A responsive microgel is provided which responds volumetrically and reversibly to a change in one or more aqueous conditions selected from the group consisting of (temperature, pH, and ionic conditions) comprised of an ionizable network of covalently cross-linked homopolymeric ionizable monomers wherein the ionizable network is covalently attached to an amphiphilic copolymer to form a plurality of `dangling chains` and wherein the `dangling chains` of amphiphilic copolymer form immobile micelle-like aggregates in aqueous solution. A responsive microgel is further provided that comprises at least one therapeutic entity and delivers a substantially linear and sustained release of the therapeutic entity under physiological conditions.

SUMMARY OF THE INVENTION

A responsive microgel is provided which responds volumetrically and reversibly to a change in one or more aqueous conditions selected from the group consisting of (temperature, pH, and ionic conditions) comprised of an ionizable network of covalently cross-linked homopolymeric ionizable monomers wherein the ionizable network is covalently attached to an amphiphilic copolymer to form a plurality of `dangling chains` and wherein the `dangling chains` of amphiphilic copolymer form immobile micelle-like aggregates in aqueous solution.

A responsive microgel is further provided that comprises at least one therapeutic entity and delivers a substantially linear and sustained release of the therapeutic entity under physiological conditions.

A responsive microgel is also provided wherein the ionizable network of covalently cross-linked homopolymeric ionizable monomers is selected from the group consisting essentially of (poly(acrylic acid), poly(methacrylic acid), poly(4-vinylpyridinium alkyl halide), poly(sodium acrylate), poly(sodium methacrylate), sulfonated polyisoprene, and sulfonated polystyrene).

A further responsive microgel is provided wherein an amphiphilic copolymer is comprised of (poly(ethylene oxide) and a monomer selected from the group consisting essentially of (poly(propylene oxide), poly(butylene oxide), polystyrene, polyisobutylene, poly(methyl methacrylate), and poly(tert-butyl acrylate)).

A method of making a responsive microgel is also provided comprising:

a) providing, an ionizable monomer, a divinyl cross-linker, a free radical, and a amphiphilic copolymer; and

b) copolymerizing the ionizable monomer with the divinyl cross-linker to produce an ionizable network, while

c) abstracting hydrogen from the amphiphilic copolymer with the free radical to progress a chain transfer reaction wherein the amphiphilic copolymer is covalently bonded onto the ionizable network to produce the responsive microgel.

A method of administering an effective amount of at least one therapeutic entity to a patient is further provided which comprises administering a responsive microgel comprising an effective amount of at least one therapeutic entity.

A method is provided for administering at least one therapeutic entity to a patient which entity is selected from the group consisting of substrates of ABC transporters such as P-glycoprotein, MRP1 MRP9; ABC half-transporters such as BCRP; other transporters that are involved into a limited drug transport across small intestinal epythlium; cerebral endothelium and other barrier tissues in the body, as well as substrates of metabolic enzyme isoforms without limitation, cytochrome P-450; esterase; epoxide hydrolase; alcohol dehydrogenase; aldehyde dehydrogenase; dihydropyrimidine dehydrogenase; NADPH-quinone oxidoreductase; uridine 5'-triphosphat glucoronosyltransferase; sulfotransferase; glutatione S-transferase; N-acetiltransferase; histamine methyltransferase; catechol-o-methyl transferase; thiopurine methyltransferase. This group of therapeutic agents include without limitation doxorubicin and other anthracyclines, mitoxantrone, mitomycin C, metatrexate, paclitaxel, docetaxel and other taxanes, topotecan ant other camptotecines, cysplatin, carboplatin, oxaliplatin and other platinum complexes; megesterol acetate and other steroids; carvedilol and other beta-blocking agents; azidothymidine, fludarabine and other nucleoside containing agents in their dephospho, mono-, di- and tri-phosphorylated forms; vinblastine, vincristine and other vinka alkaloids; etoposide and other podophilotoxins.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to stable chemically cross-linked networks (gels) of a polyelectrolyte wherein `dangling chains` of at least one amphiphilic co-polymer are bonded thereto through carbon-carbon bonding. The dangling chains are capable of forming intra-network micelle-like aggregates. The aggregates possess the ability to imbibe a large quantity of, for example, hydrophobic or amphiphilic compounds. Due to the formation of mixed aggregates, the responsive-microgel networks of the present invention display linear and sustained release of hydrophobic or amphiphilic compounds in aqueous milieu. Further, the formation of micelle-like aggregates within the chemically cross-linked polyelectrolyte network of the present invention is reversible.

The responsive microgel described herein is, for example, (1) able to imbibe large quantities of at least one ionic, amphiphilic, or hydrophobic compound, and (2) forms micelle-like aggregates within its structure when in aqueous solution and (3) allows for a sustained, substantially linear release of the compound in vitro and/or in vivo, for example, under the temperature, pH, and ionic composition of physiological conditions. A preferred embodiment of the present invention is method of delivering an effective amount of at least one therapeutic agent to a patient comprising administering an effective amount of a responsive microgel of the present invention, which comprises at least one therapeutic agent. The responsive microgels of the present invention are suitable for oral administration, for example, and hence the oral delivery of therapeutic agents.

Drug release kinetics from example responsive microgels of the present invention are provided herein. Example I shows that loading of corresponding drugs into a responsive microgel greatly affected the kinetics of release. The drugs loaded into the microgel exhibited slow, sustained release kinetics. Kinetics of doxorubicin release from a responsive microgel is shown in FIG. 7. Three cationic and one uncharged drug was loaded onto the microgel in Example VII, all of which are currently in clinical use as anticancer drugs. Doxorubicin, mitoxantrone, and mitomycin C are mono-, di-, and trivalent cationic weak bases, respectively. Taxol is uncharged (hydrophobic). The ability of responsive microgels of the invention to effectively load and hold taxol, combined with mucoadhesive properties is a feature important for delivery of taxol and other hydrophobic solutes such as steroid hormones. The taxol loading capacity provides additional evidence to the mechanism of taxol solubilization into micelle-like aggregates within the responsive microgels. Drug loading via ion-exchange are illustrated using the potent chemotherapeutic drug doxorubicin.

The responsive microgel of the present invention comprises two responsive components: An amphiphilic copolymer (nonionic copolymer) capable of aggregation in response to a change in temperature; and, an ionizable, covalently cross-linked polymeric network of monomers which responds volumetrically to changes in aqueous conditions such as pH or ionic composition by swelling or collapsing. Since both responsive components, i.e., the nonionic copolymer and the cross-linked polymermeric network of monomers which contain ionizable groups are bound through covalent bonds, each polymer has a chemical or mechanical influence over the swelling of the other polymeric component. The resulting responsive microgel exhibits volumetric changes in response to variations in pH as well as temperature. See, Examples III V. These responsive microgel graft-comb copolymers dissolve freely in aqueous solutions and self-assemble in response to changes in conditions such as pH and temperature.

The microgel covalently cross-linked polymer network of the present invention is comprised of at least one amphiphilic copolymer covalently attached (preferably a carbon-carbon bond from a single terminal region of each amphiphilic copolymer) to an ionizable network (polyelectrolyte). The amphiphilic copolymer forms the `dangling chain` component of the responsive microgel which forms micelle-like aggregates within the covalently cross-linked polymer network in aqueous solution. See, FIG. 3 (structure of the responsive microgel).

The term "responsive" in reference to the microgel of the present invention refers to reversible phase transition characteristics, e.g., volumetric change, which result from exposure to a change in one or more environmental factors under aqueous conditions, such as temperature, pH, and ionic conditions. The microgels operate as described herein within the temperature range of about -4.degree. C. to about 55.degree. C., preferably from about 0 to about 37.degree. C. The microgels will be collapsed at pH 1 3 such as in stomach and swollen at pH exceeding the pKa of their carboxylic groups, i.e. at pH>4.5 (fully swollen at pH 7.4, for example). The gel is collapsed (swelling degree preferably not exceeding 50 v/v % of water per polymer) at acidic pH such as in stomach, but fully swollen (swelling degree preferably exceeding 100 5000 v/v % of liquid per polymer) in the intestine. The gels protect the therapeutic entity, e.g., embedded drug, and hold it without release when collapsed, but rapidly release when swollen. The range of operation of the microgels of the present invention are solutions of ionic strength preferably below 1 M, or from 0M to 5 M, for example. A change in these environmental factor(s) affects the responsive microgel by causing the structure to undergo a reversible volumetric change in which the gel increases volume by expanding (swelling) or decreases volume by collapsing (contraction).

Phase transitions in gels may be explained, for example, by the following equation. One may determine the effect of ionic groups on the reduced chemical potential (.DELTA..mu..sub.1) for solvent in an isotropically swollen gel network:

.DELTA..mu..mu..mu..times..chi..times..times..times..lamda..DELTA..mu..tim- es..times. ##EQU00001## where a.sub.1 is the activity of the solvent in the network, .chi. is the interaction parameter, V.sub.2 is the volume fraction of the polymer, f(.lamda.) is the function of the deformation tensor, .DELTA..mu..sub.i is the contribution to the total chemical potential by the presence of ionic groups on the chains.

Example I describes the favorable linear release of monomeric PLURONIC.RTM. from the microgels. It was discovered that PLURONIC.RTM. 161, for example, has exceptionally low release rate and sustained release for over 10 days due to the formation of mixed micelles between added PLURONIC.RTM. 161 and PLURONIC.RTM. covalently grafted to a poly(acrylic acid) network in the process of synthesis. Such mixed, immobile micelles can provide thermodynamically stable environment for the PLURONIC.RTM. solute, making its effective partition coefficient between micelles and water to be very low. These results are unique and exceptionally well suited for the intended application of the novel microgels in drug delivery.

Compositions

I. Ionizable Network

The ionizable network is a covalently cross-linked homopolymeric network of ionizable monomers. The monomers of the ionizable network each contain at least one ionizable group. The ionizable network responds volumetrically to changes in aqueous conditions such as pH or ionic composition by swelling or collapsing. Preferred embodiments of this polyelectrolyte network (onto which the amphiphilic copolymer `dangling chains` are attached via C--C bond to form the responsive microgel) are comprised of a monomer selected from the group consisting essentially of (poly(acrylic acid), poly(methacrylic acid), poly(4-vinylpyridinium alkyl halide), poly(sodium acrylate), poly(sodium methacrylate), sulfonated polyisoprene, and sulfonated polystyrene).

Preferred polyanion-forming compounds include poly(acrylic acid), poly(methacrylic acid), and poly(2-ethylacrylic acid); preferred polycation-forming compounds include polyethyleneimine and polyethylenepiperazine. The hydrophilic blocks recited infra, (i.e., A. Hydrophilic Monomers and Polymers), can also be used in the compositions described herein either as an element of the ionizable network (polyelectrolyte).

A. Polyanion Forming Compounds

Ionizable compounds for the ionizable network of the present invention also include, but are not limited to, polyanion-forming compounds such as poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(styrenesulfonic acid), poly(itaconic acid), poly(vinyl sulfate), poly(vinylsulfonic acid), poly(vinyl phosphate), poly(acrylic acid-co-maleic acid), poly(styrenesulfonic acid-co-maleic acid), poly(ethylene-co-acrylic acid), poly(phosphoric acid), poly(silicic acid), hectorite, bentonite, alginic acid, pectic acid, kappa-, lambda- and iota-carrageenans, xanthan, gum arabic, dextran sulfate, carboxymethyldextran, carboxymethylcellulose, cellulose sulfate, cellulose xanthogenate, starch sulfate and starch phosphate, lignosulfonates, karaya gum; polygalacturonic acid, polyglucuronic acid, polyguluronic acid, polymannuronic acid and copolymers thereof; chondroitin sulfate, heparin, heparan sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate; poly-(L)-glutamic acid, poly-(L)-aspartic acid, deoxyribonucleic acid, ribonucleic acid, acidic gelatins (A-gelatins); starch, amylose, amylopectin, cellulose, guar, gum arabic, karaya gum, guar gum, pullulan, xanthan, dextran, curdlan, gellan, carubin, agarose, as well as chitin and chitosan derivatives having the following functional groups in various degrees of substitution: carboxymethyl and carboxyethyl, carboxypropyl, 2-carboxyvinyl, 2-hydroxy-3-carboxypropyl, 1,3-dicarboxyisopropyl, sulfomethyl, 2-sulfoethyl, 3-sulfopropyl, 4-sulfobutyl, 5-sulfopentyl, 2-hydroxy-3-sulfopropyl, 2,2-disulfoethyl, 2-carboxy-2-sulfoethyl, maleate, succinate, phthalate, glutarate, aromatic and aliphatic dicarboxylates, xanthogenate, sulfate, phosphate, 2,3-dicarboxy, N,N-di(phosphatomethyl)aminoethyl, N-alkyl-N-phosphatomethylaminoethyl. These derivatives may additionally comprise nonionic functional groups in various degrees of substitution, such as methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-hydroxypropyl and 2-hydroxybutyl groups, for example, as well as esters with aliphatic carboxylic acids, e.g., (C.sub.2 to C.sub.18).

B. Polycation Forming Compounds

Examples of polycation-forming compounds for the ionizable network of the present invention also include, but are not limited to, poly(alkyleneimines), especially poly(ethyleneimine), poly-(4-vinylpyridine), poly(2-vinylpyridine), poly(2-methyl-5-vinylpyridine), poly(4-vinyl-N--C.sub.1 C.sub.18-alkylpyridinium salt), poly(2-vinyl-N--C.sub.1 C.sub.18-alkylpyridinium salt), polyallylamine, polyvinylamine, aminoacetylated polyvinyl alcohol; the polysulfone dialkylammonium salts; basic proteins, poly-(L)-lysine, poly-(L)-arginine, poly(ornithine), basic gelatins (B-gelatins), chitosan; chitosan with various degrees of acetylation; starch, amylose, amylopectin, cellulose, guar, gum arabic, karaya gum, guar gum, dextran, pullulan, xanthan, curdlan, gellan, carubin, agarose, as well as chitin and chitosan derivatives having the following functional groups in various degrees of substitution: 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-diisopropylaminoethyl, 2-dibutylaminoethyl, 3-diethylamino-2-hydroxypropyl, N-ethyl-N-methylaminoethyl, N-ethyl-N-methylaminopropyl, 2-diethylhexylaminoethyl, 2-hydroxy-2-diethylaminoethyl, 2-hydroxy-3-trimethylammonionopropyl, 2-hydroxy-3-triethylammonionopropyl, 3-trimethylammonionopropyl, 2-hydroxy-3-pyridiniumpropyl and S,S-dialkylthioniumalkyl. These derivatives may additionally comprise nonionic functional groups in various degrees of substitution, such as methyl, ethyl, propyl, isopropyl, 2-hydroxymethyl, 2-hydroxypropyl and 2-hydroxybutyl groups, for example, and also esters with aliphatic carboxylic acids (C.sub.2 to C.sub.18); and also n,m-ionenes, poly(aniline); poly(pyrrole); poly(viologens) and also poly(amidoamines) based on piperazine.

II. Amphiphilic Copolymer

A preferred amphiphilic copolymer (nonionic copolymer) component for use in the methods and compositions in the present invention is a copolymer of an ionizable monomer and a hydrophobic monomer. The amphiphilic copolymer is preferably comprised of a nonionic hydrophilic monomer and nonionic hydrophobic monomer. Amphiphilic copolymers for use in constructing microgels of the present invention are selected from amphiphilic diblock copolymers, amphiphilic triblock copolymers, amphiphilic multiblock copolymers, and amphiphilic graft copolymers. The amphiphilic copolymer is preferably a di- or triblock copolymer. The amphiphilic copolymer is preferably comprised of (poly(ethylene oxide) and a monomer selected from the group consisting essentially of (poly(propylene oxide), poly(butylene oxide), polystyrene, polyisobutylene, poly(methyl methacrylate), and poly(tert-butyl acrylate)).

Amphiphilic copolymers for use in constructing responsive microgels of the present invention generally have a molecular weight in the range of from about 200 to about 1,000,000, preferably from about 500 to about 500,000, and more preferably from about 200 to about 200,000. The amphiphilic copolymers generally have a hydrophilic/lipophilic balance in the range of from about 0.001 to about 100.

A preferred embodiment of the present invention comprises an amphiphilic copolymer comprised of a diblock, triblock, or multiblock copolymer, preferably a diblock or triblock copolymer, more preferably a diblock copolymer. A particularly preferred embodiment comprises a triblock copolymer wherein one block comprises polyoxyethylene. Another particularly preferred embodiment comprises a triblock copolymer wherein one block comprises polyoxypropylene.

Any of the hydrophilic blocks of various chemistry and formula weight of the amphiphilic copolymers herein can be used in combination with any of the hydrophobic blocks of various chemistry and formula weight to compose an amphiphilic `dangling chain`. The hydrophilic blocks recited infra (i.e., A. Hydrophilic Monomers and Polymers) can be used in the compositions described herein either as an element of the ionizable network (polyelectrolyte) and/or an element of an amphiphilic `dangling chain` copolymer.

The hydrophilic blocks of the amphiphilic diblock, triblock, or multiblock copolymers can have formula weights in the range from about 200 to about 500,000, preferably from about 2,500 to about 250,000, more preferably from about 500 to about 100,000. The hydrophobic blocks of the amphiphilic diblock, triblock, or multiblock copolymers useful in the present invention can have formula weights in the range of from about 1,000 to about 500,000, preferably from about 2,500 to about 250,000, more preferably from about 500 to about 100,000.

Amphiphilic graft copolymers useful in the present invention possess rotatable side chain block regions that can rotate or fold to become part of the aggregates within the microgels of the present invention. The number of side chains present in each of the amphiphilic graft copolymers can be in the range of from about 1 to about 10000. The formula weights of the various blocks in the amphiphilic copolymers can be varied independently of each other.

A. Hydrophilic Monomers and Polymers

Examples of monomer repeat units that can be used in the preparation of hydrophilic blocks of the amphiphilic copolymer (or as monomers of the ionizable network) are set forth as follows. Poly(acrylic acid) and poly(metal acrylates) are preferred.

1. Example Monomer Units Useful as Repeat Units in Hydrophilic Blocks Polyacrylic acid Poly(metal acrylate), M=Li, Na, K, Cs Polyacrylamide Poly(methacrylic acid), R=H, alkyl Poly(metal methacrylate) Polymethacrylamide M=Li, Na, K, Cs R=H, alkyl Polystyrene sulfonic acid Polystyrene sulfonic acid metal salt, M=Li, Na, K, Cs Polystyrene carboxylic acid Polystyrene carboxylic acid, metal salt M=Li, Na, K, Cs Poly(vinyl alcohol), R=H, alkyl Poly(4-vinyl-N-alkyllpyridinium halide), R=H, alkyl Poly(2-vinyl-N-alkyllpyridinium halide)\Poly(hydroxyethyl methacrylate) Poly(itaconic acid) Poly(N,N,N-trialkyl-4-vinylphenylammonium halide) Poly(N,N,N-trialkyl-4-vinylbenzylammonium halide) Percent quaternization 10% to 70% Poly(N,N,N-trialkyl-4-vinylphenethylammonium halide) Poly(L-glutamic acid) Poly(L-aspartic acid) Hyaluronic acid Amino acids used to compose hydrophilic blocks of the amphiphilic copolymer: Serine Threonine Tyrosine Lysine Arginine Histidine Aspartic acid Glutamic acid 2. Example Polymers Useful as Hydrophilic Blocks

Polymers as hydrophilic blocks of the nonionic copolymer (amphiphilic copolymer) for employment in the `dangling chains` of the responsive microgel of the present invention also include, but are not limited to -- see Original Patent.

B. Hydrophobic Monomers and Polymers

The hydrophobic blocks of the amphiphilic diblock, triblock, or multiblock copolymers useful in the present invention can have formula weights in the range of from about 500 to about 500,000, preferably from about 500 to about 250,000, more preferably from about 500 to about 100,000. Examples of monomer repeat units that can be used in the preparation of hydrophobic blocks are set forth as follows -- see Original Patent

Method of Manufacture

A method of responsive microgel synthesis and production is further an object of the present invention. The method of the present invention involves a single synthetic step, which is advantageous for scale-up of responsive microgel fabrication. The synthesis of the microgels described herein involves a free-radical copolymerization of a vinyl monomer with a divinyl cross-linker with simultaneous hydrogen abstraction from a polymer present in the reaction system. The hydrogen abstraction leads to generation of macro-radicals that lead to the grafting of the amphiphilic copolymer `dangling chains` onto the growing microgel network. The series of reactions that occur simultaneously and yield a responsive microgel of the present invention are shown in FIG. 4 (scheme of the one-step synthesis of responsive microgels). See, e.g., Examples I and II.

A preferred chain-transfer reaction to covalently bond the nonionic copolymer to the ionizable network is a free-radical polymerization (using a redox free-radical initiator) of an ionizable monomer and a divinyl cross-linker.

A method of making the responsive microgel covalently cross-linked polymer network (graft-comb copolymer) of the present invention, for example, comprises the steps of: a) providing, an ionizable monomer, a divinyl cross-linker, a free radical, and a nonionic copolymer; and, b) copolymerizing the ionizable monomer with the divinyl cross-linker to produce an ionizable network, while c) abstracting hydrogen from the nonionic copolymer with the free radical to progress a chain transfer reaction wherein the nonionic copolymer is covalently bonded onto the ionizable network to produce a responsive microgel as defined herein.

Divinyl cross-linker as used herein refers to a reactive chemical having at least two ethylenic double bonds capable of participating in at least two growing polymer chains. Examples of cross-linkers of this type, which are normally used as crosslinkers in polymerization reactions, are N,N'-methylenebisacrylamide, polyethylene glycol diacrylates and polyethylene glycol dimethacrylates which are derived in each case from polyethylene glycols with a molecular weight of from 106 to 8500, preferably 400 to 2000, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, ethylene glycol diacrylate, propylene glycol diacrylate, butanediol diacrylate, hexanediol diacrylate, hexanediol dimethacrylate, diacrylates and dimethacrylates of block copolymers of ethylene oxide and propylene oxide, polyhydric alcohols such as glycerol or pentaerythritol which are esterified two or three times with acrylic acid or methacrylic acid, triallylamine, tetraallylethylenediamine, divinylbenzene, diallyl phthalate, polyethylene glycol divinyl ethers of polyethylene glycols with a molecular weight of from 126 to 4000, trimethylolpropane diallyl ether, butanediol divinyl ether, pentaerythritol triallyl ether and/or divinylethyleneurea. Water-soluble crosslinkers are preferably used, e.g. N,N'-methylenebisacrylamide, oligoethylene glycol diacrylates and oligoethylene glycol dimethacrylates derived from adducts of 2 to 400 mol of ethylene oxide and 1 mol of a diol or polyol, vinyl ethers of adducts of 2 to 400 mol of ethylene oxide and 1 mol of a diol or polyol, ethylene glycol diacrylate, ethylene glycol dimethacrylate or triacrylates and trimethacrylates of adducts of 6 to 20 mol of ethylene oxide and one mol of glycerol, pentaerythritol triallyl ether and/or divinylurea.

Also suitable as crosslinkers are compounds, which contain at least one polymerizable ethylenically unsaturated group and at least one other functional group. The functional group in these crosslinkers must be able to react with the functional groups, essentially the carboxyl groups in the monomers of the backbone. Examples of suitable functional groups are hydroxyl, amino, epoxy and aziridino groups.

Also suitable as crosslinkers are those compounds which have at least two functional groups able to react with carboxyl and other functional groups in the monomers used. The suitable functional groups have already been mentioned above, i.e. hydroxyl, amino, epoxy, isocyanate, ester, amide and aziridino groups. Examples of such crosslinkers are ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, glycerol, polyglycerol, propylene glycol, polypropylene glycol, block copolymers of ethylene oxide and propylene oxide, sorbitan fatty acid esters, ethoxylated sorbitan fatty acid esters, trimethylolpropane, pentaerythritol, polyvinyl alcohol, sorbitol, polyglycidyl ethers such as ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, glycerol diglycidyl ether, glycerol polyglycidyl ether, diglycerol polyglycidyl ether, polyglycerol polyglycidyl ether, sorbitol polyglycidyl ether, pentaerythritol polyglycidyl ether, propylene glycol diglycidyl ether and polypropylene glycol diglycidyl ether, polyaziridine compounds such as 2,2-bishydroxymethylbutanol tris[3-(1-aziridinyl)propionate], 1,6-hexamethylenediethyleneurea, 4,4'-methylenebis(phenyl)-N,N'-diethyleneurea, halo epoxy compounds such as epichlorohydrin and a-methylfluorohydrin, polyisocyanates such as 2,4-tolylene diisocyanate and hexamethylene diisocyanate, alkylene carbonates such as 1,3-di-oxolan-2-one and 4-methyl-1,3-dioxolan-2-one, polyquatemary amines such as condensates of dimethylamine with epichlorohydrin, homo- and copolymers of diallyldimethylammonium chloride, and homo- and copolymers of dimethylaminoethyl (meth)acrylate, which are, where appropriate, quatemized with, for example, methyl chloride.

Other suitable crosslinkers are polyvalent metal ions able to form ionic crosslinks. Examples of such crosslinkers are magnesium, calcium, barium and aluminum ions. A preferred crosslinker of this type is sodium aluminate. These crosslinkers are added, for example, as hydroxides, carbonates or bicarbonates to the aqueous polymerizable solution.

Other suitable crosslinkers are multifunctional bases which are likewise able to form ionic crosslinks, for example polyamines or their quatemized salts. Examples of polyamines are ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine and polyethyleneimines, and polyvinylamines with molecular weights of up to 4,000,000 in each case.

In a preferred embodiment of the invention, divinyl crosslinkers are used. These can be hydrophobic or most preferably amphiphilic or hydrophilic. Apart from polyvalent metal ions, all the water-insoluble crosslinkers which are described above and can be assigned to the various groups are suitable for producing gels. Some preferred hydrophobic crosslinkers are diacrylates or dimethacrylates or divinyl ethers of alkanediols with 2 to 25 carbon atoms (branched, linear, with any suitable arrangement of OH groups) such as 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, 1,9-nonanediol or 1,2-dodecanediol, di-, tri- or polypropylene glycol diacrylates or dimethacrylates, allyl acrylate, allyl methacrylate, divinylbenzene, glycidyl acrylate or glycidyl methacrylate, allyl glycidyl ether and bisglycidyl ethers of the alkanediols listed above.

Examples of suitable hydrophilic crosslinkers are N,N'-methylenebisacrylamide, polyethylene glycol diacrylates or dimethacrylates with a molecular weight from 200 to 4000, divinylurea, triallylamine, diacrylates or dimethacrylates of adducts of from 2 to 400 mol of ethylene oxide and 1 mol of a diol or polyol or the triacrylate of an adduct of 20 mol of ethylene oxide and 1 mol of glycerol and vinyl ethers of adducts of from 2 to 400 mol of ethylene oxide and 1 mol of a diol or polyol.

The polymerization initiators which can be used are all initiators which form free radicals under the polymerization conditions and which are normally used in the preparation of responsive gels. It is also possible to initiate the polymerization by the action of electron beams on the polymerizable aqueous mixture. However, the polymerization can also be started in the absence of initiators of the abovementioned type by the action of high-energy radiation in the presence of photoinitiators.

Polymerization initiators which can be used are all compounds which decompose to free radicals under the polymerization conditions, e.g. peroxides, hydroperoxides, hydrogen peroxide, persulfates, azo compounds and the redox catalysts. Initiators soluble in the mixture of the monomer and amphiphilic copolymer are preferably used. It is advantageous in some cases to use mixtures of various polymerization initiators, e.g. most preferably mixtures of lauroyl peroxide or benzoyl peroxide hydrogen peroxide with 2,2'-azobis(2,4-dimethylpentanenitrile) or 4,4'-azobis(4-cyanovaleric acid). Examples of suitable organic peroxides are acetylacetone peroxide, methyl ethyl ketone peroxide, tertbutyl hydroperoxide, cumene hydroperoxide, tert-amyl perpivalate, tert-butyl perpivalate, tert-butyl pemeohexanoate, tert-butyl perisobutyrate, tert-butyl per-2-ethylhexanoate, tert-butyl perisononanoate, tert-butyl permaleate, tert-butyl perbenzoate, di(2-ethylhexyl) peroxydicarbonate, dicyclohexyl peroxydicarbonate, di(4-tert-butylcyclohexyl) peroxydicarbonate, dimyristyl peroxydicarbonate, diacetyl peroxydicarbonate, allyl peresters, cumyl peroxyneodecanoate, tert-butyl per-3,5,5-trimethylhexanoate, acetyl cyclohexylsulfonyl peroxide, dilauroyl peroxide, dibenzoyl peroxide and tert-amyl pemeodecanoate. Also suitable polymerization initiators are water-soluble azo initiators, e.g. 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine) dihydrochloride, 2-(carbamoylazo)isobutyronitrile, 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride and 4,4,-azobis(4-cyanovaleric acid). Polymerization initiators are used in conventional amounts, e.g. in amounts of from 0.01 to 5, preferably 0.1 to 2.0, % of the weight of the monomers to be polymerized.

Also suitable as initiators are redox catalysts. The redox catalysts contain as oxidizing component at least one of the abovementioned peroxy compounds and as reducing component, for example, ascorbic acid, glucose, sorbose, ammonium or alkali metal bisulfite, sulfite, thiosulfate, hyposulfite, pyrosulfite or sulfide, metal salts such as iron (II) ions or silver ions, or sodium hydroxymethylsulfoxylate. The reducing component preferably used in the redox catalyst is ascorbic acid or sodium sulfite. Based on the amount of monomers used in the polymerization, for example, from 3.times.10.sup.-6 to 1 mol % of the reducing component of the redox catalyst system and from 0.001 to 5.0 mol % of the oxidizing component of the redox catalyst are used.

If the polymerization is initiated by the action of high-energy radiation, photoinitiators are normally used as initiator. These may be, for example, alpha-splitters, H-abstracting systems or else azides. Examples of initiators of these types are benzophenone derivatives such as Michler's ketone, phenanthrene derivatives, fluorene derivatives, anthraquinone derivatives, thioxanthone derivatives, coumarin derivatives, benzoin ethers and derivatives thereof, azo compounds like the free-radical formers mentioned above, substituted hexaarylbisimidazoles or acylphosphine oxides. Examples of azides are: 2-(N,N-dimethylamino)ethyl 4-azidocinnamate, 2-(N,N-dimethylamino)ethyl-4-azidonaphthyl ketone, 2-(N,N-dimethylamino)ethyl 4-azidobenzoate, 5-azido-1-naphthyl 2-(N,N-dimethylamino)ethyl sulfone, N-(4-sulfonylazidophenyl)maleimide, N-acetyl-4-sulfonylazidoaniline, 4-sulfonylazidoaniline, 4-azidoaniline, 4-azidophenacyl bromide, p-azidobenzoic acid, 2,6-bis(p-azidobenzylidene)cyclohexanone and 2,6-bis(p-azidobenzylidene)-4-methylcyclohexanone. The photoinitiators are, if employed, normally used in amounts of from 0.01 to 5% of the weight of the monomers to be polymerized.

In one embodiment, it is preferred to use free-radical initiators capable of abstracting tertiary and secondary hydrogens from the backbone of the amphiphilic polymer of the present invention.

Method of Use

One of the major concerns in the delivery of drugs is the bioavailability of the drug. Depending upon the nature of the drug and the route of delivery, the bioavailability may be very low due to, for example, the degradation of oral-delivered drugs by hepato-gastrointestinal first-pass elimination or rapid clearance of the drug from the site of application. The net result is that frequent dosing may be required with higher than needed amounts of drug, which can lead to undesired side effects. Thus, it is desired by the pharmaceutical industry to have ways of administering drugs such that their availability can be controlled in an even dosing manner, the amounts of drugs can be kept as low as possible to minimize side effects, and dosing regime can be kept to a minimum to provide greater convenience to the subject, thus promoting greater compliance with appropriate dosing.

The responsive microgels of the present invention are useful in a wide variety of chemo-mechanical applications in that they display diverse phase transition characteristics. A method, for example, of delivering at least one therapeutic or cosmetic agent to a mammalian subject is a preferred embodiment of the invention which comprises administering a responsive microgel of the present invention to the subject which comprises at least one such agent.

A method of delivering an effective amount at least one therapeutic agent to a patient is a preferred method of the invention which comprises administering an effective amount of a responsive microgel of the present invention which comprises at least one therapeutic agent. Therapeutic regimens for the prevention and/or treatment of cancer frequently requires, for example, the administration of an effective amount of a cationic, hydrophobic, and/or amphiphilic compound, individually or in combinations. The responsive microgel of the present invention is particularly suited for therapeutic administration of these types of agents or entities. The responsive microgels are provided as a long-term delivery device for therapeutic agents and to enhance the therapeutic profile. The responsive microgels provide improved and substantially linear sustained release of therapeutic agents to improve and prolong the bioavailability of the agent. The reversibly gelling responsive microgel of this invention has the physico-chemical characteristics that make it a suitable delivery vehicle for conventional small chemical drugs as well as new macromolecular (e.g., peptides) drugs or therapeutic products.

The responsive microgel of the present invention is particularly suited for oral administration. The responsive microgel of the present invention may also be employed to deliver therapeutic entities (including cosmetic agents), for example, by intranasal, ocular, pulmonary, colonic, vaginal, as well as topical administration. The temperature-responsive mode of solute solubilization, for example, by microgels of the present invention is useful for medicinal as well as cosmetic formulations. Preferred therapeutic entities for use in the present invention include but are not limited to doxorubicin, mitoxantrone, mitomycin C, as well as the Taxanes including but not limited to (paclitaxel (TAXOL.RTM.), and docetaxel (TAXOTERE.RTM.)).

Examples of therapeutic entities that might be utilized in a delivery application of the invention include literally any hydrophilic or hydrophobic biologically active compound. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use by the appropriate governmental agency or body. For example, drugs for human use listed by the FDA under 21 C.F.R. 330.5, 331 through 361; 440 460; drugs for veterinary use listed by the FDA under 21 C.F.R. 500 582, incorporated herein by reference, are all considered acceptable for use in the present responsive microgel.

Drugs that are not themselves liquid at body temperature can be incorporated into the responsive microgel of the present invention. Moreover, peptides and proteins which may normally be rapidly degraded by tissue-activated enzymes such as peptidases, can be passively protected in the microgels described herein.

A responsive microgel which comprises at least one therapeutic entity is particularly preferred. A responsive microgel which comprises at least one anticancer agent is a preferred embodiment of the present invention wherein, for example, at least one anticancer agent is selected from the group consisting of (a steroidal antiandrogen, a non steroidal antiandrogen, an estrogen, diethylstilbestrol, a conjugated estrogen, a selective estrogen receptor modulator (SERM), a taxane, and a LHRH analog). Non steroidal antiandrogen as referred to herein includes but is not limited to the group consisting essentially of (finasteride (PROSCAR.RTM.), flutamide (4'-nitro-3'-trifluoromethyl isobutyranilide), bicalutamide (CASODEX.RTM.), and nilutamide). SERM as referred to herein includes but is not limited to the group consisting essentially of (tamoxifen, raloxifene, droloxifene, and idoxifene). LHRH analog as referred to herein includes but is not limited to the group consisting essentially of (goserelin acetate (ZOLADEX.RTM.), and leuprolide acetate (LUPRON.RTM.)).

A method of prevention or treatment of a tumor is provided comprising administering a therapeutically effective amount of a responsive microgel which comprises at least one therapeutic entity to a patient wherein the patient is either at risk of developing a tumor or already exhibits a tumor. A method of prevention or treatment of a tumor is provided wherein at least one agent described herein--or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug--is administered in a therapeutically effective amount comprised within a responsive microgel of the present invention to a patient wherein the patient is either at risk of developing a tumor or already exhibits a tumor. Methods of employing the responsive microgel of the present invention for the prevention or treatment of a tumor is provided wherein at least one agent is comprised within the microgel selected from the group consisting of (a steroidal antiandrogen, a non steroidal antiandrogen, an estrogen, diethylstilbestrol, a conjugated estrogen, a selective estrogen receptor modulator (SERM), a taxane, and a LHRH analog) and an effective amount of the microgel is administered to a patient in need of treatment.

The term therapeutic entity includes pharmacologically active substances that produce a local or systemic effect in a mammal. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in a mammal.

Therapeutic entities for employment with the responsive microgels described herein therefore include small molecule compounds, polypeptides, proteins, nucleic acids, and PLURONIC.RTM., for example, as described herein (e.g., and for the formation of mixed micelles).

Examples of proteins include antibodies, enzymes, growth hormone and growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogues, somatostatin and its analogues, gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide-T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin, kallidin, adrenocorticotropic hormone, thyroid stimulating hormone, insulin, glucagon and the numerous analogues and congeners of the foregoing molecules.

Classes of pharmaceutically active compounds which can be loaded onto responsive microgel compositions of the invention include, but are not limited to, anti-AIDS substances, anti-cancer substances, antibiotics, immunosuppressants (e.g. cyclosporine) anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, antihistamines, tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants, miotics and anti-cholinergics, antiglaucoma compounds, anti-parasite and/or anti-protozoal compounds, anti-hypertensives, analgesics, anti-pyretics and anti-inflammatory agents such as NSAIDs, local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents, specific targeting agents, neurotransmitters, proteins, cell response modifiers, and vaccines.

A more complete listing of classes of compounds suitable for loading into polymers using the present methods may be found in the Pharmazeutische Wirkstoffe (Von Kleemann et al. (eds) Stuttgart/New York, 1987, incorporated herein by reference). Examples of particular pharmaceutically active substances are presented below:

Anti-AIDS substances are substances used to treat or prevent Autoimmune Deficiency Syndrome (AIDS). Examples of such substances include CD4, 3'-azido-3'-deoxythymidine (AZT), 9-(2-hydroxyethoxymethyl)-guanine acyclovir( ), phosphonoformic acid, 1-adamantanamine, peptide T, and 2',3' dideoxycytidine.

Anti-cancer substances are substances used to treat or prevent cancer. Examples of such substances include methotrexate, cisplatin, prednisone, hydroxyprogesterone, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, testosterone propionate, fluoxymesterone, vinblastine, vincristine, vindesine, daunorubicin, doxorubicin, hydroxyurea, procarbazine, aminoglutethimide, mechlorethamine, cyclophosphamide, melphalan, uracil mustard, chlorambucil, busulfan, carmustine, lomusline, dacarbazine (DTIC: dimethyltriazenomidazolecarboxamide), methotrexate, fluorouracil, 5-fluorouracil, cytarabine, cytosine arabinoxide, mercaptopurine, 6-mercaptopurine, thioguanine.

Antibiotics are art recognized and are substances which inhibit the growth of or kill microorganisms. Antibiotics can be produced synthetically or by microorganisms. Examples of antibiotics include penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vanomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromicin and cephalosporins.

Anti-viral agents are substances capable of destroying or suppressing the replication of viruses. Examples of anti-viral agents include a-methyl-P-adamantane methylamine, 1,-D-ribofuranosyl-1,2,4-triazole-3 carboxamide, 9->2-hydroxy-ethoxy!methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, and adenine arabinoside.

Enzyme inhibitors are substances which inhibit an enzymatic reaction. Examples of enzyme inhibitors include edrophonium chloride, N-methylphysostigmine, neostigmine bromide, physostigmine sulfate, tacrine HCl, tacrine, 1-hydroxy maleate, iodotubercidin, p-bromotetramisole, 10-(alpha-diethylaminopropionyl)-phenothiazine hydrochloride, calmidazolium chloride, hemicholinium-3,3,5-initrocatechol, diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor II, 3-phenylpropargylamine, N.sup.6-monomethyl-L-arginine acetate, carbidopa, 3-hydroxybenzylhydrazine HCl, hydralazine HCl, clorgyline HCl, deprenyl HCl, L(-)-,deprenyl HCl,D(+)-, hydroxylamine HCl, iproniazid phosphate, 6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCl, quinacrine HCl, semicarbazide HCl, tranylcypromine HCl, N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride, 3-isobutyl-1-methylxanthne, papaverine HCl, indomethacind, 2-cyclooctyl-2-hydroxyethylamine hydrochloride, 2,3-dichloro-a-methylbenzylamine PCMB), 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride, p-aminoglutethimide, p-aminoglutethimide tartrate,R(+)-, p-aminoglutethimide tartrate,S(-)-, 3-iodotyrosine, alpha-methyltyrosine,L-, alpha -methyltyrosine,D L-, acetazolamide, dichlorphenamide, 6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.

Neurotoxins are substances which have a toxic effect on the nervous system, e.g. nerve cells. Neurotoxins include adrenergic neurotoxins, cholinergic neurotoxins, dopaminergic neurotoxins, and other neurotoxins. Examples of adrenergic neurotoxins include N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride. Examples of cholinergic neurotoxins include acetylethylcholine mustard hydrochloride. Examples of dopaminergic neurotoxins include 6-hydroxydopamine HBr, 1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride, 1-methyl-4-phenyl-2,3-dihydropyridinium perchlorate, N-methyl-4phenyl-1,2,5,6-tetrahydropyridine HCl, 1-methyl-4phenylpyridinium iodide.

Opioids are substances having opiate like effects that are not derived from opium. Opioids include opioid agonists and opioid antagonists. Opioid agonists include codeine sulfate, fentanyl citrate, hydrocodone bitartrate, loperamide HCl, morphine sulfate, noscapine, norcodeine, normorphine, thebaine. Opioid antagonists include nor-binaltorphimine HCl, buprenorphine, chlomaltrexamine 2HCl, funaltrexamione HCl, nalbuphine HCl, nalorphine HCl, naloxone HCl, naloxonazine, naltrexone HCl, and naltrindole HCl.

Hypnotics are substances which produce a hypnotic effect. Hypnotics include pentobarbital sodium, phenobarbital, secobarbital, thiopental and mixtures, thereof, heterocyclic hypnotics, dioxopiperidines, glutarimides, diethyl isovaleramide, a-bromoisovaleryl urea, urethanes and disulfanes.

Antihistamines are substances which competitively inhibit the effects of histamines. Examples include pyrilamine, chlorpheniramine, tetrahydrazoline, and the like.

Lubricants are substances that increase the lubricity of the environment into which they are delivered. Examples of biologically active lubricants include water and saline.

Tranquilizers are substances which provide a tranquilizing effect. Examples of tranquilizers include chloropromazine, promazine, fluphenzaine, reserpine, deserpidine, and meprobamate.

Anti-convulsants are substances which have an effect of preventing, reducing, or eliminating convulsions. Examples of such agents include primidone, phenytoin, valproate, Chk and ethosuximide.

Muscle relaxants and anti-Parkinson agents are agents which relax muscles or reduce or eliminate symptoms associated with Parkinson's disease. Examples of such agents include mephenesin, methocarbomal, cyclobenzaprine hydrochloride, trihexylphenidyl hydrochloride, levodopa/carbidopa, and biperiden.

Anti-spasmodics and muscle contractants are substances capable of preventing or relieving muscle spasms or contractions. Examples of such agents include atropine, scopolamine, oxyphenonium, and papaverine.

Miotics and anti-cholinergics are compounds which cause bronchodilation. Examples include echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, epinephrine, neostigmine, carbachol, methacholine, bethanechol, and the like.

Anti-glaucoma compounds include betaxalol, pilocarpine, timolol, timolol salts, and combinations of timolol, and/or its salts, with pilocarpine.

Anti-parasitic, -protozoal and -fungals include ivermectin, pyrimethamine, trisulfapyrimidine, clindamycin, amphotericin B, nystatin, flucytosine, natamycin, and miconazole.

Anti-hypertensives are substances capable of counteracting high blood pressure. Examples of such substances include alpha-methyldopa and the pivaloyloxyethyl ester of alpha-methyldopa.

Analgesics are substances capable of preventing, reducing, or relieving pain. Examples of analgesics include morphine sulfate, codeine sulfate, meperidine, and nalorphine.

Anti-pyretics are substances capable of relieving or reducing fever and anti-inflammatory agents are substances capable of counteracting or suppressing inflammation. Examples of such agents include aspirin (salicylic acid), indomethacin, sodium indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodium salicylamide.

Local anesthetics are substances which have an anesthetic effect in a localized region. Examples of such anesthetics include procaine, lidocain, tetracaine and dibucaine.

Ophthalmics include diagnostic agents such as sodium fluorescein, rose bengal, methacholine, adrenaline, cocaine, and atropine. Ophthalmic surgical additives include alpha-chymotrypsin and hyaluronidase.

Prostaglandins are art recognized and are a class of naturally occurring chemically related, long-chain hydroxy fatty acids that have a variety of biological effects.

Anti-depressants are substances capable of preventing or relieving depression. Examples of anti-depressants include imipramine, amitriptyline, nortriptyline, protriptyline, desipramine, amoxapine, doxepin, maprotiline, tranylcypromine, phenelzine, and isocarboxazide.

Anti-psychotic substances are substances which modify psychotic behavior. Examples of such agents include phenothiazines, butyrophenones and thioxanthenes.

Anti-emetics are substances which prevent or alleviate nausea or vomiting. An example of such a substance includes dramamine.

In topical skin care applications, a variety of active substances may be advantageously employed. By way of example only suitable active agents which may be incorporated into the cosmetic composition include anti-aging active substances, anti-wrinkle active substances, hydrating or moisturizing or slimming active substances, depigmenting active substances, substances active against free radicals, anti-irritation active substances, sun protective active substances, anti-acne active substances, firming-up active substances, exfoliating active substances, emollient active substances, and active substances for the treating of skin disorders such as dermatitis and the like.

Imaging agents are agents capable of imaging a desired site, e.g. tumor, in vivo. Examples of imaging agents include substances having a label which is detectable in vivo, e.g. antibodies attached to fluorescent labels. The term antibody includes whole antibodies or fragments thereof.

Specific targeting agents include agents capable of delivering a therapeutic agent to a desired site, e.g. tumor, and providing a therapeutic effect. Examples of targeting agents include agents which can carry toxins or other agents which provide beneficial effects. The targeting agent can be an antibody linked to a toxin, e.g. ricin A or an antibody linked to a drug.

Neurotransmitters are substances which are released from a neuron on excitation and travel to either inhibit or excite a target cell. Examples of neurotransmitters include dopamine, serotonin, q-aminobutyric acid, norepinephrine, histamine, acetylcholine, and epinephrine.

Cell response modifiers are chemotactic factors such as platelet-derived growth factor (PDGF). Other chemotactic factors include neutrophil-activating protein, monocyte chemoattractant protein, macrophage-inflammatory protein, platelet factor, platelet basic protein, and melanoma growth stimulating activity; epidermal growth factor, transforming growth factor (alpha), fibroblast growth factor, platelet-derived endothelial cell growth factor, insulin-like growth factor, nerve growth factor, and bone growth/cartilage-inducing factor (alpha and beta), or other bone morphogenetic protein.

Other cell response modifiers are the interleukins, interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 10; interferons, including alpha, beta and gamma; hematopoietic factors, including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor; tumor necrosis factors, including alpha and beta; transforming growth factors (beta), including beta-1, beta-2, beta-3, inhibin, and activin; and bone morphogenetic proteins.

As those skilled in the art will appreciate, the foregoing list is exemplary only. Because the responsive microgel of the present invention is suited for application under a variety of physiological conditions, a wide variety of pharmaceutical agents may be loaded onto the responsive microgels described herein and administered.

Formulations

Tablet Excipients. It has been demonstrated that standard pharmaceutical processes, such as lyophilization and air-drying can process the responsive microgel of the invention. The reversible thermal viscosifying responsive microgel may be reconstituted with water, phosphate buffer or calcium chloride solution, without loss or degradation of rheological properties. Thus, it is contemplated that the responsive microgel of the invention may also be incorporated as excipients into tablets or granules for oral delivery, for example. The responsive microgel may be coated on an outer surface of the tablet or may be introduced in powder form into the tablet along with the active agent and other ingredients. The poloxamer:poly(acrylic acid) composition may be used to promote bioadhesion of the tablet and its contents with the mucosal lining of the gastro-intestinal tract to extend transit time.

Also, when incorporated as a powder, the slow dissolution rate of the end-modified responsive microgel makes it a suitable excipient to sustained release tableting formulation. The addition of such responsive microgel would yield to a slow release of the incorporated drug.

Injectibles. The end-modified responsive microgel composition of the invention is well-suited for use in injectable applications. A depot formulation may be prepared and administered at low viscosity to a subdermal or intramuscular site, for example. The responsive microgel will viscosify and form a depot site, which will slowly release the active agent. The reversible thermally viscosifying responsive microgel, upon contact with body fluids including blood or the like, undergoes gradual release of the dispersed drug for a sustained or extended period (as compared to the release from an isotonic saline solution). This can result in prolonged delivery (over, say 1 to 2,000 hours, preferably 2 to 800 hours) of effective amounts (say, 0.0001 mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage form can be administered as is necessary depending on the subject being treated, the severity of the affliction, the judgment of the prescribing physician, and the like.

Preparation of pharmaceutic compositions may be accomplished with reference to any of the pharmaceutic formulation guidebooks and industry journals which are available in the pharmaceutic industry. These references supply standard formulations which may be modified by the addition or substitution of the reversible viscosifying composition of the present invention into the formulation. Suitable guidebooks include Pharmaceutics and Toiletries Magazine, Vol. 111 (March, 1996); Formulary: Ideas for Personal Care; Croda, Inc, Parsippany, N.J. (1993); and Pharmaceuticon: Pharmaceutic Formulary, BASF, which are hereby incorporated in their entirety by reference.

The pharmaceutic composition may be in any form. Suitable forms will be dependant, in part, of the intended mode and location of application. Ophthalmic and otic formulations are preferably administered in droplet or liquid form; nasal formulations are preferable administered in droplet or spray form, or may be administered as a powder (as a snuff); vaginal and rectal formulations are preferably administered in the form of a cream, jelly or thick liquid; veterinary formulations may be administered as a cream, lotion, spray or mousse (for application to fur or exterior surface); esophageal and buccal/oral cavity applications are preferably administered from solution or as a powder; film forming applications or dermal applications may be administered as a lotions, creams, sticks, roll-ons formulations or pad-applied formulations.

Exemplary drugs or therapeutics delivery systems which may be administered using the aqueous responsive composition compositions of the invention include, but are in no way limited to, mucosal therapies, such as esophageal, otic, rectal, buccal, oral, vaginal, and urological applications; topical therapies, such as wound care, skin care and teat dips; and intravenous/subcutaneous therapies, such as intramuscular, intrabone (e.g., joints), spinal and subcutaneous therapies, tissue supplementation, adhesion prevention and parenteral drug delivery. In addition, further applications include transdermal delivery and the formation of depots of drug following injection. It will be appreciated that the ionic nature of the biocompatible component of the responsive composition provides an adhesive interaction with mucosal tissue.
 

Claim 1 of 15 Claims

1. A responsive microgel comprised of an ionizable network of covalently cross-linked homopolymeric ionizable monomers wherein the ionizable network is covalently attached to a single terminal region of an amphiphilic copolymer to form a plurality of `dangling chains` and wherein the `dangling chains` of amphiphilic copolymer form immobile intra-network aggregates in aqueous solution.

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