorption

Info

Publication number: CA2121687A1
Application number: CA002121687A
Authority: CA
Inventors: Sergio Nacht; Richard Won; Martin Katz; Tai Cheng; Christine J. Y. Liau; Robert P. Eury; Michael Froix
Original assignee: Individual
Current assignee: Heron Therapeutics LLC
Priority date: 1991-10-21
Filing date: 1992-10-19
Publication date: 1993-04-29
Also published as: EP0612241A4; KR940702731A; JP2516322B2; JPH07500596A; EP0612241A1; AU2881592A; KR100295333B1; WO1993007862A1; AU662181B2

Abstract

Ionic compositions comprise an active ingredient absorbed within a network of internal pores defined by a plurality of polymeric particles. The particles are preferably crosslinked polymeric beads having a diameter in the range from about 5 to 100 microns and a surface charge density from about 0.1 to 10 meq/qm hydrogen ion capacity. The active ingredients are released from the ionic polymer beads over time when orally administered, applied to a keratinic material, typically human skin or hair or otherwise delivered to a target environment. The use of a cationic charge promotes adhesion of the beads to the keratinic material.

Description

2 212l6~7 PCI/US92/08907 ONIC BE~DE3 ~8EFIJL FOR CO~T~OLLED REL~ASE AND AD~;ORP~ION

BACgGRO~JND OF_~RE IN~Nq~ION
1. Fiel~ of th~ In~ention The present invention relates generally to the preparation of topical and oral compositions. More particularly, it relates to the preparatisn of ionic polymer delivery systems which prolong the activity of various topically active ingr dients by increasing the substantivity on keratinic materials, such as hair and~
skin, and to orally delivered polymers which release active substances via ion-exchange.
The adherent properties of topically-applied substances on hair and skin af-ects both initial adsorption and retention, particularly on subsequent exposure to water. The combined charactexistics of adsorption and retention constitute the property referred to as "substantivity," which can ~e definad as the ability of a substance to ~e adsorbed onto keratin and to resist removal by water rinse-off.
An ideal topi~al substance would have adsorptive affinity ~or keratinic materials, re~ain activity for long periods of time, resist being washed ~way by perspiration and other contact with wa er, and be free of adverse interaction~ with other ingredients of which incorporation is desirous. No topical substance has yet been discovered which adequately satisfies all of these objectives~
Some of the most popular topically active preparations available in the market today include, for example, fragrance substances; cosmetic substances, such as lipsticks, make-up and foundation powders; insect repellents; anti-bacterials; acne treatment formulations;

W093/07~2 2 1 2 1 6 87 PCT/US92/08~7 hair treatment formulations, such as conditioners and hair growth promoting agents; and skin protection formulations, such as age-prevention agents; and ultraviolet absorbing substances (sunscreens). These ingredients, substances, or formulations may be used alone, or in combinaticn with each other, and may be applied in pure form or diluted in a suitable solvent or carrier.
A frequently observed problem with such topically active substances is the rapid loss of activity after application to the skin. Under usual conditions of heavy perspiration and/or contact with water, concentration of the above substances in their respective topical compositions is either diluted, thereby reducing effectiveness, or washed away, thereby losing all effectiveness. One way to extend activity is by increasing the concentrations of the active ingredien~ in their respective formulations. However, as concentrations are increased, so too are the risks of toxic and allergic reactions to the user. These reactions often occur with the higher concentrations, even if exposure to the product is relatively short.
A second drawback, unrelated to the safety of administration of such compositions, is the increased expense of u~ing such compositions which are so easiIy washed away. For instance, to maintain an adequate level of protection from the sun, a sunbather would have to re~pply sunscreen each time after entering the water and frequently after perspiring~
It would therefore be highly desirable to provide an approach for increasing the adsorptivP
affinity of topically active compositions to keratinic materials, and for prolon~ing the activity of such compositions, while simultaneously reducing the likelihood of toxic and/or allergic reaction to the user.
Compositions and methods for the release of an active substance, such as a drug, from a reservoir over W093/07862 2 1 2 1 6 8 7 PCr/US92/08907 time are known, and numerous specific approaches exist to achieve such controlled release. Two widely practiced approaches are of particular interest to the present invention. In the first such approach, drugs or other s active substances are encapsulated or ~oated with a material which dissolves or degrades in response to a change in environmental conditions. For example, pH-response coatings (referred to as enteric coatings) may be provided on drugs to protect the drug in the low pH
environment of t~e stomach but dissolve when the pH rises as the drug passes to the intestines. Such coatings include cellulose acetate, phthalate-polyvinyl acetate phthalate, hydroxypropylcellulose phthalate, methyl cellulose phthalate, and the like. Although these coatings are very effective in protecting drugs in the stomach, they do not generally provide a controlled release rate once the drug raaches the intestines.
A less widely employed delivery approach utilizes porous polymeric particles for absorbing and releasing drugs and other active substances at a controlled release rate. See, e.g., U.S. Pa.tent No.
4,692,462, discussed below. In such systems, the diffusion rate of the drug or other active substance throu~h the pores determines the release rate. The di~fusion rate, of course, depends on pore size, drug viscosi~y, temperature, and the like. In the case of drug delivery, drugs absorbed in porous polymeric particles are usually combined in an adhesive or other matrix material as part of a transdermal drug delivery system. In another example, drugs have been adsorbed onto porous resin beads which are then coated with a membrane diffusion barrier, e.g., ethylcellulose, in order to effect sustained release. See, European Patent Application 171 528, discussed below.
One difficulty with these systems is that a coating or blocking agènt must be introduced in order to achieve a desired release rate for particular active W093tO7862 PCT~US92/08~7 21216~7 4 substances. The physical characteristics of drugs and other active substances may vary widely, including changes in viscosity, charge characteristics, molecular weight, and the like and the release rate in any delivery system may vary widely depending on the nature of the substance which is being delivered. This problem is particularly evident when employing porous particle delivery systems where modification of the pore characteristics can be achieved only within certain limitations. Synthetic resin-based ion exchangers are conventionally produced by post-polymerization modification of preformed, cross-linked beads. For example, anion exchange resins are made from cross-linked polystyrene by halogen-alkylation and subsequent amination. Cation exchange resins can be made by either carboxylation or sulfonylation of the preformed, cross-linked beads. ~uch ion exchange resins are typically discolored, have capacities for the exchange of ion less than 2meq/gm, and regeneration can be a lengthy process.
Naturally occurring ion exchangers, such as cellulose-based or dextran gels which are made by introducing functional groups onto the cross-linked natural polymers, have gel structures which are not mechanically strong enough to pre~ent the gel matrix from shrinking or collapsing as the active ingredient is removed. The-natural polymer-~ased materials are unstable in the presence of oxidants or strong acids, at elevated temperatures (e.g., 120C for 30 minutes), and because of their biologicaI origins, they will support bacterial and microbial growt~.
Thus, it would be desirable to provide improved compositions and methods for the delivery of drugs and other active substances. It would be particularly desirable if the compositions could be readily modified to achieve a desired release rate for active substances having a wide range of physical and chemical characteristics. It would be further desirable if the ~, wo g3/07862 2 1 2 1 fi ~ 7 PCT/US92/08907 compositions could be modified to control the release rate of such diverse active substances under a variety of different external conditions, such as pH, temperature, ionic strength, and the like. It would also be desirable if compositions could be readily modified to allow absorption of bile salts in a controlled and predictable manner.
Des~riDtion of the Bac~ground Art U.S. Patent No. 4,590,825, discloses an uncharged polymer bead delivery system suitable for topical application. U.S. Patent No. 4,304,563 discloses cationic polymers (and methods for their preparation) useful as gels for treatment of keratinic materials, such as hair. European patent application Z25615 discloses the use of cationic beads formed from a polystyrene ;
sulfonate-divinyl benzene copolymer for the controlled oral delivery of negatively-charged dru~s. South African patent application no. 872554 and U.S. 4,221,778 discloses sulfonic acid cationic ion ~xchange resin particles which have been impregnatad with certain agents to enhance their suitability for oral drug delivery.
U.S. Patent No. 3,691,270 discloses cosmetic compositions for the skin comprising microcapsules formed from an alveolar poly~er, including polyvinylpyridine. The microcapsules, however, are uncharged~ U~S. Patent N~.

3,880,990 discloses orally-administratable compositions comprising drugs encapsulated in an anionic polymer.
U.S. Patent No. 4,198,395, disclo~es a charged polymeric resin material which is u~eful for the treatment of hypercholesterolemia by oral administration. V.S. Patent No. 4,552,812, discloses the preparation of fluoresoent and ~agnetic anionic beads useful in performing assays.
European patent application 060 138 disclose~ the preparation of porous copolymeric blocks capable of a~sorbing and acting as a reservoir for liquids, such as perfume. European patent application 143 608 discloses a polymeric bead composition having a releasa~le lipophilic W093/07862 2 1 2 1 6 ~ 7 PCT/US92/08907 compound retained therein. British patent 1,482,663 describe polymeric bead compositions capable of holding water-soluble drugs. Cationic polymeric ion exchange resins, including styrene-divinylbenzene copolymers, are commercially available from suppliers such as Interaction Chemicals, Inc., Mountain View, California 94043; and Reilly Tar & Chemical Corp., Indianapolis, Indiana 46204 The ability of cationic materials to adsorb to the skin and hair iæ discussed in Goddard (1987) Cosmetics &
Toiletries 102:71-80.
81JM~ARY OF THE IN~ENTION
The present invention provides for the incorporation of active and inert substances in an ionic polymer bead delivery system to form novel compositions.
It has been found that when a cationic functionality is imparted on the surface o~ the polymeric bead surface, the substantivity of the topically active substances~when the beads are applied to the skin or hair is enhanced.
Cationic topical poiymeric delivery systems according to the present invention are keratinophilic compositions which exhibit an affinity for skin, hair, and other hiological molecules and can be used to adsorb bile salts when delivered orally. The anionic delivery systems can deliver basic drugs orally. The ionic polymer bead delivery ~ystem compri~es crosslinked polymer beads =
charactexized by ionic functionalities on the bead surface, usually positively charged pyridine and quaternary ammonium groups in the cationic beads, and negatively charged sul~onates and carboxylates in the anionic beads. The beads form a porous network capable of retaining large amounts of inert and active substances. The beads are non-collapsible, small diameter, havin~ relatively large pores and a relatively high ratio of pore volume to bead volume~
The cationic polymer bead delivery system having topically active ingredients incorporated therein may be used as a topical product by itself or may be W093/07862 2 1 2 1 6 8 7 PCT/~S92/08907 further incorporated into a carrier composition-or other cosmetic product. When used alone, the cationic polymeric delivery system with incorporated topîcally active ingredient is a dry, free-flowing product which can be rubbed directly onto the skin, providing controlled release of the topically active ingredient over a prolonged period of time. In the more usual situation where the cationic polymeric delivery system is incorporated in other carriers, vehicles, solvents, or cosmetic preparations, use of this delivery system avoids incompatibilities, typically chemical or physical interactions, which might otherwise exist between the active ingredient and other ingredients in tAe topical preparation, or between the active substance and the carrier, vehicle, or solvent.
A variety of physiologically-acceptable solvent or medium may be used as a carrier. To preserve the .
cationic functionality on the pyridine-based polymeric bead surface in topical formulations, however, the carrier should ~e at least slightly acidic, preferably being below about 5, and most preferably being in the range from about 3 to 4. With carboxylate-based beads, thie carrier should have a pH above about 5. It will oftsn bs desirable to incorporate a physiolog~cally-acceptable buffer in the carrier to main~ain the pH within the range of interest.
The ionic polymer bead delivery systems may be fo~med ~y suspension or inverse suspension polymerization of suitable monomers, at least some of which include functionalities carrying or capable of carrying either a positive or negative charge under the conditions of use, in an immiscible phase (including a porogen for suspension polymerization of non-aqueous monomers).
Generally, the monomers (and the porogen if used) are first mixed together and the resulting mixture is then suspended in the immiscible phase. The immiscible phase is then agitated to form droplets of the monomer mixture, ,, W093/0786~ 2 1 2 1 6 8 7 PCT/~S92/08907 and polymerization of the monomer mixture is initiated to form the desired beads.
Cationicity (i.e., cationic functionality) may be obtained using a preformed cationic monomer, e.g., a quaternary amine monomex ~which carriers a substantially permanent charge under the conditions of use), or by protonating ~or quaternizing) surface functionalities in the formed ~ead, e.g., protonating a quaternary nitrogen in pyridine with an acid medium. Such protonation may be performed either before or after entrapping the active ingredient, depending on the conditions and t~e chemical characteristics of the particular ingredient sought to be incorporated.
Anionicity (i.eO, anionic functionality) may be obtained by suspending, fo~ example; sulfonated styrenic beads in a basic solution.
In some cases, the topically active ubstance may be used as a porogen in a one-step process where there will be no s~bstantial degradation of the substance under the conditions of polymerization and the sub tance is otherwise suitable. More commonly, for more labile ingredients (particu~arly those which are heat or radiation labile), the compositions of the present invention may be formed using a two-step process. In this process, the polymeric beads may be preformed usi~g a substitute poro~en, for example, an alkan4, cycloalakane, or aromatic solv~nt. The beads are formed by suspension polymerization or inverse suspension polymerization and the ~ubstitute porogen is extracted from the resulting bead product~ The desired active substance may then be introduced into the beads, typically by contact absorption, to create the desired product. Again, the polymeric beads may be rendered cationic or anionic either before or after entrapping the active substance into the delivery system, or by the use of charged monomers. In addition to allowing the incorporation of labile substances, such a two-step wo g3/07862 2 1 2 1 6 8 7 PCT/US92tOX907 preparation process allows greater control over the structure of the bead based on a wider choice of porogen substances in reaction conditions, and thus may be the desired preparatory method even for less labile substances.
In addition to enhanced su~stantivity, active substances incorporated into the topically applied cationic polymer bead delivery system of the present invention have been found to provide enhanced effectiveness when compared to similar concentrations of the ingredient in non-cationic polymeric bead delivery systems. For example, sunscreen preparations incorporated into systems comprising cationic polymeric beads will be expected to have an enhanced SPF (Sun Protection Factor) rating when compared to otherwise identical prepara~ions comprising a non-cationic polymer bead delivery system.
Orally deliverable polymeric particles according to the present invention comprise ionic polymeric hydrogel particles, each defining a network of internal pores, composed of an ionic monoethylenically unsaturated monomer and a highly water-soluble polyethylenically unsaturatsd cross-linXing monomer. An oppositely charged counter ion is included for rendering the hydrogels neutral. The hydrogels are unique in that the ~welling ratio, r~, determined as the ratio of the swollen particle size (water) to the non-swollen particle size (dioxane) is not directly proportional to the amount of cro~s-linking monomer used during polymerization of the particles, an unexpected result. Further, the equilibrium water fraction (EWF) of the particles upon equilibration with water is directly proportional to the amount of water used during polymerization. These properties allow the ionic hydroqels to function as sustained release ion exchangers whose diffusion path may be adjusted to suit the particular environment and drug W093/07862 2 1 2 1 ~ 8 7 PCT/US92~08907 delivered. They also allow "blank" hydrogels to adsorb bile salts.
Oral composition~ according to the present invention comprise the ionic hydrogels and counterion, wherein the counterion is either inert or pharmaceutically active, such as a drug, and ionically held within the internal pore network. The counter ion is exchanged for a solute ion in a predetermined aqueous environment, such as an animal or human digestive track.
In a particular embodiment, the counter ion is a weakly basic, positively-charged drug which is delivered to the gastrointestinal tracX upon change in pH and/or ionic strength of the gastrointestinal track.
According to the method of making the hydrogel particles of the present invention, the ionic hydrogels are formed by inverse suspension radical pol~merization ; of suitable ionic monomers cross-linked with a monom~r that is soluble in aqueous solutions in all proportions.
- Generally, the ionic monomer is mixed with the counterion and the resulting mixture combined with the water-soluble cross-linXin~ monomer to form an aqueous phase. An initiator is added to the aqueous phase and the resulting mixture suspended in an organic phase. The organic phase ~s then agitated to form droplets of the aqueous monomer pha~e, and polymerization o~ the monomers initiated--to ~orm the desired beads fr~m the dropletsO The precise dimensions and characteristics of the beads are controlled by varying process parameters ~uch as the amount of water used during polymerization, agitation speed, and varying the amount or type of monomer chosen.
Once tbe ionic hydrogel beads are formed, t~e beads can either be ussd as is ~if an inert or stable active ingredient was used as counterion) or loaded with an appropriate labile active counterion by repeated exposure to a drug in a chromatographic column, or by prolonged contact of the hydrogel beads with the drug solution~
".

, ~ :
, WO 93/07862 2 1 2 1 ~ 8 7 PCl`/llS92/08907 1 1 !
B~IEF DE CRIPTION OF T~E: DRAWING8 Fig. 1 shows the effect of cross-link density of poly(trimethylammoniumethylmethacrylic chloride-co-N,N'-methylenebisacrylamide~ hydrogels on their aqueous swelling ~% swelling v/v; 83% water; ~ swelling, 70%
water; E.W.F. (equilibrium water fraction), 83% water.
Fig. 2 shows release profiles of D&C Red No. 28 from various beads, including a cationic hydrogel (-); a cationic hydrogel in an anionic surfactant (~); and an 10 uncharged bead (-~.
Fig. 3 shows how the equilibrium water fraction of the hydrogels increases in direct proportion to the water content during polymerization and is substantially independent of the cross-linked density.
Fig. 4 shows that no D&C Red No. 28 (an anionic dye3 was released from a cationic hydrogel loaded macroporous carrier until an anionic surfactant (sodium dodecyl sulfate) was present.
Fig. 5 shows release profiles of tetracycline-20 HC1 from anionic hydrogels when a cationic surfactant is added.
Fig. 6 shows the swelling behavior of.hydrogels as a function of pH.
D~TAI~ pB8Ç~IPTIO~ ~F THE 8P~CIF~C ~ODIMEN~S
The beads or microspheres used in connection wi~h the present invention can be riqid or non-rigid, and are open-pore, ~hemical and biologically inert particles, with a positive or negati~e charge imparted on the surfaces and an impregnant held inside the pores by 30 c~pillary and ionic for~es, where the impregnant is a topically or orally active substance or an inert counter ion. In topical compositions, the charge (positive) is suf icient to promote adhesion of the particles to keratinic materials, such as human skin and hair. The 35 pores are interconnected and open to the particle surface so that substantially full CQmmunication is provided between the internal pore space and the exterior of the W093/07862 2 1 2 1 6 8 7 PCT/US92/OXgO7 particle whereby the impregnant may be released over time after the beads are applied to the user's skin or hair, or, in the case of orally delivered drugs, to the GIT.
When cationic beads are used, the cationicity of the polymeric beads of the present invention derives from the presence of a functionality capable of being protonated (or already charged) on at least some of the monomers being polymerized. For oral delivery systems, the beads will have charge density sufficient to produce a binding affinity for a counter ion measured by the weight distribution coefficient method of at least about l.Ox106 ml/gm. (See Lange's Handbook of Chemistry, 13th Edition, pages 5-119--5-122.) The ionic hydrogels will also have porosity and charge density sufficient to afford a counter-ion capacity of at least 45% by weight of total hydrogel. The cationic functionalities of particular interest to the present invention include~both pyridine which has a tertiary nitrogen and ammonium which has a quaternary nitrogen, each of which i5 capable of carrying a positive charge under the conditions of use of the topical compositions. The anionic functionalities of particular interest include sulfonates and carboxylates.
Beads according to the present invention will have surface charge densities ranging from about 0.1 to lO
milliequivalent/gram (meq/gm) capacity for hydrogen ion in water (determined by conventional acid base titration), usually from a~out 0.2 to 10 meq/gm, more u ually fro~ about 0.5 to ~0 meq/gm, and preferably from.
about S.0 to 10 meq~gm ~al~o determined by conventional acid-base titration~.
In their most convenient fonm, the particle~
are generally sphsrical in shape, due to the use of suspension or inverse suspension polymerization as the preferred methods of preparation. While such microspheres vary widely in size, those fallin~ within the range of about 5 to about 100 microns in diameter, preferably from about 10 to about 40 microns, will provide the best results. Microspheres within these size ranges are appealing from an aesthetic point of view by imparting a smooth feel to the touch when applied topically, and are easily expelled when delivered orally.
The pore dimensions within the spheres may also vary widely, with optimum dimensions depending on the chemical characteristics of the polymers used, as well as the diffusive characteristics of the impregnant.
Different systems will thus call for different optimum ranges of pore volume distribution to obtain the most desirable properties for the overall formulation. In general, however, the best results are obtained with total pore volumes ranging from about 0.01 to a~out 4.0 cc/g, preferably from about 0.1 to about 2.00 cc/g, surface areas ranging from about 1 to about 500 m2/g, preferably from about 20 to about 200 m2/g, and the average pore diameters ranging from about 0.001 to ab~ut 3.0 micron~ preferably from about Q.003 to about 1.0 micron. Following conventional methods of measuring and expressing pore sizes, the pore diameters are calculated from the measurement of the surface area by B.E.T.
nitrogen analysis (Brunaer et al. (1938) J. Am. Chem.
Soc~. 60:309-316) and from the measurement of the pore volum~c by the mercury intrusion method.
The particles are conveniently formed as micro~pheres by suspension polymerization in a liquid-liquid system. In general, a solution containing the desired monomers, a polymerization catalyst (if used), and an inert fluid ~porogen) is formed in a first liquid phase, where the porogen i5 miscible with the first fluid phase but immiscible with a second liquid phase. The solution is then suspended in the second liquid phase which is immiscible with the first liquid phase. In the case of organic-soluble monomers, e.g., vinyl pyridine and its derivatives! the first liquid phase will usually be an organic solvent capable of dissolving the monomers but which is immiscible with water, and the second liquid . ~
,~

W093~07862 PCT/US92J08~7 phase will be water. In the case of water-soluble monomers, e.g., quaternized acrylate and methacrylate derivatives, the first liquid phase will be aqueous (with water as the porogen) while the second phase will be a hydrophobic organic solvent.
Once the suspension is established with dis-crete droplets of a desired size, polymerization is effected (typically by activating the reactants by either increased temperature or irradiation). After polymerization is complete, the resulting beads are recovered from the suspension. The beads are, at this point, subætantially porous structures, the polymer having formed around the inert fluid thereby forming the pore networX. The fluid has accordingly served as lS porogen, or pore-forming agent, and occupies the pores of the formed beads. Suitable porogen fluids will be described in more detail hereinafter. When an organic phase serves as the porogen, the process will be known as suspension polymerization. When water serves as the porogen (in the case of water-soluble monomers~, the process will be known as inverse suspension~
polymerization.
Certain impregnants may ~erve as porogen and, as previously m~ntioned, may be entr~pped within the porous network of the presenk invention before or after the charge producing st~ps described above. The critical factor in choosing the impregnant for topical applications is its eleetrical charge~ That is, in order to preserve the ionic funct~onality of the beads when applied to the skin or hair, the impregnant must be substantially neutral. Slightly negative or positive substances may be used; however, their entrapment must not neutralize or otherwise affect the surface charge of the bead.
Where the impregnant so selected serves as the porogen, the porous beads reco~ered from the suspension im~ediately after polymerization are substantially ready W093/07862 PCr/US92/08~7 2~21fi87 for use, following removal of surface moisture, and any further processing steps of this nature, including ionization. In these cases, microsphere formation and incorporation of the impregnant is performed in a single step. This may accordingly be termed a one-step procedure. Those impregnants which are capable of serving as porogens will be liquid impregnants meeting the following criteria:
1) They are either wholly miscible with a monomer mixture or capable of being made fully miscibla by the addition of a minor amount of a solvent which is non-miscible with the second liquid phase;
2) They are i~mi~cible with the second liquid phase (or at most slightly soluble);
3) They are inert with respect to the monomers, and stable when in contact wi~h any pQlymerization catalyst used and when subjected to any conditions needed to induce polymerization (such as temperature ~ and radiation);
; 4) They are normally liquids or have melting points below the polymerization temperature. Solid~ can frequently be 2S con~erted to liquid form by being dissolved in a solvent or by forming eutectic mixtures; and 5) They are neutral with respect to their electrical charge (or at most either slightly negative nr positive).
When using this method, the steps must be performed under an inert atmosphere such as nitrogen. If a polymerization catalyst is used, it must be one which does not oxidize the impregnant, if the latter is susceptible to oxidation. Azo catalysts are examples of such catalysts. Also, polymerization temperatures are being held within a moderate range.

W093/07862 2 1 2 1 6 8 7 PCr/US92/08~7 As an alternative to the one-step procedure, the substantially neutral impregnant may be placed inside the pores of preformed dry porous polymer beads. Thus, the product is prepared in two steps, performed in sequence, wherein polymerization is performed first with a substitute porogen which is then removed and replaced by the desired active ingredient. Hence, the porogen and active ingredients are distinct components in this two-step process. Materials suitable as substitute porogens will be substances which meet the five criteria listed above for porogen impregnants.
Preferred among these substances suitable as substitute porogens when hydrophobic monomers are used are hydrocarbons, particularly inert, non-polar organic sol~ents. Some of the most convenient examples are alkanes, cycloalkanes, and aromatics. Examples of such so~vents are alkanes of 5 to 12 carbon atoms, straig~t or branched chain, cycloalkanes of 5 to 8 carbon atoms, benzene, and alkyl-substituted benzenes such as toluene and the xylanes. Porogens of other types include C4 - C~
aIcohols, perfluoro polyethers, and oils. Removal of the porogen may be effected by solvent extr~ction, evaporation, or similar conventiona~ operations. As noted above, in the case of water- oluble monomers, water serves as porogen.
A further advantage of the use of this two step prscess is that it permits the removal of unwanted species formed within the polymerized structures prior to incorporation of the impregnant. Examples of unwanted species include unreacted monomers, residual catalysts, and surface active agents and/or dispersants remaining on the sphere surfaces. A further advantage of thîs technique is that it permits one to select the amount and type of porogen as a means of controlling the pore characteristics of the finished bead. One is thus no longer bound by the limitations of the impregnant as it ~ affects ~he structure of t~e bead itself~ This permits :` :

W093/~7862 PCT/US9~/08~7 2 :1 2 1 6 ~ 7 partial, rather than full, filling of the pores with the impregnant, and further control of the pore size and distribution by selection among swelling and non-swelling porogens.
Extraction of the porogen and its replacement with (i.e., impregnation of the dry bead with) the impregnant in the two-step procedure may be effeoted in a variety of ways, depending on the chemical nature of the porogen and its behavior in combination with that of the lo other species present. The beads are first recovered from the suspension by filtration, prefe~ably using vacuum filtration apparatus ~such as a Buchner funnel).
The beads are then washed with an appropriate solvent to remove organic species not bound to the polymer, including surfactants having deposited on the bead surfaces from the aqueous phase, unreacted monomers and residual catalysts, and the porogen itself r An examp~e of such a solvent is isopropanol, either alone or in aqueous solution. Once wa6hing is complete, the solvent itself is removed by drying, preferably in a vacuum.
In certain cases, an alternative method of ex raction may be used -- i.e., where the porogen, un-reacted monomer and water will form an azeotrope. In these cases, stea~ distillation i-~ an e~fective way of extracting porogen from the beads. This a~ain may be followed by drying under vacuum.
Assuming that the beads were already rendered ionicO or that protonation will follow entrapment (as described in more detail hereinbelow), once the beads are rendered dry and free of the substitute poxogen and any unwanted organic materials, they may be used orally as is to absorb oppositely ~harged species or are impregnated with the impregnant according to conventional techniques.
The most convenient uch technique is contact absorption.
Solid active ingredients are first dissolved in a solvent, and the resulting solution is absorbed by the beads. ~he solvent may either be retained in the wo g3/07862 2 1 2 1 ~ 8 7 PCT/US92/08~7 finished product or removed by conventional means such as evaporation or extraction using a further solvent. For those solid ingredients having limited solubility in a particular solvent, high contents in the finished bead can be attained by repeated absorptions each followed by solvent removal.
In the case of oral delivery systems, the impregnant may be, for example, a basic positively-charged drug which is loaded into a matrix of anionic (negatively-charged) beads via chromatographic methods, such as ion exchange chromatography. In that case, the positively-charged counter ion is exchanged with the drug molecules.
The polymerization process and the various parameters and process conditions involved in the poly-merization can be selected and adjusted as a means of controlling the po~e characteristics and consequently the capacity and releasç characteristics of the ultimate product. For example, proper selection of the cros~linking means, the amount and type of crosslinking agent, and th~ amount and type of porogen are means of attaining such control. Certain polymerization conditions may also be varied to such effect, including - temperature, degree of radiation where used, degree of agitation and any other factors affecting the rate of the polymerization reaction.
Crosslinking in t~e polymer formation is a ma~or means of pore size control. Monomers whîch may be polymerized to produce crosslinked polymer beads in accordance with the present invention include polyethy-lenically unsaturated monomers, i.e., those having at least two sites of unsaturation, and monoethylenically unsaturated monomers in combination with one or more polyethylenically unsaturated monomers. ~n the l~tter 3~ case, the percentage of crosslinking may be controlled by balancing the relative amounts of monoethylenically unsaturated monomer and polyethylenically unsaturated WOg3/07862 PCT/US92/0~907 21216~7 monomer. Usually, such systems will include a single monoethylenically saturated monomer and a single polyethylenically unsaturated monomer, although it will be possible to add additional compatible monomers of each type to the system, if desired. For a discussion of the preparation of such copolymer systems, see Guyot and Bartholin, Design and Properties of Polymers as Materials for Fine Chemistry, Prog. Pol~m. Ed. (1982) Vol. 8, pp 303-307.
Monoethylenically unsaturated monomers which may be used as part of the monoethylenically unsaturated monomer content of the polymer delivery system include ethylene, propylene, isobutylene, diisobutylene, styrene, sodium styrene sulfonate, ethylvinylbenzene, vinylbenzene chloride, vinyl pyridine and its derivatives, vinyltoluene, and dicyclopentadiene; esters of acrylic and methacrylic acid, including the methyl, ethyl, propyl, isopropyl, b~tyl, sec-butyl, tert-butyl, amyl, hexyl, octyl, ethylhexyl, decyl, dodecyl, cyclohexyl, isobornyl, phenyl, benzyl, alkylphenyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, ethoxyphenyl, ethoxybenzyl, and ethoxycyclohexyl esters; vinyl esters, including vinyl acetate, vinyl propionate, vinyl butyrate and vinyl laurate; vinyl ketones, including vinyl m~ithyl ketone, ~inyl eithyl ketone, vinyl isopropyl ketone, a~d methyl isopropenyl ketone; vinyl ethers, including vinyl methyl ether, vinyl ethyl ether, ~inyl propyl ether, and vinyl isobutyl ether; vinyl compounds containing silicon and other metals, such as vinyl siloxanes, and the like.
Moreover, polyethylenically unsaturated monomers which ordinarily act as though they have only one unsaturated group, such as isopropene, butadiene and chloroprene, may also be used as part of the monoethylenically unsaturated monomer content.
Polyethylenically unsaturated crosslinking monomers suitable for preparing such polymer beads in-21~16~,7 ", clude diallyl phthalate, ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylolpropanetri-methacrylate, divinylsulfone; polyvinyl and polyallyl ethers of ethylene glycol, of glycerol, of pentaery-thritol, of diethyleneglycol, of monothio- and dithio-derivatives of glycols, and of resorcinol; divinylketone, divinylsulfide, allyl acrylate, diallyl maleate, diallyl fumarate, diallyl succinate, diallyl carbonate, diallyl malonate, diallyl oxalate, diallyl adipate, diallyl sebacate, divinyl sebacate, diallyl tartrate, dia:Llyl silicate, triallyl tricarballylate, triallyl acon:itate, triallyl citrate, triallyl phosphate, divinyl naphthalene, divinylbenzene, trivinylbenzene;
alkyldivinylbenzenes having from 1 to 4 alkyl groups of 1 ~5 to 2 carbon atoms substitute on the benzene nucleus;
alkyltrivinylbenzenes having 1 to 3 alkyl groups of 1 to 2 carbon atoms substitute on the benzene nucleus;
trivinylnaphthalenes, polyvinylanthracenes, and water-soluble acrylates and methacrylates (as specifically set ~orth below), and the like~
At least a portion of the monomer-content will comprise protonatable functionalities which are capable of retaining a positive charge under the conditions of us~. Such protonable functionalities may be present on the monoethylenically unsaturated monomers, the polyethylenically unsaturated monomers, or both, where suitable functionalities include pyridine and ammonium.
Exemplary monomers includa vinyl pyridines, such as 2-vinyl pyridine, 4-vinyl pyridine, 3-methyl-2-vinyl pyridine, 4-methyl-2-vinyl pyridine, 6-methyl-2-vinyl pyridine, 3-ethyl-2-vinyl pyridine, 5-ethyl-2-vinyl pyridine, 2-methyl-3-vinyl pyridine, ~-methyl-4-vinyl pyridine, 2-methyl-5-vinyl pyridine, and 2 ethyl 5-vinyl pyridine, as well as water-solu~le acrylated and 3S methacrylates, ~uch as methacrylamidopropylhydroxy-ethyldimethyla~mmonium acetate, methacrylamidopropyl-trimethylammonium chloride, and the quaternization W093/0~862 P~T/US92/08907 products of dimethylaminoethylmethacrylate and dimethyl sulfate, diethylaminoethylacrylate and dimethyl sulfate, vinylbenzyl chloride and divinylbenzene, and vinylbenzyl and ethylene glycol dimethacrylate. When quaternized monomers are used, a counter ion such as Cl-, F, Br~, I-, or CH30S03 iS incorporated into the structure.
When usin~ the water-soluble acrylate and methacrylate monomers, it is necessary that all monomers employed be water soluble. Suitable polyethylenically unsaturated monomers (required for cross-linking) include N,N'-methylenebisacrylamide; N,N'-nonamethylenebis-acrylamide; and alkoxylated water soluble multi-functional acrylates. The inverse suspension polymerization protocol described above for water-soluble quaternized monomers will be employed. The microspheres produced from water soluble quaternized monomers are generally non-rigid hydrogels which are useful for absorbing polar (water and alcohol) soluble materials, such as hydroquinones, methyl salicylate, insect repellents (in alcohols), sunscreens (in alcohol~, and the like, while negatively charged hydrogels~are useful for absorbing basic drugs, such as alkaloids, steroids, etc.
The preferred polymer bead of the present invention will be free fro~ reacti~e groups which will react or interact with the porogen andlor the active ingredient which is ultimately incorporated in the composition other than through ionic intexaction, such as that seen in ion-exchange proces~es. Such beads should not readily undergo u~wanted reactions, should be stable over the expected pH range of use, should resist moderate oxidation and reduction, will be stable at temperatures within the expected range of use, and should have a relatively long shelf life.
Preferred cationic topical polymer delivery systems of the present invention comprise substantially non-collapsible beads which are formed by the W093/07862 2 1 2 1 6 8 7 22 PCT/US92/~8~7 copolymerization of 4-vinylpyridine and ethylene glycol dimethacrylate, 4-vinylpyridine and divinylbenzene, 2-vinylpyridine and divinylbenzene, 2-vinylpyridine and ethylene glycol dimethacrylate, ethyl methyl vinylpyridine and divinylbenzene, and ethyl methyl vinylpyridine and ethylene glycol dimethacrylate. Of these systems, 4-vinylpyridine and divinylbenzene is particularly preferred, while the copolymer of 4-vinylpyridine and ethylene glycol dimethacrylate is even more particularly preferred.
Ionic polymeric hydrogel materials in accordance with the present invention will comprise the copolymerization product of an ionic monoethylenically unsaturated monomer and a polyethylenically unsaturated cross~ king monomer which is soluble in aqueous solutions in all proportions.
Preferred cationic polymers for oral delivery systems are formed from cationic monoethylenically unsaturated quaternary ammonium monomers selected from the group consisting of:

R3 - N+ - (CH2)~ - 0 - C - C - R' X-wherein Rl, R2, R3, and R4 are the same or different saturated alkyl grQups having from one to six carbon atoms, n = 1-4, X is celected from the group consisting of Cl, F, Br, I, and CH30S03 and said water-soluble polyethylenically unsatuxated cross-linking monomer is selected from the group consisting of N,N'-methylene-bisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.
Particularly preferred cationic polymers include the copolymerization product of trimethylammonium-ethylmethacrylic chloride and N,N'-methylenebisacrylamide (poly(PTMAEMCl-co-MBA)).

WOs3/078C2 PCT/US92/0~907 2121fi87 Preferred anionic polymers for oral delivery systems are formed from the copolymerization product of an anionic monoethylenically unsaturated monomer selected fro~ the group consisting of:

C R ~ ~R ~ y, wherein Rl, R2, R3, R4, and R5 are the same or different and are selected from the group consisting of H-saturated alkyls having from 1-4 carbon atoms, wherein Y is selected from the group consisting of Na and K, wherein said water-soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylene- -~i~acrylamide, and alkoxylated water-soluble multi-functional acrylates. Particularly preferred anionic hydrogel beads are ~he copolymerization products of methacrylic acid and N,N'-methyl~nebi~acrylamide ((poly)MA-co-MBA), and the copolymerization product of ~odium styrene sulfonate and N,N'-methylene~isacrylamide ~poly(SSS-~o-MB~
The polymer beads of the pr~ent invention will hav~ grea~er than 10% crosslinking, preferably from about 10% to about 80% crosslinXing, and most preferably from about 20% to about 60% cros~linkinq. The percentage crosslinking is defined among those skilled in the art as the weight;of polyethylenically unsaturated monomer or monomers divided by the total weight of monomer, including both polyethylenically unsaturated and monoethylenically unsaturated monomers. Usually, the monoethylenically unsaturated monomer will be present at from about 20% to 80% of the monomer mixture, preferably 40%, with the polyethylenically unsaturated monomer : 40 for~ing the remainder of the mi~ture.

,;

W093/07862 PCT/US92/08~7 2 1 2 1 6 ~ 7 In the case of topically applied, neutral impregnants, protonation of the polymeric ~eads may be performed either before or after entrapping the desired impregnant within the porous network. One way of obtaining the cationic beads of the present invention is, for example, protonating the beads thus xecovered from the suspension with an acid medium. In particular, to obtain the positive charge on the surfac~ of the beads of the present invention, an acid wash such as, for example, a 3~ aqueous hydrochloride solution, is performed after the beads are recovered from the polymerization step.
Excess acid is removed with a second hydrochloride solution having a pH ranging from about 1 to about 4;
preferably, however, pH 3.
Alternatively, the beads of the present invention may be protonated with a pH 3 buffered rinse, comprising O.lN potassium hydrogen phthalate, O.lN ~Cl and deionized water. Use of this buffered rinse does not require removal of excess acid, instead the beads so treated are directly filtered and dried.
Once the microspheres are formed~and dried, they may be impregnated with the impregnant by contact absorption (this step may be performed either before or aftar protonation unless ion-exchange is the method of intro~ucing the active ingredient~. As an option,-the impregnant may be used in the form of a ~olution in a suitable organic solvent for purposes of decreasing ~iscosity and facilitating absorption, decreasing potency, or the like. Examples of such solvents are liquid petrolatum, ether, petroleum ether, alcohols including methanol, ethanol and highPr alco2lols, aromatics including benzene and toluene, alkanes including pentane, hexane and heptane, ketones încluding acetone and methyl ethyl ketone, chlorinated hydrocarbons including chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride, acetates including ~ ethyl acetate, and oils in~luding isopropyl myristate, ,: -WO9~/07862 2 1 2 1 fi ~ 7 PCT/US92/089~7 diisopropyl adipate and, mineral oil. After absorption of the solution, the solvent can be evaporated or, if desired, retained inside the pores together with the impregnant. Other formulating materials typically used in topical formulations may be incorporated, such as carriers or adjuvants such as fragrances, preservatives, antioxidants, and other emollients can also be present, and will be incorporated into and onto the beads together with the impregnants and any other materials present.
Substances incorporated in the ionic polymer bead delivery system of the present invention may be used individually or may be combined to achieve a desired effect. The impregnant, whether it be pure active substance, a mixture of active substances or a solution of active substance(s), will generally comprise between approximately 5% and approximately 65% of the total weight of the impregnated beads. When the active substance is particularly potent, it will generally be in the form of a dilute so~ution, and the weight percent of the activP ingredient it~elf may range as low as 0.01%
based on the total weight of the impregnated~beads.
Suitable topically active impregnan~s include a wide variety of active substances intended for topieal application, comprising cosmetic, therapeutic, and other uses. Specific substances include ultraviolet absorbing substances (sunscreens), ~teroids, insect repellents, retinoic acid, fragrances, minoxidil, emollients, and the like. ^~pecific methods for incorporating such substances in pclymer bead delivery systems are taught in copending application serial numbers 091,647 and 112,971, the disclosures of which are incorporated herein by reference.
Once the topical compositions have been prepared, by either the one-step or two-step procedures described above, it may be used alone or further in~or-porated in a carrier or vehicle or in virtually any type of product, provided that they are incapable of W093/07862 PCT/US92/0~907 21216~

neutralizing the surface charge on the bead surface, having at least a slightly acidic pH, preferably being below about pH 6, more preferably having a pH in the range from about 3 to 4. The composition may be used alone by simply applying the composition, which is a dry powder, to the skin.
The impregnated beads useful for topical application of the present invention may also be incorporated in fluid or solid compositions or preparations of the type commonly used for skin treatment, including gels, creams, lotions, ointments, sprays, powders, oils, sticks, and the like. Appropriate vehicles for particular areas or methods of application will be readily apparent to those skilled in the art.
~5 For instance, the compositions of the present inven~ion, particularly the W absorbing compositions, will be incorporated in other products in order to impart cosmetic as well as.sunscreen properties. For example, the W absorbing compositions of the present invention are ideally suited ~or combining with make-up foundations, suntan preparations, and the like, wherein high adsorption and water-repulsion of the fin~l production is sought.
In the topical composition and formulations of the present invention utilized by application to keratinic material, particularly human skin and hair, the c~tionic surface charge on the individual pol~meric particles promotes adhesion of the compositions to the skin and hair, enhancing the persistence of the active substance which is being applied.
Most often, the ionic hydrogel compositions of the present invention will be used to deliver an active ingredient to a human or other animal for purposes of therapy, hygiene, analgesics, cosmetics, or the like.
For such purposes, the compositions may be delivered orally intravascularly, intraoccularly, intraperitoneally, and similar in vivo uses.

212 1 fi87 The major in vivo use for the hydrogel compositions of the present invention will be for the delivery of drugs and other pharmaceutical agents in human and veterinary applications. Exemplary drugs which may be delivered by the system of the present invention include analgesics, anesthetics, anthelmintics, antimicrobials, antipyrretics, antiseptics, antituburculotics, antitussives, antivirals, cardioactive drugs, cathartics, chemotherapeutic agents, chorticoids (steroids), depressants, diagnostic aids, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetics, potassium supplements, sedatives, sulfonamids, stimulants~
sympathomimetics, tranquilizers, urinary anti-infectives, vasoconstrictors, vasodilators, vitamins, xanthine derivatives, and the like.
The anionic hydrogels of the present invention are particularly useful for the oral delivery of cationic drugs which are to be released in the intestines rather than in the stomach. Such drugs include antibiotics, vitamins, non-steroidal anti-inflammatory substances, and the like. The negative surface charge will ionically bind the drug to the hydrogel during storage and while the composition pas~es through the stomach. On exposure to the high pH en~ironment on the intestine~, however, the drug will exchange with positively-charged ions such as sodium and potassium in the intestines in a typical ion exchange process. The drug will then be released from the internal pore network of the hydrogel particles.
In the case of anionic drugs, cationic hydrogels will be used for oral delivery. In that case, bile salts present in the intestines will exchange with the positive surface charge on the beads to effect release of the drugs.
For oral drug delivery, the polymeric hydrogel particles carrying the drug may be incorporated into a variety of known dosage forms, as descri~ed in, for ~-W093/07862 PCT/US92/~8~7 2121fi8~

example, ~emington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 16th Ed., 1982, the disclosure of which is incorporated herein by reference.
The composition or formulation to be administered will contain a preselected quantity of the drug contained within the ionic hydrogel particles. Usually, a pharmaceutically-acceptable non-toxic dosage form is prepared using conventional excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium arbonate, and the like.
Such compositions may be in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
For parenteral administration, including both intravascular and intramuscular administration, the ionic hydrogel polymeric particles of the present inventio~n will normally be suspended in an injectable water or saline carrier. Such formulations are well known in the art.
The following are ~ome of the considerations specific to various particular types of impregnants, plus examples of preparation and utility. The examples are offered solely for purposes of illustration, and are not intended to limit the invention in any manner. All parts and percentages are by weight, unless otherwise stated.

EXPgR~MENT~L
A. Tonical Formulations E~a~E_~
This example illustrates the preparation of 4-vinylpyridine/ethyleneglycoldimethacrylate polymeric beads of the present invention. The procedure is set forth below:
A 1000 ml four-necked reaction flask equipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet was evaluated and purged with W093/07862 2 1 2 1 6 8 7 PCT/US92~08~07 nitrogen. 300 parts of deionized water, 2.5 parts gum arabic and 2.5 parts lignosulfonate under the trademark Marasperse N-22 (Reed Lignin), were added to the reaction flask. The mixture was heated, with stirring, in an oil bath at about 50C until the dispersants (gum arabic and Marasperse N-22) dissolved to form an aqueous phase.
To this mixture was added a solution of 40 parts of 4-vinylpyridine, 60 parts ethyleneglycoldimeth-acrylate, 0.80 parts benzoyl peroxide (70% active ingredient and 30~ water), and 50 parts toluene (porogen)~ The aqueous phase and organic solution were agitated by stirring at a rate (approx. 900 rpm) adjusted to give a plurality of droplets having a droplet diameter in the range of 5 to 100 microns, as dete~mined by visual observation of a sample of the droplets with an optical microscope with the droplets being stabilized by the dispersants.
The reaction mixture was then heated to 60 to 65C for 20 minutes, and heating was continued for another 8 hours at 74-76C to form poro~s beads of crosslinked 4-vinylpyridine~ethyleneglycoldimethacrylate having toluene entrapped within the network of.pores.
~he reaction mixture was th~n cooled to room temperature and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beadc were wa hed initially twice with one liter portions of deionized water to remove the di~persants, followed by tw~ washes with one liter portions of isopropanol to remove any residual, unreacted monomers and the toluene~
The beads were then dried in an oven at 8 0 to 9 0 C f or about 8 hours.
The yield was 87.0g of opaque beads. The average particle diameter of these beads was 25 microns, as measured by Sedimentation Micromeritics Instrument Co.
The particle diameter determination method is described in detail in the Nicrosizer 5300 Particle Size Analyzer W093/07862 PCT/US92/08~7 2 1 2 1 fi 8 7 Instruction Manual, ( 1984 ) associated with the instrument.
The surface area of a sample of the purified beads was determined by the B.E~T. Nitrogen Analysis method to be 11.05 m2/g, while the pore volume was de-termined by the mercury intrusion method to be 0.14 ml/g.
EXAM~E II
This example illustrates the protonation of the 4-vinylpyridine/ethyleneglycoldimethacrylate polymeric beads of Example I.
To a 1000 ml flask was added 80.0g of p:refo~med porous beads from Example I and 300 ml of 3% aqueous hydrochloride solution.
After stirring the slurry for three hours, the lS porous polymeric cationic bead were filtered and washed with a dilute hydrochloride solution, pH 3 t to remove excess 3% acid solution from the polymeric beads. ~he beads were then dried in an oven at 75~C for 8 to 10 hours. Hydrogen ion (H+) capacity in water was measured to be 0.78 meq/g.
EX~E~E III
This example illustrates the preparation and protonation of 4-vinylpyridine/divinylben2ene polymeric beads. The procedure is set forth below:
The reaction apparatus was prepared as in Example I. To the reaction flask was added 600 parts deionized H20, 6.0 parts gum arabir, and 6.0 parts Mar-asperse N~22. The aqueous solution was stirred at room temperature until all solids were dissolved.
, To the flask was added an organic solution containing 35 parts 4-vinylpyridine, 65 parts divinyl-benzene (SS~ divinylbenzene, 45% ethylvinylbenzene), 100 parts isob~tanol, and 1.0 part 2, 2'-azo~is (~-methylbutanenitrile~ available from the DuPont Co. under the tradename VAZ0 67. The reaction mixture was agitated at approximatel~ 1300 rpm until droplets were formed as in Example I. The reaction mixture was then heated to W093~07862 PCT/USg2/08907 2121 6,~7 75C at which point agitation was reduced to 800 rpm.
The reaction was allowed to continue for 8 hours at this temperature.
Opaque porous beads were collected by filtration and washed three times with 500 ml portions of deionized water. Protonation was effected by ~tirring the beads in 500 ml of O.lN HCl solution for 30 minutes.
The beads were filtered and washed with a dilute hydrochloride solution, pH 3, to remove excess acid.
Residual monomers and porogen were removed as in Example I. A dry powder was obtained after drying the beads in an 80 to 90C o~en for approximately 8 hours. The yield was 93 g. The average particle diameter~ surface area, and pore volume were 36 micron, 2.21 m2/g, and 0.073 ml/g, respectively.
EXAMPLE IV
This example illustrates an alternative me~hod for protonizing the polymeric beads of the present invention, using a buffered rinse. The procedure is set ~orth below:
To a 1000 ml beaker was added lOOg of preformed porous beads from Example I, 250 ml of a pH 3.0 buffer (consisting of 500 parts O.lN potassium hydrogen phthalate and 223 parts O.lN HC1), and 250 ml deionized ~20. This mixture was stirred for 30 minutes, then filtered. The quaternized beads were dried in an 80 to 90C oven for 6 to 10 hours.
EXAMPLE V
This example illustrates the preparation of 4-vinylpyridine/ethyleneglycoldimethacrylate beads using xylene as the porogen. The procedure is set forth be~ow:
A 1000 ml reaction flask was charged with an aqueous dispersion solution as described in Example I.
An organic solution was prepared as in Example I~ with the exception of using 50 parts xylenes (a mixture of ortho, meta and para isomers) as porogen rather than toluene. The reaction was agitated at 1300 rpm until W093/07862 PCT/V~92/08907 droplet sizes ranged from 10 to 60 microns. The reaction was then heated to 65C and maintained at this temperature for 20 minutes. Agitation was reduced to 800 rpm, and the reaction was heated to 75C. The reaction was allowed to continue at this temperature for 8 hours.
The porous beads were collected by filtration and rinsed with 500 ml deionized H20. The beads were then quaternized with a pH 3.0 buffer as described in Example IV. The residual monomers and porogen were removed by rinsing the beads three times with 500 ml portions of acetone. After drying approximately 8 hours in a 80 to 90C oven, 61g of beads were obtained. The average particle diameter, surface area, and pore volume were 22.5 microns, 3.03 m2/g, and 0.68 ml/g, respectively.
EXAMPLE VI
This example illustrates the subs'itution of an u~traviolet absorbing substance (sunscreen) in the , cationic beads of Example II. The procedure is set forth below:
An 18 .0 parts portion of the porous cationic polymeric beads obtained from Example II was mixed at room temperature with 30 parts of isopropanol in a glass flask with an agitator. Then 12.0 parts of a sunscreen ~ixture containing 7 parts octyldimethyl PABA and 2 parts Oxybenzone were added slowly. The resulting suspension was stirred for about 20 minutes. ~he solvent wAs then allowed to evaporate to dryness in a fume hood at room temperature for 24 hours. Approximately 40% of the sunscreen mixture was entrapped within the pores of the cationic polymeric beads.
EXAMRLE VII
~he adherence and retention of the 4-vinylpyridine/ethyleneglycoldimethacrylate (4-VP/EGD~) copolymer beads to human skin was investigated in two huma~ subjects. Unprotonated and protonated 4-VP/EGDMA
beads were prepared as described in Examples I and II, above, and loaded with an oil soluble dye (Oil Red EGN).

W093/07862 2 1 2 1 ~ ~ 7 PCT/USg2/08907 The dye was extracted from a small sample of beads and the percentage loading (wt. dye/ ~wt. dye + beads) x 100) was quantitated using a spectrophotometric method. The unprotonated beads were found to have 0.9% loading while the protonated beads were found to have 1.0% loading.
Measured amounts of each bead preparation (one polymer on each hand) were applied to the marked areas of the forearms of the subjects covering an area of 6.14 cm2.
The arms were then immersed in water for five seconds and then removed. This cycle was repeated five times (the hands were not dried between dips), and the polymer retained on the skin was recovered by washing with surfactant solution. The amount of beads retained was determined by extracting out the dye, quantitating it using a spectrophotometric method and correlating the amount of dye extracted to the amount of polymer. The results are present in Table 1.
~,ABI.E: 1 2 0 Amount Amount Polymer Applied/ Retained B~ad~ Subject cmZ (mg) (mg) ¦c* 9~ Retained Unpro-tonated 1 1. 86 0 . 67 1.89 ~.~1 34.26 Protonated 1 l. 61 0 . 81 2 1 . 86 1 . 25 58 . ~3 , The results demonstrate that a greater amount of the protonated polymer was retained on the skin compared to the unprotonated polymer.
B. Ionic Hydroqels:
Preparation and Qral Formulations EXAMPLE VIII
This example illustrates the preparation of PTMAEM~L cationic hydrogel beads using inverse suspension polymerization.
The following materials are used:

W093/07862 2 1 2 1 6 8 7 PCT/US92~08907 Continuous Phase .
The continuous phase is premixed with the following components:
EMSORB 2500 24 g (Sorbitan monooleate) Heptane 600 g The EMSORB 2500 was easily mixed with heptane by hand stirring.
~iscontinuous Phase The discontinuous phase is premixed wit:h the following components:
Deionized Water 300 ml Potassium persulfate 1.~ g MBA 30 g ~S Sipomer (TMAEMCL) 90 g The MBA was dissolved in water at a temper~ture of about 550-60C. The sipomer was then mixed with the solution when the MBA was completely dissolved. An initiator ~K2S208) was then added. The discontinuous phase solution was kept at a temperature below 64C before mixing with the continuous phase.
The continuous solution was preheated in a 2 litex reaction kettle at 60C. The reaction kettle was purged with nitrogen for about one-half hour beforë the addition of the monomers. Agitation was begun at 1000 rpm and the monomer solution added to the reaction k~ttle. The reaction temperature was increased to 750C.
Polymerizatisn started gradually at about 64~C, with no significant exothermal foaming observed during polymerization.
The agitation speed was reduced to 600 rpm after formation of the hydrogel beads, and the stirring rate was kept at 600 rpm ~or 6 bours at 75C.
After the reaction vessel had cooled, the mixture was filtered and washed with deionized water until the filtrate was colorless.

W093/07862 PCT~US92/08907 ` 212I6~7 The hydrogel beads were then suspended in 500 ml methanol and stirred for one-half hour and again filtered. This process was repeated twice until the filtrate was colorless. The hydrogel beads were again washed with water to make sure there was no residual monomer left in the filtrate (if the filtrata was hazy, the washing steps were repeated until the filtrate became clean). Once the filtrate was colorless, the hydrogel beads were washed with a mixture of a solution of methanol and acetone (1:1~ and the hydrogel beads gradually dried by increasing the ratio of acetone. The hydrogel beads were set still in the evacuation hood for evaporating out the acetone. The hydrogel beads were then dried in a vacuum oven at 50C for 8 hours.
Photomicrographs of the beads were taken both before and after swelling. These are shown in Figure 1.
Characterization of Hydroqel Beads Cationic hydxogels made as in Example VIII were made with 20%-60% cross-linked content according to the procedure described above. The gels were cast into square discs (2.5 cm. x-2.5 cm. x 0.16 cm.)~in order to investigate the amount of water that the microgels could absorb. The equilibri~m water fractions (EWF~ were mea~ur~d as the weight change between the swollen and dried discs. The EWF decreased from O.85 to 0.78 as the cross~ ked content increased from 20% to 80~
(Figure 1). The discontinuous phase for all the samples contained 83% water ~y weight. The release profile of D&C Red No. 28 was indicative of a ~ontrolled release trigger (Figure 2). Figure 2 shows a comparison of a macroporous bead alone (curve A), a cationic hydrogel in accordance with the present invention (curve B) when mixed with an anionic surfactant (to simulate biosalts~, and a cationic hydrogel (curve C) in a neutral surfactant (polyox) no detectable release occurred when the ionic hydrogels were incubated in either water or water plus non-ionic surfactant ~0.5% polyox). However, the dye was W093/07862 2 1 2 1 ~ 8 7 PCT/US92108907 released when the sample was added to a release fluid containing anionic surfactant (o.5% sodium lauryl sulfate). The release rate was slower than the control (curve A) and was the result of an ion exchange mechanism wherein the anioni~ surfactant (simulating biosalts) with exchange for the anionic dye which was complexed to the cationic polymer.
The relationship between equilibrium water fraction as a function of the water content during polymerization and cross-linked density was determined by measuring the weight gain of hydrogel discs which were swollen in water. Figure 3 shows how the equilibrium water fraction of the hydrogels increases in direct proportion to the water content during polymerization and is substantially independent of the cross-linked density.
This indicated that the hydrogels were polymerized in a greatly distended form which then became the limiting factor for s~bs~quent hydration. The ionic hydrogel was poly(TMA~MCl-co-MBA).
The same general type of material was polymerized inside the psres of a macroporous material, such as that produced and disclosed in U.S. Patent No.
4,590,825. Representative release profiles of D&C Red No. 28 ar~ sho~n in Figure 4 for release fluids which contain either Polyox or SDS surfactantO As was shown for the hydrogel systems, no anionic dye was-released from the cationic gel-loaded sponges until an anionic surfactant (SDS) was present. The relea e rate of dye into the SDS release fluid was the same as the ,microsponge material with no gel. Thus, several mechanisms are available for manipulating the release profiles of active ingredients via ionic hydxoqel loaded microsponges. The hydrogel could swell when e~posed to water and thus re}ease active ingredients by squeezing the active out o~ the pores or the hydrogel could act as a dense coating or plug which does not become permeable to active until swollen. Further, the hydrogels could . 21216~7 control the release of ionic actives through ion exchange mechanisms as already demonstrated.
EXAM~LE IX
The poly(TMAEMCl-co-MBA) hydrogels discussed in Example VIII contain stable cationic charges (quaternary amine groups) which were shown to entrap acidic types of ingredients and not release those ingredients until exposed to an anion suitable for exchange. Many pharmaceutically active substances are basic materials, thus the previous basic hydrogel materials do not bind the basic drugs. Therefore, poly(methacrylic acid-C0-N, N'-methylenebisacrylamide), [poly(MA-C0-M8A)] hydrogels were synthesized to broaden the applicability of t:he hydrogels to basic active ingredients, for example, alkaloids.
Hydrogel~ consisting of 10%-lS% cross-linking (W/W) were prepared by the inverse suspension polymerization as discussed in Example VIII~ As was seen for the poly(TMA~NC1-co-MBA) hydrogels, poly(MA-co-MBA) materials with a lower cross-linked content tended to clump during drying.
Tetracycline-HC1 was chosen as the mcdel basic active ingredient for the release rate studies since it was W detectable and water soluble. The release characteristics of tetracycline-HCl into deionized water from swollen gel matrices was determined ~or 50% cross-linked beads~ The effec~ of th~ gels charge density on the tetracycline-HCl diffusion coefficient was also inYestîgated for release fluids containing 0.5%
benzalkonium chloride, a cationic surfaGtant. The release profile (Figure 5) of tetracycline-HCl from poly(MA-co-MBA~ polymer systems into dis~olution mediums of 0.5~ benzalkonium chloride or water did not show much difference from that of the control.
3~ Figure 6 shows the swelling behavior of cationic and anionic hydrogels as a function of pH. The charge density on poly(TMAEMCl-co-MBA), 25% TMAEMCL, and poly(SSS-co-MBA), 30% SSS, are independent of pH.
Therefore, the swelling behavior of these materials was independent of pH. The charge density on poly(MA-CO-MBA), 10% MA, is a function of pH with the material becoming more negatively charged at higher pH. Thus, the degree of swelling increases with increasing pH for this material. The swelling was determined by placing one gram of dry material into a graduated cylinder and adding the buffer solution to a depth of 25 cm. The material and buffer were allowed to equilibrate before the volume reading was taken.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.
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Claims

WHAT IS CLAIMED IS:

1. A composition of matter suitable for use as an ion-exchanger comprising an ionic polymeric hydrogel, the ionic polymeric hydrogel comprising the copolymerization product of an ionic monoethylenically unsaturated monomer and a polyethylenically unsaturated cross-linking monomer which is soluble in aqueous solutions in all portions, wherein the ionic hydrogel has a swelling ratio directly proportional to the weight percent of said cross-linking monomer in the copolymer while the equilibrium water fraction of the hydrogel when equilibrated with water is dependent upon the amount of water used during polymerization.

2. The ionic hydrogel of claim 1, wherein said hydrogel has a charge density sufficient to produce a binding affinity for a counter ion having a charge opposite to the hydrogel measured by the weight distribution coefficient method of at least about 1.0 x 106 ml/gm.

3. The ionic hydrogel of claim 1, wherein said ionic hydrogel has a porosity and charge density sufficient to afford a capacity for a counter ion having charge opposite of the hydrogel of at least about 45% by weight of the total weight of hydrogel and counter ion.

4. The ionic hydrogel of claim 2 wherein the charge density ranges from about 1 to about 10 meq/gm of hydrogel.

5. The ionic hydrogel of claim 2 wherein the charge density ranges from about 5 to about 10 meq/gm in the hydrogel.

6. The ionic hydrogel of claim 1 wherein said ionic hydrogel exhibits a swelling ratio ranging from about 1.0 to about 2.0 when the weight percent cross-linking monomer used ranges from about 10% to about 80%
by weight of total hydrogel and when the volume percentage of water used during polymerization ranges from about 70% to about 90% of the total volume of reaction mixture.

7. The ionic hydrogel of claim 1 wherein said ionic hydrogel exhibits a swelling ratio ranging from about 1.2 to about 1.8 when the weight percent cross-linking monomer used ranges from 20% to about 60% by weight of total hydrogel and when the volume percentage of water used during polymerization ranges from about 75%
to about 85% of the total volume of reaction mixture

8. The ionic hydrogel of claim 1 wherein said ionic hydrogel is cationic and said ionic monoethylenically unsaturated monomer is a quaternary ammonium compound selected from the group consisting of:
wherein R1, R2, R3, and R4 are the same or different saturated alkyl groups having from 1 to 6 carbon atoms, n = 1-4, X is selected from the group consisting of Cl, F, Br, and I, and said water-soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

9. The ionic hydrogel of claim 1 wherein said ionic hydrogel is anionic and said ionic monoethylenically unsaturated monomer is selected from the group consisting of acrylic acid and alkylacrylic acids selected from the group consisting of CH2 = C(R)-COOH, where R is a saturated alkyl having from 1-4 carbon atoms, and said water soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N, N'-methylenebisacrylamide, N, N'-nonamethylenebisacrylamide, and alkoxylated water soluble triacrylates.

10. Composition of matter in accordance with claim 1 wherein said ionic hydrogel is anionic and said ionic monoethylenically unsaturated monomer is selected from the group consisting of wherein R1, R2, R3, R4, and R5 are the same or different and are selected from the group consisting of H and saturated alkyls having from 1-4 carbon atoms, wherein Y
is selected from the group consisting of Na and X, and wherein said water-soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

11. A composition for the controlled ion-exchange of a counter ion with a solute ion in a preselected environment, said composition comprising cross-linked ionic polymeric hydrogel particles, each defining a network of internal pores having therein the counter ionically bond, the hydrogel particle having physical and chemical characteristics selected to modify the exchange rate of the counter ion with a solute ion from the internal pores in response to changes in the environmental conditions.

12. A composition as in claim 11, wherein said particles are cationic and are composed of a cross-linked copolymer polymerized from a polyethylenically unsaturated monomer selected from the group consisting of wherein R1, R2, R3, and R4 are the same or different saturated alkyl groups having from 1 to 6 carbon atoms, n = 1-4, X is selected from the group consisting of Cl, F, Br, I, and CH3OSO3- and said water-soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

13. A composition in accordance with claim 11 wherein said ionic hydrogel is anionic and said ionic monoethylenically unsaturated monomer is selected from the group consisting of acrylic acid and alkylacrylic acids selected from the group consisting of CH2 = C(R)-COOH, where R is a saturated alkyl having from 1-4 carbon atoms, and said water soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

14. A composition of matter in accordance with claim 11 wherein said ionic hydrogel is anionic and said ionic monoethylenically unsaturated monomer is selected from the group consisting of wherein R1, R2, R3, R4, and R5 are the same or different and are selected from the group consisting of H and saturated alkyls having from 1-4 carbon atoms, wherein Y
is selected from the group consisting of Na and K, and wherein said water-soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

15. A composition of matter in accordance with claim 11, wherein the ionic hydrogel is in the form of a substantially spherical and porous bead having an average diameter ranging from about 1 to about 200 microns, a total pore volume ranging from about 0.01 to about 4.o cc/gm, and an average pore surface area ranging from about 1 to about 200 m2.

16. A composition of matter in accordance with claim 11, wherein said ionic hydrogel is in the form of a substantially spherical and porous bead having an average diameter ranging from about 1 to about 50 microns, total pore volume ranging from about 0.1 to about 1.0 cc/gm, and an average pore surface area ranging from about 1 to about 20m2.

17. A composition of matter as in claim 13 wherein the environment is the gastrointestinal tract of an animal or human, and the counter ion is a positively charged pharmaceutically active ingredient selected from the group consisting of analgesics, anesthetics, anthelmintics, antidotes, antiemitics, antihistamines, antimalarials, antimicrobials, antipyretics, antiseptics, antituberculotics, antitussives, antivirals, cardioactive drugs, cathartics, chemotherapeutic agents, cortocoids (steroids), depressants, diagnostic aides, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetics, potassium supplements, sedatives, sulfonamides, stimulants, sympathomimetics, tranquilizers, urinary antiinfectives, vasoconstrictors, vasodialators, vitamins, and xanthine derivatives.

18. A composition in accordance with claim 14 wherein the environment is the gastrointestinal tract of an animal or human, and the counter ion is a positively charged pharmaceutically active ingredient selected from the group consisting of analgesics, anesthetics, anthelmintics, antidotes, antiemitics, antihistamines, antimalarials, antimicrobials, antipyretics, antispectics, antituberculotics, antitussives, antivirals, cardioactive drugs, cathartics, chemotherapeutic agents, cortocoids (steroids), depressants, diagnostic aides, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetics, potassium supplements, sedatives, sulfonamides, stimulants, sympathomimetics, tranquilizers, urinary antiinfectives, vasoconstrictors, vasodialators, vitamins, and xanthine derivatives.

19. A composition in accordance with claim 12 wherein the environment is the gastrointestinal tract of an animal or human, and said counter ion is an inert negatively charged moiety selected from the group consisting of Cl-, Br-, F-, I-, and CH3OSO3-, and said solute ion is the negatively charged portion of a bile salt present in said gastrointestinal tract.

20. A composition in accordance with claim 19 wherein said moiety is Cl-.

21. A composition in accordance with claim 11 wherein said change in environmental condition includes change of pH and ionic strength of the environment.

22. A composition as in claim 11, further comprising an inert carrier for the hydrogel and counter ion, the carrier composed of a macroporous copolymer bead selected from the group consisting of styrenedivinylbenzene, methacrylate-ethylene glycol dimethacrylate, vinyl stearate-divinylbenzene, 4-vinylpyridine-ethylene glycol dimethatrylate, and 4-vinylpyridine-divinylbenzene.

23. A method for preparing an ion-exchange composition, said method comprising performing the following steps in predetermined order:
(a) combining a counter ion having a first charge with an ionic monoethylenically unsaturated monomer, said monomer having charge opposite of the charge of the counter ion to form a first solution;
(b) combining a water-soluble polyethylenically unsaturated cross-linking monomer with water for a time and at a temperature sufficient to completely dissolve the cross-linking monomer, thus forming a second solution; and (c) mixing the first and second solutions with an initiator to form a discontinuous phase and mixing the discontinuous phase with an organic continuous phase comprising a suspending agent and inert, non-polar organic solvent to form a reaction mixture, and agitating the reaction mixture for a time and at a temperature sufficient to form droplets of the aqueous phase and polymerize the monomers within the droplets to form porous, ionic polymeric hydrogel beads having the counter ion ionically entrapped therein.

24. A method in accordance with claim 7.3, wherein the hydrogel is cationic and derived from an ionic monoethylenically unsaturated monomer selected from the group consisting of:

wherein R1, R2, R3, and R4 are the same or different saturated alkyl groups having from 1 to 6 carbon atoms, n 1-4, X is selected from the group consisting of Cl, F, Br, and I, and said water-soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

25. A method in accordance with claim 23, wherein the hydrogel is anionic and derived from an ionic monoethylenically unsaturated monomer selected from the group consisting of acrylic acid and alkylacrylic acids selected from the group consisting of CH2 = C(R3-COOH, where R is a saturated alkyl having from 1-4 carbon atoms, and said water soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

26. A method in accordance with claim 23, wherein the hydrogel is anionic and derived from an anionic monoethylenically unsaturated monomer selected from the group consisting of wherein R1, R2, R3, R4, and R5 are the same or different and are selected from the group consisting of H and saturated alkyls having from 1-4 carbon atoms, wherein Y
is selected from the group consisting of Na and R, and wherein said water-soluble polyethylenically unsaturated cross-linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water soluble multi-functional acrylates.

27. A method in accordance with claim 23, wherein the weight percentage of water used during polymerization has a percentage of the total monomer weight is adjusted to provide a predetermined equilibrium water fraction of a water equilibrated hydrogel.

28. A method in accordance with claim 23, wherein the weight percentage of water used during polymerization ranges from about 20 to about 80 weight percent of the total weight of monomer used during polymerization, the water providing a hydrogel which has an equilibrium water fraction upon equilibration with water ranging from about 20 to about 80 percent by weight of the total hydrogel plus water.

29. A method in accordance with claim 23, wherein the weight percentage of cross-linking monomer if the percentage of total monomer is increased, thereby increasing the swelling ratio of the product ionic hydrogel.

30. A method in accordance with claim 29 wherein the weight percent cross-linking monomer used ranges from about 10% to about 80% by weight of total monomer and wherein the swelling ratio ranges from about 1.0 to 2Ø

31. A method for the controlled ion-exchange of a counter ion for a solute ion in a predetermined aqueous environment, the method comprising administering to said environment a composition comprising a porous water-insoluble ionic copolymer hydrogel particle having an internal network of pores with a counter ion ionically held within the network of pores, said ionic hydrogel having a swelling ratio directly proportional to the weight percent of a cross-linking monomer in the copolymer, the cross-linking monomer soluble in aqueous solutions in all proportions.

32. A method in accordance with claim 31, wherein said aqueous environment is an animal or a human body.

33. A method in accordance with claim 31, wherein said counter ion is a pharmaceutically active agent.

34. A method in accordance with claim 31, wherein the particle has an average diameter ranging from about 1 to about 200 microns, a pore volume ranging from 0.01 to about 4.0 cc/gm, and an average pore surface area ranging from about 1 to about 200 m2.

35. A method in accordance with claim 31, wherein the particle has an average diameter ranging from about 1 to about 50 microns, total pore volume ranging from about 0.1 to about 1.0 cc/gm, and an average pore surface area ranging from about 1 to about 20 m2.

36. A method in accordance with claim 31, wherein said ionic hydrogel has a charged density sufficient to produce a binding affinity for a counter ion having a charge opposite to the hydrogel measured by the weight distribution coefficient method of at least about 1.0 x 106 ml/gm.

37. A method in accordance with claim 31, wherein the ionic hydrogel has a porosity and charge density sufficient to afford a capacity for fee counter ion having charge opposite of the hydrogel of at least about 45% by weight of the total weight of hydrogel and counter ion.

38. A method in accordance with claim 36, wherein the charged density ranges from about 1 to about 10 meq/gm of ionic hydrogel.