The present invention is related to hydrogel particles and aggregates formed therefrom having characteristics including, without limitation, shape-retentiveness, elasticity, controllable pore sizes and controllable degradation rates that render them useful for a wide variety of applications including, without limitation, the controlled release of biologically active substances, in vivo medical devices, tissue growth scaffolding and tissue replacement.

Description of the Invention

SUMMARY OF THE INVENTION

Thus, an aspect of this invention is a shape-retentive aggregate comprising a plurality of hydrogel particles, each particle comprising a plurality of polymeric strands obtained by polymerization of one or more monomers at least one of which comprises one or more hydroxy and/or one or more ether groups; from 10 to 90 weight percent of one or more absorbed liquid(s), at least one of which comprises one or more hydroxy groups, wherein the liquid(s) is/are absorbed into the hydrogel particles; and, from 10 to 90 weight percent of one or more non-absorbed liquids, which may be the same as, or different from, the absorbed liquid(s) and at least one of which comprises one or more hydroxy groups, the non-absorbed liquid occupying voids between the hydrogel particles of the aggregate.

Another aspect of this invention is a shape-retentive aggregate comprising at least 50 volume percent of hydrogel particles, each hydrogel particle comprising a plurality of polymeric strands obtained by polymerization of one or more monomers at least one of which comprises one or more hydroxy and/or one or more ether groups; up to 50 volume percent of one or more working substances; from 10 to 90 weight percent of one or more absorbed liquid(s), at least one of which comprises one or more hydroxy groups, wherein the liquid(s) is(are) absorbed into the hydrogel particles; and, from 10 to 90 weight percent of one or more non-absorbed liquids, which may be the same as, or different from, the absorbed liquid(s) and at least one of which comprises one or more hydroxy groups, the non-absorbed liquid occupying voids between the hydrogel particles of the aggregate, wherein the working substance(s) is(are) dissolved or suspended in the absorbed liquid or the working substance(s) is(are) dissolved or suspended in the non-absorbed liquid or one or more of the working substance(s) is(are) dissolved or suspended in the absorbed liquid and one or more of the working substances is(are) dissolved or suspended in the non-absorbed liquid.

In an aspect of this invention, the working substance comprises one or metals, or alloys thereof.

In an aspect of this invention, the working substance comprises one or more metals individually having oxidation states of one or higher.

In an aspect of this invention, the working substance comprises one or more semiconductor elements or compounds.

In an aspect of this invention, the working substance comprises one or more pharmaceutical agents.

In an aspect of this invention, the working substance further comprises one or more pharmaceutically acceptable excipients.

In an aspect of this invention, the pharmaceutical agent is a peptide or protein.

In an aspect of this invention, the one or more pharmaceutical agents are useful for the treatment of cancer.

In an aspect of this invention, the one or more pharmaceutical agents are useful for the treatment of coronary artery disease.

In an aspect of this invention, the one or more pharmaceutical agents are useful for the treatment of respiratory diseases.

In an aspect of this invention, the one or more pharmaceutical agents are useful for the treatment of infectious diseases.

A further aspect of this invention is a method for preparing a composition for controlled release of a working substance comprising adding one or more monomers, at least one of which includes one or more hydroxy and/or one or more ether groups, to one or more liquids, at least one of which includes one or more hydroxy groups; adding from 0.01 to 10 mol percent of a surfactant to the liquid(s); polymerizing the monomers to form a suspension in the liquid of hydrogel particles comprising a plurality of polymeric strands and from 10 to 90% of an absorbed liquid(s); dissolving or suspending one or more working substance(s) in remaining non-absorbed liquid(s); and, removing non-absorbed liquids until a shape-retentive aggregate forms.

In the above method, the working substance(s) is(are) dissolved or suspended in the remaining non-absorbed liquid(s) after polymerization of the monomers resulting in a shape-retentive aggregate comprising 10 to 90 weight percent working-substance-containing, non-absorbed liquid and hydrogel particles comprising 10 to 90 weight percent non-working-substance-containing absorbed liquid, in an aspect of this invention.

In the above method, the working substance(s) is(are) dissolved or suspended in the liquid(s) before polymerization of the monomers resulting in a shape-retentive aggregate comprising 10 to 90 weight percent working-substance-containing, non-absorbed liquid and hydrogel particles comprising 10 to 90 weight percent working-substance-containing absorbed liquid, in another aspect of this invention.

In the above method, after polymerization but before removing non-absorbed liquid to form the shape-retentive aggregate, the working substance is removed from the non-absorbed liquid resulting in a shape-retentive aggregate comprising 10 to 90 weight percent non-working-substance-containing, non-absorbed liquid and hydrogel particles comprising 10 to 90 weight percent working-substance-containing absorbed liquid, in an aspect of this invention.

In an aspect of this invention, the shape-retentive aggregate is elastomeric.

In an aspect of this invention, the monomer(s) is/are selected from the group consisting of a 2-alkenoic acid, a hydroxy(2C-4C)alkyl 2-alkenoate, a hydroxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate, a (1C-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate and a vicinyl epoxy(1C-4C)alkyl 2-alkenoate.

In an aspect of this invention, the monomer(s) is(are) selected from the group consisting of acrylic acid, methacrylic acid, 2-hydroxyethyl acrylate, 2-hydroxyethylmethacrylate, diethyleneglycol monoacrylate, diethyleneglycol monomethacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methyacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, dipropylene glycol monoacrylate, dipropylene glycol monomethacrylate, gylcidyl methacrylate, 2,3-dihydroxypropyl methacrylate, glycidyl acrylate and glycidyl methacrylate.

In an aspect of this invention the monomer is 2-hydroxyethyl methacrylate, 3-hydroxypropyl methacrylate, or a combination thereof.

In an aspect of this invention the absorbed and the non-absorbed liquids are independently selected from the group consisting of water, a (1C-10C) alcohol, a (2C-8C)polyol, a (1C-4C)alkyl ether of a (2C-8C)polyol, a (1C-4C)acid ester of a (2C-8C)polyol; a hydroxy-terminated polyethylene oxide, a polyalkylene glycol and a hydroxy(2C-4C)alkyl ester of a mono, di- or tricarboxylic acid.

In an aspect of this invention, the absorbed and the non-absorbed liquids are independently selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200-600, propylene glycol, dipropylene glycol, 1,4-butanediol, 2,3-butanediol, 1,6-hexanediol, 2,5-hexanediol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, methylcellosolve ether, ethylene glycol monoacetate, propylene glycol monomethyl ether, glycerine, glycerol monoacetate, tri(2-hydroxyethyl)citrate, di(hydroxypropyl)oxalate, glycerine, glyceryl monoacetate, glyceryl diacetate, glyceryl monobutyrate and sorbitol.

In an aspect of this invention, the absorbed liquid is water.

In an aspect of this invention, the non-absorbed liquid is water.

In an aspect of this invention, the absorbed and the non-absorbed liquid are water.

In an aspect of this invention, the hydrogel particles comprise from 0.1 to 15% mol percent of a cross-linking agent.

In an aspect of this invention, the cross-linking agent is selected from the group consisting of ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,4-dihydroxybutane dimethacrylate, diethylene glycol dimethacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, divinyl benzene, divinyltoluene, diallyl tartrate, diallyl malate, divinyl tartrate, triallyl melamine, N,N'-methylene bisacrylamide, diallyl maleate, divinyl ether, 1,3-diallyl 2-(2-hydroxyethyl) citrate, vinyl allyl citrate, allyl vinyl maleate, diallyl itaconate, di(2-hydroxyethyl) itaconate, divinyl sulfone, hexahydro-1,3,5-triallyltriazine, triallyl phosphite, diallyl benzenephosphonate, triallyl aconitate, divinyl citraconate, trimethylolpropane trimethacrylate and diallyl fumarate.

In an aspect of this invention, the cross-linking agent is selected from the group consisting of .alpha.-hydroxy acid esters.

In an aspect of this invention, the plurality of hydrogel particles is of narrow polydispersivity.

In an aspect of this invention, the hydrogel particles are uncharged, charged or a combination thereof.

In an aspect of this invention, the plurality of hydrogel particles comprises particles of two or more different sizes and/or two or more different chemical compositions.

In an aspect of this invention, the cross-linked polymer strands have an average molecular weight of from about 25,000 to about 2,000,000.

In an aspect of this invention, the aggregate is degradable.

In an aspect of this invention, the hydrogel particles of the aggregate are degradable.

DETAILED DESCRIPTION OF THE INVENTION

Discussion

The shape-retentive hydrogel aggregates of this invention should find use in a host of applications including, without limitation, as controlled release vehicles for chemical compounds such as agrochemicals, pharmaceuticals and the like, as adjuncts, e.g., coatings on medical devices and as medical devices per se, as tissue growth matrices and as tissue replacement materials. The aggregates, which can be constructed of biologically inert polymers and which can absorb large quantities of water, are particularly useful for in vivo applications.

The aggregates of this invention may be formed by creating the hydrogel particles in situ or by mixing pre-formed hydrogel particles in one or more liquid(s). In either case, the liquid(s) is/are absorbed by the individual particles and then excess liquid is removed by, without limitation, vacuum drying, air evaporation or centrifugation until the particles are drawn so close together that their circumferences essentially touch and the only non-absorbed liquid remaining is that in the voids between the particles. The aggregates realize their characteristic shape-retentiveness by virtue of strong inter-particle attractive forces such as, without limitation, hydrogen bonds, and by virtue of hydrogen bonding between the particles and the liquid in the voids between the particles.

The chemical composition of the polymers, making up the individual hydrogel particles can be manipulated such that aggregates of them are very stable and do not readily degrade under environmental or physiological conditions. Or the chemical composition of the particles can be such that aggregates of them do degrade under certain conditions in a predictable and controllable fashion. For example, without limitation, by selecting the appropriate hydrogel particle composition, which will become apparent from the disclosures herein, aggregates that decompose under various conditions of temperature, pH, ionic strength, electric current and the like, can be constructed. In addition to manipulating the composition of the hydrogel particles themselves, excipients can be entrapped in the aggregate matrix during its formation. The excipients can be selected such that aggregates containing them will degrade as the excipients change structure, composition and/or reactivity upon exposure to a variety of environmental and/or physiological conditions. Excipients can also be added to imbue the resulting aggregate with a variety of different properties such as, without limitation, mechanical, optical, conductive or cosmetic properties.

In an embodiment of this invention, hydrogel particles, having nominal diameters in the 10.sup.-9 meters (m, nano scale) to the 10.sup.-6 m (micro scale) range are produced by redox, free radical or photo-initiated polymerization in the presence of a surfactant and water. In this manner, particles of relatively narrow polydispersivity, i.e., narrow range of diameters, can be produced. While narrow polydispersivity is a presently preferred embodiment of this invention, for some applications, which will become apparent to those skilled in the art based on the disclosures herein and which are within the scope of this invention, a broader polydispersivity may be desirable.

The resulting aqueous suspension of hydrated hydrogel particles may be treated to remove unreacted monomers and surfactant from the water absorbed by the particles. The treatment may include, without limitation, dialysis, extraction or tangential flow filtration. Simultaneously, unreacted monomer and surfactant can be removed from the non-absorbed water in which the particles are suspended. The suspension of purified particles is then centrifuged to remove excess water and compact the particles into the shape-retentive aggregate of this invention. An advantage of using nano- or micro-size particles is that they have a high surface area to volume ratio and can be relatively easily purified.

Preferred classes of monomers useful in the preparation of the hydrogel particles and subsequent aggregates of this invention include, without limitation, hydroxyalkyl 2-alkenoates such as the hydroxy(2C-4C)alkyl methacrylates and the hydroxy(2C -4C)alkyl acrylates; the hydroxy((2C-4C)alkoxy(2C.-4C)alkyl) alkenoates such as 2-hydroxyethoxyethyl acrylate and methacrylate; the (1C-4C)alkoxy(1C-4C)alkyl methacrylates, e.g., ethoxyethyl methacrylate; the 2-alkenoic acids, such as acrylic and methacrylic acid; the (1C-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl) alkenoates such as ethoxyethoxyethyl acrylate and methacrylate; the N-vinylpyrrolidones such as the N-mono- and di-(1C-4C)alkyl vinylpyrrolidones; the 2-alkenamides such as the N-(1C -4C) alkyl-2-alkenamides and N,N-di(1C-4C)alkyl-2-alkenamides, for example, the N-(1C-4C)alkylacrylamides, the N-(1C-4C)alkylmethacrylamides, the N,N-di(1C-4C)alkylacrylamides and the N,N-di(1C-4C)alkylmethacrylamides; the dialkylaminoalkyl 2-alkenoates, e.g., diethylaminoethyl acrylate and methacrylate; the vinylpyridines; the vicinal-epoxyalkyl 2-alkenoates such as the vicinal epoxy(1C-4C)alkyl)methacrylates and the vicinal epoxy(1C-4C)alkyl acrylates, and combinations thereof. Other monomers capable of hydrogen-bonding will become apparent to those skilled in the art based on the disclosures herein and are within the scope of this invention.

Non-polymerizing excipients such as, without limitation, the alkyl alkanoates, e.g., methyl butyrate, butyl acetate, etc. may be added to the polymerization reaction to modify the physical and chemical characteristics of the resulting hydrogel particles.

Presently preferred monomers include 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, diethylene glycol monoacrylate, diethylene glycol monomethacrylate, 2-hydropropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, dipropylene glycol monomethacrylate, dipropylene glycol monoacrylate, glycidyl methacrylate, 2,3-dihydroxypropyl methacrylate, and the like. Presently, the most preferred monomer is 2-hydroxyethyl methacrylate (HEMA).

Examples of presently preferred co-monomers used in conjunction with the above preferred monomers are acrylamide, N-methylmethacrylamide, N,N-dimethacrylamide, methylvinylpyrrolidone, N,N-dimethylaminoethyl methacrylate N,N-dimethylaminoethyl acrylate, acrylic acid and methacrylic acid.

If desired, a cross-linking agent may be added to the polymerization reaction to strengthen the three-dimensional structure of the resulting hydrogel particles. The cross-linking agent can be non-degradable, such as, without limitation, ethylene glycol diacrylate or dimethacrylate, 1,4-butylene dimethacrylate, diethylene glycol dimethacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, divinyl benzene, divinyltoluene, triallyl melamine, N,N'-methylene bisacrylamide, diallyl maleate, divinyl ether, diallyl monoethylene glycol citrate, vinyl allyl citrate, allyl vinyl maleate, divinyl sulfone, hexahydro-1,3,5-triallyltriazine, triallyl phosphite, diallyl benzene phosphonate, a polyester of maleic anhydride with triethylene glycol, diallyl aconitrate, divinyl citraconate, trimethylolpropane trimethacrylate and diallyl fumarate. Other non-degradable cross-linking agents will become apparent to those skilled in the art based on the disclosures herein and are within the scope of this invention. Other methods of achieving a three-dimensional polymeric network that are well-known in the art may be used in preparing the hydrogel particles and aggregates of this invention and all such methods are within the scope of this invention.

The cross-linking agent may be selected such that it is degradable under selected conditions, if such is desired for the intended use. Examples without limitation, of degradable cross-linking agents include diallyl tartrate, allyl pyruvate, allyl maleate, divinyl tartrate, diallyl itaconate and ethylene glycol diester of itaconic acid.

A presently preferred class of degradable cross-linking agents is provided in U.S. patent application Ser. No. 091338,404, which is incorporated by reference, including any drawings, as if fully set forth herein. These cross-linkers are monomers or oligomers comprised of a molecule having at least two carboxyl groups and at least two cross-linking functional groups. Between at least one of the cross-linking functional groups and one of the carboxyl groups is a degradable poly(hydroxyalkyl acid ester) sequence of 1-6 repetitions.

In another embodiment, aggregates of this invention are prepared from bulk hydrogel polymers. The bulk polymer is prepared by conventional polymerization techniques such as, without limitation, solution, suspension and aqueous bulk polymerization and the resultant polymer is isolated, treated to remove residual monomer and any other undesirable materials and dried. The dry, brittle bulk polymer is broken up by grinding, micropulverizing and the like, and the fragments are sieved using techniques known in the industry. Particles of the desired size range are stirred in a selected liquid or liquids until they have absorbed the desired amount of liquid.

Preferred liquids for use in this invention are chemically, particularly biologically, inert, non-toxic, polar, water-miscible organic liquids such as, without limitation, ethylene glycol, propylene glycol, dipropylene glycol, butanediol-1,3, butanediol-1,4, hexanediol-2,5,2-methyl-2,4-pentanediol, heptanediol-2,4, 2-ethyl-1,3-hexanediol, diethylene glycol, triethylene glycol, tetraethylene glycols, and the higher polyethylene glycols and other water-soluble oxyalkylene homopolymers and copolymers having a molecular weight up to 2000, and higher, preferably up to 1600. For example, hydroxy-terminated polymers of ethylene oxide having average molecular weights of 200-1000, the water-soluble oxyethyleneoxypropylene polyol (especially glycol) polymers having molecular weights up to about 1500, preferably up to about 1000, propylene glycol monoethyl ether, monoacetin, glycerine, tri(hydroxyethyl) citrate, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, di(hydroxypropyl) oxalate, hydroxypropyl acetate, glyceryl triacetate, glyceryl tributyrate, liquid sorbitol ethylene oxide adducts, liquid glycerine ethylene oxide adducts, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and ethylene glycol diacetate may be used. Other hydroxy and hydroxy/ether liquids capable of hydrogen bonding with the hydrogel particles will become apparent to those skilled in the art based on the disclosures herein and are within the scope of this invention.

In a presently preferred embodiment of this invention, the organic liquid(s) has/have boiling points above about 60.degree. C., preferable above about 200.degree. C. The use of these liquids results in the formation of intricate, tough aggregates. Thus, organic liquids that are particularly useful in forming the aggregates of this invention are the water-miscible oxyalkylene polymers, e.g., the polyalkylene glycols, especially those characterized by a plurality of oxyethylene (--OCH.sub.2CH.sub.2--) units in the molecule and a boiling point above about 200.degree. C.

Criteria which will affect the chemical and physical characteristics of the aggregates of this invention include the molecular weight of the polymer forming the individual hydrogel particles, the particle size, the cross-linking agent, if any, and its cross-linking density, and the molecular weight and chemical composition of the liquids used. For example, hydrogel particles consisting of low molecular weight polymers will generally not form stable, strong aggregates. Smaller hydrogel particles will generally provide aggregates that are thoroughly and effectively solvated, resulting in a more resilient matrix. If the hydrogel polymer contains a large amount of cross-linking agent and/or if the cross-linking agent is highly hydrophobic, the resulting branched polymeric network may not permit optimal absorption of liquid resulting in inferior aggregates and in some cases no aggregates result.

In an embodiment of the present invention, nano- or micro-size hydrogel particles are produced by polymerizing non-ionic monomers in water containing a surfactant. The suspension of hydrogel particles is treated to remove unreacted monomer and other impurities. Aggregates are then formed by removing water until the particles self-assemble into a compact elastic matrix. The aggregate can then be, without limitation, pressure shaped, extruded, or molded. The aggregate will retain the shape indefinitely so long as it is maintained in the hydrated state.

In another embodiment of the present invention, monomers having various degrees of ionic character are co-polymerized with non-ionic monomers to form hydrogel particles that are subsequently coalesced into aggregates. These aggregates are susceptible to decomposition under the appropriate environmental conditions. That is, the ionic character of the individual hydrogel particles can result in their degradation depending on the pH, temperature, ionic strength, electric current, etc. of their immediate environment. Breakdown of the hydrogel particles leads to degradation of the aggregate. Such controlled degradation of aggregates of this invention is a desirable characteristic for certain uses.

Breakdown of the individual hydrogel particles and thereby breakdown of the aggregate may also be accomplished by using degradable cross-linking agents in the formation of the hydrogel particles. The resulting aggregate will dissemble under environmental conditions that cause degradation of the cross-linker. Cross-linking agents can be prepared that will degrade under selected conditions of, without limitation, pH, temperature, ionic strength and electric current.

The aggregates of this invention have many uses, among which the delivery of biologically active substances to a selected target is particularly noteworthy. The target may be agricultural, such as, without limitation, the delivery of a fungicide, insecticide or herbicide to a commercial crop; e.g. corn, cotton, soy beans, wheat, etc. Or, the target may be the growth medium, e.g., the soil, in which the crop is growing and may involve the delivery of nutrients and the like. The target may be environmental contaminants in soil, which contaminants may be controllably degraded using aggregates of this invention. The target may be veterinary, involving delivery of medicaments to animals such as reptiles, mammals and birds. In particular, the target may be a human involving the controlled, directed delivery of pharmaceutical agents to the patient.

The delivery of biologically active substances using aggregates of this invention can be accomplished primarily in two ways, and combinations thereof. The first approach involves dissolving or suspending the biologically active material in a suspension of hydrated hydrogel particles before the excess liquid is removed to create an aggregate. A water-soluble substance is preferred to ensure homogeneity of the bulk liquid before concentration. However, adjuvants, such as surfactants, can be added to the mix to render a suspension of a limited solubility biologically active substance relatively homogeneous. As the suspension is concentrated to the point that an aggregate forms, the biologically active substance becomes entrapped in the liquid that fills the voids between the particles of the aggregate. The resulting resilient, shape-retentive aggregate can be washed to remove any biologically active substance adhered to its surface. The aggregate can then be shaped for the intended use, if desired. For example, without limitation, if the contemplated use is treatment of an infection, the aggregate could be shaped to fit directly into a wound and to release an antibiotic therein. Likewise, if the use is delivery of a chemotherapeutic, such as, without limitation, paclitaxel or cisplatin, to a target organ in a cancer patient, the aggregate could be shaped to facilitate implantation at the afflicted site.

The second approach involves dissolving or suspending the biologically active substance in the polymerization medium before formation of the hydrogel particles. When polymerization is initiated and the particles form, liquid containing the biologically active substance is entrapped within the individual particles. When the particles are treated as discussed above to remove excess monomer and surfactant, excess biologically active substance not trapped within the particles will also be removed. The suspension of biologically active substance-containing particles is then concentrated until the particles coalesce into an aggregate.

As noted above, it is possible to combine the two approaches. That is, rather than removing the biologically active substance with the excess monomer and surfactant before concentration of the hydrogel particle suspension, the active substance can be left in the suspension liquid. In this manner, the resulting aggregate will have biologically active substance entrapped both within the individual hydrogel particles and in the voids between the particles. On the other hand, the suspension of hydrogel particles can be purified as above and then the biologically active substance or, if desired, an entirely different biologically active substance can be re-introduced into the mixture before concentration. The substance in the voids in the aggregate will normally be released at a very different rate from the substance in the particles. In this manner, a broad range of delivery profiles and rates and be achieved. Diversity can also be achieved by varying the chemical composition of the individual hydrogel particles of the aggregate.

If no chemical modification is incorporated into the individual hydrogel particles such as, without limitation, ionic character or the use of degradable cross-linkers, the aggregate will be essentially impervious to normal environmental conditions. This type of aggregate will generally provide release rates similar to monolithic matrix devices, that is, an initial burst of substance followed by an exponential drop off with time. However, if the hydrogel particles are designed such that they degrade under the environmental conditions encountered at the delivery site and if the biologically active substance will be released from the aggregate only upon disintegration of the particles, extremely fine control of delivery rate is possible. Assuring that active substance release will occur only upon disintegration of the hydrogel particles can be accomplished by using particles of a size that will result in an aggregate having pores too small for the entrapped active substance to traverse when the aggregate is intact. Likewise, the individual particles can be formed such that active substance entrapped within them cannot escape absent particle disintegration.

In addition to the above, water soluble adjuncts may be added to the aggregates to alter disintegration rate and, therefore, the release rate of the entrapped active substance. Furthermore, particles comprising cationic and/or anionic charges can be mixed with non-ionic hydrogel particles to provide controlled disintegration of the aggregates under a variety of conditions including the ionic character of the environs or the existence of an external electric charge. The inclusion of charged species may also increase aggregation efficiency due to electrostatic charge interaction.

Using one or more of the above procedures, zero-order, or at least pseudo-zero order, release rates should be attainable.

The type and amount of a substance that can be entrapped in a hydrogel particle or aggregate of this invention depends upon a variety of factors. The substance cannot interfere, due to its size, surface charges, polarity, steric interactions, etc., with the coalescence of the hydrogel particles into an aggregate. The size of the hydrogel particles will affect the quantity of substance that can be incorporated. That is, by appropriate selection of particle size, the resulting aggregate pore size can be manipulated so as to retain small substances, such as individual antibiotic molecules or very large substances such as monoclonal antibodies, proteins, peptides, or other macromolecules.

Using the methods herein, exquisite control of substance delivery, in particular delivery kinetics, should be attainable. That is, hydrogel particles of differing sizes and chemical compositions could be loaded with a particular substance and, depending on the degradation characteristics of the various particles, the substance could be released over virtually any desired timeframe. In addition, some of the substance could be encased in the hydrogel particles and some could be trapped in the voids between particles of the aggregate to provide even more delivery flexibility. Different substances, even those normally incompatible, could be loaded into different types of particles and sequentially or simultaneously released. Sequential release would prevent the incompatible substances from encountering one another while simultaneous release would allow them to interact at the release site. This latter scenario could be particularly useful in the case of two or more non- or minimally bioactive substances that, when combined, form an extremely potent drug. The formation of the active drug could be postponed until an aggregate containing the precursors has been delivered to the site where the effect of the drug is required thereby minimizing side effects.

Thus, the present invention provides an extremely versatile drug delivery platform. A drug or combination of drugs may be delivered over an extended time period. A combination of drugs may be delivered sequentially so that one has its effect and dissipates before the next is released. A combination of drugs may be released simultaneous to synergistically interact. Other uses will become apparent to those skilled in the art based on this disclosure; such uses are within the scope of this invention.

Another area of potential utility for the aggregates of this invention is tissue scaffolding. The macroporous structure of the aggregates provides a composition that will allow substantial ingrowth, a property not found in typical microporous bulk hydrogels. In addition, the aggregates herein exhibit physical properties such as elastic, shear and bulk moduli that are significantly greater than those of conventional bulk hydrogels, approaching in some cases the properties of articular cartilage. Furthermore, the ability to mold and layer the aggregates of this invention could be used to optimize the release of growth factor at specific locations within a tissue scaffold. Possible orthopedic applications include cartilage and bone repair, meniscus repair/replacement, artificial spinal discs, artificial tendons and ligaments, and bone defect filler.

The shape retentive property of the aggregates herein suggests numerous other in vivo uses. For example, a medicated or unmedicated aggregate could be molded into a soft contact lens. A wound dressing or skin donor site dressing, with or without incorporated antibiotics or other drugs, could be fabricated from the present aggregates. An aggregate could be formed into an in-dwelling medicated or non-medicated catheter or stent. Numerous other such uses will become apparent to those skilled in the art based on the disclosure herein and are within the scope of this invention.

Other uses for the aggregates of this invention include using a mixture of particles, some of which will degrade over a predetermined time interval, in applications that require a change in material morphology with time. Also, aggregates composed of a mixture of hydrogel particles and other types of particles, such as metals, radioactive particles, semiconductors, non-hydrogel-forming polymers, ceramics, colorants, UV and IR filters, radiopaque materials, and the like.

For example, without limitation, metals could be entrapped in the hydrogel particles, in the voids in the aggregate or both. The metals would confer varying degrees of conductivity on the aggregates. The metals may also be incorporated as ions, that is, metals in oxidation states other than zero. Once again, these ions can also confer degrees of conductivity on the aggregates. To the contrary, the hydrogel particles or the aggregates may be infused with semiconductor metals or compounds. Shape retentive semiconductor aggregates or even aggregates with some hydrogel particles that are semi-conducting by virtue of incorporation of semiconductor materials and some of which are conducting by incorporation of metals should find use in MEMS (MicroElectroMechanical System) and NEMS (NanoElectroMechanical System) devices. Entrapment of magnetic materials such as magnetic polymers or magnetic metal particles could afford a three dimensional computer memory device. Incorporation of polynucleotide segments in the particles of an aggregate could lead to three-dimensional array analytical tools for use in the biotechnology industry. These and may other uses for the shape-retentive aggregates of this invention will become apparent to those skilled in the art based on the disclosures herein. Such uses are within the scope of this invention.

Claim 1 of 19 Claims

1. A method for preparing a shape-retentive hydrogel aggregate composition comprising: (a) adding a monomer or two or more different monomers selected from the group consisting of a 2-alkenoic acid, a hydroxy(2C-4C)alkyl 2-alkenoate, a hydroxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate, a (IC-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate and a vicinyl epoxy(1C-4C)alkyl 2-alkenoate to one or more liquid(s) having one or more hydroxyl groups; (b) adding from 0.1 to 15 mole percent of a cross-linking agent and from 0.01 to 10 mol percent of a surfactant to the liquid(s), where said surfactant is sodium dodecyl sulfaofate; (c) polymerizing the monomers to form a suspension in the liquid(s) of a plurality of hydrogel particles comprising a plurality of polymeric strands, wherein the hydrogel particles have an average diameter of less than 1,000 nanometers, and from 10 to 90% of absorbed liquids(s); and (d) removing non-absorbed liquids until the plurality of hydrogel particles coalesce into a shape-retentive aggregate held together by non-covalent inter-particle and particle-liquid physical forces, thereby forming a shape-retentive hydrogel aggregate composition.

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