MXPA06012496A - Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use - Google Patents

Abstract

Crosslinkable compositions are provided that readily crosslinkin situto provide crosslinked biomaterials. The composition contains at least two biocompatible, non-immunogenic components having reactive groups thereon, with the functional groups selected so as to enable inter-reaction between the components, i.e., crosslinking. In one embodiment, a first component has nucleophilic groups and a second component has electrophilic groups. Additional components may have nucleophilic or electrophilic groups. Methods for preparing and using the compositions are also provided as are kits for delivery of the compositions. Exemplary uses for the crosslinked compositions include tissue augmentation, biologically active agent delivery, bioadhesion, and prevention of adhesions following surgery or injury.

Description

COMPOSITIONS AND SYSTEMS FOR FORMING BIOMATERIALS WITH CROSS LINKS AND ASSOCIATED METHODS OF PREPARATION AND USE Technical Field This invention relates generally to compositions and systems for forming crosslinked biomaterials, to crosslinked biomaterials prepared by this means, and to methods of using such compositions as, for example, bioadhesives for tissue augmentation, for prevention of surgical adhesions, for synthetic implant coating surfaces, and drug delivery matrices, for ophthalmic applications, for orthopedic applications, as sealants, as hemostats, and in other applications, as discussed herein and / or as appreciated by someone commonly experienced in the art.

Background of the Invention Much work has been devoted to the development of bioadhesive materials. US Patent No. 5,162,430 to Rhee et al. describes the use of collagen-synthetic polymer conjugates prepared by collagen covalently bonded to synthetic hydrophilic polymers such as various polyethylene glycol derivatives. In a related patent, US Pat. No. 5,328,955 as Rhee et al., Various activated forms of polyethylene glycol and various connections are described, which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties. US Patent No. 5,324,775 to Rhee et al. it also discloses synthetic hydrophilic polyethylene glycol conjugates, but the conjugates include naturally occurring polymers such as polysaccharides. EP 0 732 109 Al a Rhee discloses a cross-linked biomaterial composition which is prepared using a hydrophobic cross-linking agent, or a mixture of hydrophilic and hydrophobic cross-linking agents, where the preferred hydrophobic agents for cross-linking formation Cross-links include hydrophobic polymers that contain, or can be chemically derived to contain, two or more succinimidyl groups. US Patent No. 5,580,923 to Yeung et al. discloses adhesive surgical material comprising a substrate material and an anti-adhesion binder. The substrate material is preferably collagen and the binder preferably comprises at least one tissue reactive functional group and at least one substrate reactive functional group. US Patent No. 5,614,587 to Rhee et al. describes bioadhesives that comprise collagen that has its bonds cross-linked using a multifunctionally activated synthetic hydrophilic polymer. US Patent No. 5,874,500 to Rhee et al. discloses a crosslinked polymer composition comprising a component having multiple nucleophilic groups and other component having multiple electrophilic groups. The covalent bonds of the nucleophilic and electrophilic groups form a three-dimensional matrix that possesses a variety of medical uses including tissue adhesion, surface coating for synthetic implants, and drug delivery. More recent advances include the addition of a third component having nucleophilic or electrophilic groups, as described in US Pat. No. 6,458,889 to Trollsas et al. However, despite advances in technology, the need for improved cross-linked biomaterials that are easy to use and store persists. This need, as well as others, is satisfied by the present invention, which is a mixture of two components, each component having a core substituted with reactive groups, wherein the reactive groups in one component are capable of reacting with the reactive groups of the other component. . The components are essentially non-reactive in a dry medium, and react to form a three-dimensional matrix.

BRIEF DESCRIPTION OF THE INVENTION One aspect of the invention relates to a homogeneous dry powder composition composed of: a first component having a core substituted with m nucleophilic groups, where m = 2; and a second component having a nucleus substituted with n electrophilic groups, where n 2 and m + n > 4; where the nucleophilic and electrophilic groups are not reactive in a dry medium but become reactive when exposed to an aqueous medium so that the components inter-react in the aqueous medium to form a three-dimensional matrix. A pharmaceutically acceptable carrier can also be included. In one embodiment of the homogeneous dry powder composition, the nucleophilic and electrophilic groups undergo a nucleophilic substitution reaction, a nucleophilic addition reaction, or both. The nucleophilic groups can be selected from -NH2, -NHR1, -N (R1) 2, -SH, -OH, -COOH, -C6H4-OH, -H, -PH2, -PHR1, -P (R1) 2, -NH-NH2, -CO-NH-NH2, and -C5H4N, where R1 is a hydrocarbyl group, and each R1 may be the same or different. The electrophilic groups can be selected from -CO-Cl, - (CO) -O- (CO) -R (where R is an alkyl group), -CH = -CH-CH = 0 and -CH = CH- C (CH3) = 0, halo, -N = C = 0, -N = C = S, -S02CH = CH2, -O (CO) -C = CH2, ~ 0 (CO) -C (CH3) = CH2 , -SS- (C5H4N), -0 (CO) -C (CH2CH3) = CH2, -CH = CH-C = NH, -COOH, - (CO) O- (COCH2) 2, -CHO, - (CO) 0-N (COCH2) 2 -S (0) 20H, and -N (COCH) 2. In another embodiment of the homogeneous dry powder composition, the nucleophilic groups are amino groups and the electrophilic groups are amino-reactive groups. The amino-reactive groups may contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine. The amino-reactive groups may be selected from carboxylic acid esters, acid chloride groups, anhydrides, ketones, aldehydes, halo, isocyanate, thioisocyanate, epoxides, activated hydroxyl groups, olefins, carboxyl, succinimidyl ester, sulfoester succinimidyl, maleimido , epoxy, and ethenesulfonyl. In yet another embodiment of the homogeneous dry powder composition, the nucleophilic groups are sulfhydryl groups and the electrophilic groups are sulfhydryl reactive groups. The sulfhydryl-reactive groups may be selected so as to form a thioester, imido thioester, thioether, or bisulphide linkage by reacting with the sulfhydryl groups. Where sulfhydryl-reactive groups form a bisulfide bond, they may have the structure -S-S-Ar where Ar is a heteroaromatic moiety containing substituted or unsubstituted nitrogen or a non-heterocyclic aromatic group substituted with a moiety that yields electrons. Where the sulfhydryl-reactive groups form a thioether linkage, they may be selected from maleimido, substituted maleimido, haloalkyl, epoxy, imino, aziridino, olefins, and α, 3-unsaturated aldehydes and ketones. The sulfhydryl-reactive groups can be selected from mixed anhydrides; phosphorus ester derivatives; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters; 1-hydroxybenzotriazole esters; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydroquinazolin-4-one; carbonylimidazole derivatives; acid chlorides; Ketenes; and isocyanates. In yet another embodiment of the homogeneous dry powder composition, the number of nucleophilic groups in the mixture is approximately equal to the number of electrophilic groups in the mixture. For example, the ratio of moles of nucleophilic groups to moles of electrophilic groups can be from about 2: 1 to 1: 2, with a preferred 1: 1 ratio. In a further embodiment of the homogeneous dry powder composition, the core is selected from hydrophilic polymers, hydrophobic polymers, polymers amphiphilic, C2-14 hydrocarbyl, and C2-14 hydrocarbyls containing heteroatoms. Where the core is a hydrophilic polymer, the core can be a synthetic or natural hydrophilic polymer. The hydrophilic polymer may be a linear, branched, dendrimer, hyperbranched or star polymer.

The hydrophilic polymer can be selected from polyalkylene oxides; polyols; poly (oxyalkylene) -substituted diols and polyols; polyoxyethylated sorbitol; polyoxyethylated glucose; poly (acrylic acids) and analogs and copolymers thereof; polymaleic acids; polyacrylamides; poly (olefinic alcohols); poly (N-vinyl lactam); polyoxazolines; polyvinylamines; and copolymers thereof. The hydrophilic polymer can also be selected from proteins, carboxylated polysaccharides, amino polysaccharides, and activated polysaccharides, such as, for example, collagen and glycosaminoglycans. Where the hydrophilic polymer is a polyalkylene oxide or polyols, the hydrophilic polymer can be selected from polyethylene glycol and copolymers of poly (ethylene oxide) -poly (propylene oxide). Where the hydrophilic polymer is polyols, the hydrophilic polymer can be selected from glycerol, polyglycerol and propylene glycol. Where the hydrophilic polymer is a polyol poly (oxyalkylene) -substituted, the hydrophilic polymer can be selected from mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and trimethylene glycol mono- and di-polyoxyethylated. Where the hydrophilic polymer is a poly (acrylic acid), analog or copolymer thereof, the hydrophilic polymer may be selected from poly (acrylic acid), poly (methacrylic acid), poly (hydroxyethyl methacrylate), poly (hydroxyethyl acrylate), poly (methylalkylsulfoxide acrylates), and poly (methylalkylsulfoxide methacrylates). Where the hydrophilic polymer is a polyacrylamide, the hydrophilic polymer can be selected from polyacrylamide, poly (methacrylamide), poly (dimethylacrylamide), poly (N-isopropylacrylamide), and copolymers thereof. Where the hydrophilic polymer is a poly (olefinic alcohol), the hydrophilic polymer can be selected from poly (vinyl alcohols) and copolymers thereof. Where the hydrophilic polymer is a poly (N-vinyl lactam), the hydrophilic polymer can be selected from poly (vinyl pyrrolidones), poly (vinyl caprolactams), and copolymers thereof. Where the hydrophilic polymer is a polyoxazoline, the hydrophilic polymer can be selected from poly (methyloxazoline) and poly (ethyloxazoline).

Where the core is a selected hydrophobic polymer, the core can be selected from polylactic acid and polyglycolic acid. Where the core is a C2-14 hydrocarbyl, the core can be selected from alkanes, diols, polyols, and polyacids. Where the core is a C 2-14 hydrocarbyl containing heteroatom, the core can be selected from di- and poly-electrophiles. In another embodiment of the homogeneous dry powder composition, the first component has the structure of formula (I) (I) [X- (Ll) p] mR, and the second component has the structure of formula (II) [ Y- (L2) q] n -R ', where m and n are integers from 2-12 and m + n > 4; R and R 'are independently selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C2-14 hydrocarbyls, and C2-14 hydrocarbyls containing heteroatoms; X is a nucleophilic group; And it's an electrophilic group; Ll and L2 are union groups; and p and q are integers from 0-1. The components can interreact to form covalent bonds, non-covalent bonds, or both. Non-covalent links include ionic bonds, hydrogen bonds, or the association of hydrophobic molecular segments. In a preferred embodiment, all molecular segments are the same. The homogeneous dry powder composition may further comprise a biologically active agent with or without a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be a micelle, a microsphere, or a nanosphere. Where the pharmaceutically acceptable carrier is a microsphere or a nanosphere, the pharmaceutically acceptable carrier can be a degradable polymer, such as polyester, and the polyester can be a glycolide / lactide copolymer. The degradable polymer can also be composed of residues of one or more monomers selected from the group consisting of lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone. , gaitimavalerolactone,? -decanolactone, d-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1, 5-dioxepan-2one. ). The homogeneous dry powder composition may further comprise a biologically active agent.

In one embodiment of the invention, the homogeneous dry powder composition further comprises a biologically active agent which is an antifibrotic agent. As used in the homogeneous dry powder composition, the anti-fibrotic agent can be used to inhibit any of the following: cell regeneration, angiogenesis, fibroblast migration, fibroblast proliferation, extracellular matrix deposition, tissue remodeling, adenosine deaminase, purine ring synthesis, dihydrofolate reduction, synthesis or function of ribonucleotidosynthesis or thymidine monophosphate function, DNA synthesis, protein synthesis and microtubular function. The antifibrotic agent can also be used to block thymidine monophosphate, cause DNA damage, and cause adduction to DNA. Any of the following antifibrotic agents can be used in the homogeneous dry powder composition: an angiogenesis inhibitor; an inhibitor or 5-lipoxygenase antagonist; a chemokine receptor antagonist; a cell cycle inhibitor; a taxane; an antimicrotubular agent; paclitaxel; an analog or derivative of paclitaxel; a vinca alkaloid; camptothecin or an analogue or derivative thereof; to podophyllotoxin, where podophyllotoxin can be an etoposide or an analog or derived from them; an anthracycline, wherein the anthracycline can be doxorubicin or an analogue or derivative thereof or the anthracycline can be mitoxantrone or an analogue or derivative thereof; a platinum compound; a nitrosourea; a nitroimidazole; a folate antagonist; a cytidine analogue; a pyrimidine analogue; a pyrimidine fluoroanalog; a purine analogue; a nitrogen mostase or an analogue or derivative thereof; a hydroxyurea; a mitomycin or an analogue or derivative thereof; an alkyl sulfonate; a benzamide or an analogue or derivative thereof; a nicotinamide or an analogue or derivative thereof; a halogenated sugar or an analogue or derivative thereof; a DNA alkylating agent; an anti-microtubule agent; a topoisomerase inhibitor; an agent of adhesion to DNA; an antimetabolite; a nucleotide interconversion inhibitor; a hydroorotate dehydrogenase inhibitor; an agent for DNA intercalation; an inhibitor of RNA synthesis; a pyrimidine synthesis inhibitor; a cyclin-dependent protein kinase inhibitor; an epidermal growth factor kinase inhibitor; an elastase inhibitor; a factor Xa inhibitor; a farnesyltransferase inhibitor; a fibrinogen antagonist; a guanylate cyclase stimulant; a heat shock protein 90 antagonist; which can be a geldanamycin or an analog or derivative of the same; a guanylate cyclase stimulant; a reductase inhibitor HMGCoA, which may be simvastatin or an analogue or derivative thereof; an IKK2 inhibitor; an antagonist gives IL-1; an ICE antagonist; an IRAK antagonist; an IL-4 agonist; an immunomodulatory agent; sirolimus or an analogue or derivative thereof; everolimus or an analogue or derivative thereof; tacrolimus or an analogue or derivative thereof; biolmus or an analogue or derivative thereof; tresperimus or an analogue or derivative thereof; auranofin or an analogue or derivative thereof; 27-0-demethylrapamycin or an analogue or derivative thereof; gusperimus or an analogue or derivative thereof; pimecrolimus or an analogue or derivative thereof; ABT-578 or an analogue or derivative thereof; an inhibitor of inosine monophosphate dehydrogenase (IMPDH), which may be a mycophenolic acid or an analog or derivative thereof or l-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof; a leukotriene inhibitor; an MCP-1 antagonist; an MMP inhibitor; an NF kappa B inhibitor, which may be Bay 11-7082; a NO antagonist; a p38 MAP kinase inhibitor, which may be SB 202190; a phosphodiesterase inhibitor; a TGF beta inhibitor; an A2 thromboxane antagonist; a TNF alpha antagonist; a TACE inhibitor; a tyrosine kinase inhibitor; a vitronectin inhibitor; an inhibitor of fibroblast growth factor; a protein kinase inhibitor; a PDGF receptor kinase inhibitor; an inhibitor of endothelial growth factor receptor kinase; a retinoic acid receptor antagonist; a platelet-derived growth factor receptor kinase inhibitor; a fibrinogen antagonist; an antifungal agent; sulconazole; a bisphosphonate; an Al inhibitor of phospholipase; an H1 / H2 / H3 receptor antagonist histamine; a macrolide antibiotic; a GPIIb / lIIa receptor antagonist; an endothelial receptor antagonist; a peroxisome proliferator-activated receptor antagonist; an estrogen receptor agent; a somatostatin analogue; a neurokinin 1 antagonist; a neurokinin 3 antagonist; a VLA-4 antagonist; an osteoclast inhibitor; a DNA topoisomerase ATP hydrolyzing inhibitor; an angiotensin converting enzyme inhibitor; an angiotensin II antagonist; an enkephalinase inhibitor; a gamma-isosin sensitizer of proliferator-activated peroxisome receptor; a protein kinase C inhibitor; a ROCK inhibitor (rho-associated kinase); a CXCR3 inhibitor; an Itk inhibitor; an inhibitor of cytosolic phospholipase A2-alpha; a PPAR antagonist; an immunosuppressant; an Erb inhibitor; an antagonist of apoptosis; an antagonist of lipocortin; a VCAM-1 antagonist; a collagen antagonist; an alpha 2 integrin antagonist; a TNF inhibitor; a nitric oxide inhibitor and a cathepsin inhibitor. In another embodiment of the invention, the homogeneous dry powder composition further comprises a biologically active agent which is a fibrosing agent. As used in the homogeneous dry powder composition, the anti-fibrotic agent can be used to promote any of the following; regeneration; angiogenesis; migration of fibroblasts; proliferation of fibroblasts; extracellular matrix deposition (ECM); and tissue remodeling. The fibrosing agent can also be used as an irritant of the arterial vessel wall. Fibrosing agents that can be used in the homogeneous dry powder composition can be or can be composed of silk; silkworm silk; spider silk; recombinant silk; raw silk; hydrolyzed silk; silk treated with acid; aciloda silk; mineral particles; talcum powder; cytosan; polylysine; fibronectin; Bleomycin; or CTGF. The fibrosing agent may also be in the form of a particulate, which may be a biodegradable particulate or a non-biodegradable particulate. Particulate biodegradable can be understood from a material selected from the group consisting of polyester, polyanhydride, poly (anhydride ester), poly (ester-amide), poly (ester-urea), polyorthoester, polyphosphoester, polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaloronic acid, chromic catgut, alginate, starch, cellulose and cellulose ester. Non-particulate biodegradable can be comprised of a material selected from a group consisting of polyester, polyurethane, silicon, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylate, and silk. Examples of preferred particulates may be a particulate form of a member selected from the group consisting of silk, talc, starch, glass, silicate, silica, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethyl methacrylate, nitrate silver, ceramic and other inorganic particles. In a further embodiment of the homogeneous dry powder composition, the biologically active agent promotes bone growth. Within this embodiment, the fibrosing agent can promote bone growth. Fibrosing agents that can promote bone growth may include a bone morphogenic protein and an osteogenic growth factor, the latter being able to be selected from growth factor of transformation, platelet-derived growth factor, and fibroblast growth factor. In another embodiment of the invention, the homogeneous dry powder composition with a fibrosing agent further comprises a pharmaceutical agent that induces sclerosis (a sclerosing agent), wherein the sclerosing agent can be a surfactant or can be selected from the group consisting of ethanol , dimethyl sulfoxide, sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morruate, and sotradecol. In a further embodiment of the invention, the homogeneous dry powder composition with a fibrosing agent further comprises an inflammatory cytokine, which can be selected from the group consisting of TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM- CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone. In yet another embodiment of the invention, the dry powder composition homogenous with a fibrosing agent further comprises an agent that stimulates cell proliferation, which can be selected from the group consisting of dexamethasone, isotretinoin (13-cis retinoic acid ), 17-ß-estradiol, estradiol, la-25 dihydroxyvitamin D3, diethylstibesterol, cyclosporin A, L- ÑAME, all-trans retinoic acid (ATRA), and analogs and derivatives thereof. In a further embodiment of the homogeneous dry powder composition, the biologically active agent is mixed with the first and second components to form a mixture. In another embodiment of the homogeneous dry powder composition, the biologically active agent is chemically coupled to the first component or to the second component. Another aspect of the invention relates to a cross-linkable composition composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected from the group consisting of amino acids comprising primary amino groups and amino acids comprising thiol groups, the second component comprises a polyethylene glycol moiety, and each of the first and second components capable of cross-linking is biocompatible, synthetic, and non-immunogenic, and also where the formation of links Crosses of the composition result in a biocompatible, non-immunogenic, cross-linked matrix. Any of the following are preferred embodiments of the crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. In a preferred embodiment, the selected amino acid residues are lysine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. In another preferred embodiment, the amino acid residues selected are cysteine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. Still another aspect of the invention relates to a crosslinkable composition composed of: (a) a first crosslinkable component with m nucleophilic groups, where m = 2; and (b) a second cross-linked component with n groups electrophilic capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected from the group consisting of amino acids comprising primary amino groups and amino acids comprising thiol groups , the second component comprises a polyethylene glycol moiety, the electrophilic moieties are succinimidyl moieties, and each of the first and second components capable of cross-linking is biocompatible, synthetic, and non-immunogenic, and furthermore where the cross-linking of the composition results in a biocompatible, non-immunogenic, cross-linked matrix. Any of the following are preferred embodiments of the crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. In a preferred embodiment, the selected amino acid residues are lysine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical.

In another preferred embodiment, the amino acid residues selected are cysteine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. Yet another aspect of the invention relates to a crosslinkable composition composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected of the group consisting of amino acids comprising primary amino groups and amino acids comprising thiol groups, the second component comprises a polyethylene glycol multifunctionally activated, and each of the first and second crosslinkable components is biocompatible, synthetic, and non-immunogenic, and also where cross-linking of the composition results in a biocompatible, non-immunogenic, cross-linked matrix.

Any of the following are preferred embodiments of the crosslinkable composition described immediately above: m >; 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, the multifunctionally activated polyethylene glycol is tetrafunctionally activated polyethylene glycol, and the polyethylene glycol is multifunctionally activated It is a star-branched polyethylene glycol. In a preferred embodiment, the selected amino acid residues are lysine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, and the multifunctionally activated polyethylene glycol is tetrafunctionally activated polyethylene glycol or the polyethylene glycol multifunctionally activated it is a star-branched polyethylene glycol. In another preferred embodiment, the amino acid residues selected are cysteine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, and polyethylene Multifunctionally activated glycol is tetrafunctionally activated polyethylene glycol or the multifunctionally activated polyethylene glycol is a star-branched polyethylene glycol. Another aspect of the invention relates to a method of forming a three-dimensional matrix comprising the steps of: (a) providing a composition of the invention; and (b) making the reactive nucleophilic and electrophilic groups by exposing the composition to an aqueous medium to effect the inter-reaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution with a pH within the range of about 6.0 to 11.0 to the homogeneous solution; and (c) allow a three-dimensional matrix to be formed. A preferred composition for use in this method is the homogeneous dry powder composition. The three-dimensional matrix of the invention described immediately above can be formed without input of any external energy or by polymerization. In a preferred embodiment, the pH of the first buffer solution is selected to retard the reactivity of nucleophilic groups in the first component by rendering the nucleophilic groups relatively non- nucleophilic In this preferred embodiment, the second buffer solution neutralizes the effect of the first buffer solution, so that the nucleophilic groups of the first component recover their nucleophilic character and interreact with the electrophilic groups of the second component. In another preferred embodiment, the composition, first buffer solution and second buffer solution are housed separately multi-compartment syringe system having multiple drums, a mixing head, and an exit orifice; step (b) (i) comprises adding the first buffer solution to the cylinder housing the composition to dissolve the composition and form a homogeneous solution, and extruding the homogeneous solution towards the mixing head; step (b) (ii) comprises simultaneously extruding the second buffer solution towards the mixing head; and step (c) further comprises extruding the resulting composition through the hole on a surface. Yet another aspect of the invention relates to a method of sealing tissue of a patient comprising the steps of: (a) providing a composition of the invention; (b) making the reactive nucleophilic and electrophilic groups by exposing the composition to an aqueous medium to effect interreaction; where said exposure it comprises: (i) dissolving the composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution with a pH within the range of about 6 0 to 11.0 to the homogeneous solution to form a mixture; and (c) placing the mixture in contact with tissue and allowing a three-dimensional matrix to form and seal the tissue. A preferred composition for use in this method is the homogeneous dry powder composition. Yet another aspect of the invention relates to a method of avoiding adhesions between tissues of a patient comprising the steps of: (a) providing a composition of the invention; (b) making the reactive nucleophilic and electrophilic groups by exposing the composition to an aqueous medium to effect interreaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution with a pH within the range of about 6.0 to 11.0 to the homogeneous solution to form a mixture; and (c) placing the mixture in contact with tissue and allowing a three-dimensional matrix to form on the tissue. A preferred composition for use in this method is the homogeneous dry powder composition.

Another aspect of the invention relates to a method of forming a three-dimensional matrix on the surface of a device comprising the steps of: (a) providing a composition of the invention; and (b) making the nucleophilic and electrophilic reactive groups by exposing the composition to an aqueous medium to effect interreaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution with a pH within the range of about 6.0 to 11.0 to the homogeneous solution; and apply the homogeneous solution to the surface of a device; and let the three-dimensional matrix form. A preferred composition for use in this method is the homogeneous dry powder composition.

Another aspect of the invention relates to a method of preventing scarring in the vicinity of a medical implant comprising the steps of: (a) providing a composition of the invention; and (b) making the nucleophilic and electrophilic reactive groups by exposing the composition to an aqueous medium to effect interreaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second solution buffer with a pH within the range of about 6.0 to 11.0 to the homogeneous solution to form a mixture; and applying the mixture to the surface of a medical implant and allowing a three-dimensional matrix to form on the surface of the medical implant; and (d) placing the medical implant in an animal host, where the antifibrotic agent of the composition is allowed to inhibit cicatrization in the animal host. In one embodiment, the antifibrotic agent is released into the tissue in the vicinity of the implant after deployment of the implant. A preferred composition for use in this method is the homogeneous dry powder composition with an antifibrotic agent. Yet another aspect of the invention relates to a method of promoting healing in the vicinity of a medical implant comprising the steps of: (a) providing a composition of the invention; and (b) making the nucleophilic and electrophilic reactive groups by exposing the composition to an aqueous medium to effect interreaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution with a pH within the range of about 6.0 to 11.0 to the homogeneous solution; and (c) apply the mixture to the surface of a medical implant and allowing a three-dimensional matrix to form on the surface of the medical implant; and (d) placing the medical implant in an animal host, where the fibrotic agent of the matrix is allowed to inhibit healing in the animal host. In a preferred embodiment, the fibrotic agent is released into the tissue in the vicinity of the implant after deployment of the implant. A preferred composition for use in this method is the homogeneous dry powder composition with a fibrosing agent. Another aspect of the invention relates to a kit for use in medical applications, comprising: (a) a homogeneous dry powder composition composed of: (i) a first component having a core substituted with m nucleophilic groups, where m = 2; and (ii) a second component having a core substituted with n electrophilic groups, where n = 2 and m + n > 4; where the nucleophilic and electrophilic groups are not reactive in a dry medium but become reactive when exposed to an aqueous medium so that the components inter-react in the aqueous medium to form a three-dimensional matrix; (b) a first buffer solution with a pH within the range of about 1.0 to 5.5; and (c) a second buffer solution with a pH within the range of about 6.0 to 11.0; where each component is packed separately and mixed immediately before use. It is preferred, of course, that before use, each component is in individual sterile packaging. Another aspect of the invention relates to a kit for use in medical applications, comprising: (a) a composition of the invention; (b) a first buffer solution with a pH within the range of about 1.0 to 5.5; and (c) a second buffer solution with a pH within the range of about 6.0 to 11.0, where each component is packaged separately and mixed immediately before use. A preferred composition of the invention for use in this kit is a homogeneous dry powder composition. It is preferred that each component of the kit be in individual sterile packaging. The kit may further comprise an administration device, which in one embodiment, may be a multi-compartment device. A preferred multi-compartment device of the invention is a multi-compartment syringe system having multiple cylinders, a mixing head, and an exit orifice. Where the kit is a multi-compartment syringe system, a homogeneous dry powder composition, the first buffer solution, and the second buffer solution are housed separately in the multi-compartment syringe system.

In another embodiment of the invention, the delivery device is a pressurized delivery system. A preferred pressurized delivery system comprises: a plurality of fluid component inputs each adapted to communicate with a source of different fluid components; at least one carrier fluid inlet adapted to communicate with a source of a pressurized carrier fluid; a diffusing surface located downstream of the plurality of fluid component inlets and at least one fluid carrier inlet; and an outlet that extends through the diffusing surface, where the diffusing surface is adapted to receive fluid components therein and has an effective way to direct and maintain each received fluid component in a different flow path to the mixing outlet and dispensing them through the pressurized carrier fluid from at least one fluid carrier inlet. Within this embodiment, a preferred pressurized carrier fluid is pressurized air and the preferred fluid components are the first buffer solution and the second buffer solution of the invention. Another embodiment of the kit for use in medical applications also comprises a biologically active agent and the medical application includes administration of the agent biologically active The biologically active agent can be packaged with a homogeneous dry powder composition and can further comprise a pharmaceutically acceptable carrier packaged with the biologically active agent and a homogeneous dry powder composition. The biologically active agent can also be packaged as a solution with the first buffer or as a solution with the second buffer. The kit may further comprise a pharmaceutically acceptable carrier as a fourth component. The biologically active agent is packed with the pharmaceutically acceptable carrier. Yet another embodiment of the kit for use in medical applications also comprises living cells or genes, and the medical application includes the administration of living cells or genes. Other medical applications of the kit can be used to include adhering or sealing biological tissue, bioadhesion, ophthalmic applications, tissue augmentation, adhesion prevention, synthetic implant formation or synthetic implant coating, aneurysm treatment, and laparoscopic procedures. Still another aspect of the invention relates to a kit for use in medical applications, comprising: (a) a first component having a core substituted with m nucleophilic groups, where m = 2; (b) a second componenthaving a nucleus substituted with n electrophilic groups, where n > 2 and ra + n > 4; (c) a first buffer solution with a pH within the range of about 1.0 to 5.5; and (d) a second buffer solution with a pH in the range of about 6.0 to 11.0, where the nucleophilic and electrophilic groups are not reactive in a dry medium but become reactive when exposed to an aqueous medium so that the components inter-react in the aqueous medium to form a three-dimensional matrix and in addition where each component is packed separately and mixed immediately before use. These and other aspects of the present invention are described in detail below.

BRIEF DESCRIPTION OF THE DRAWINGS FIG 1 discloses a multi-compartment syringe device of the present invention. FIGS. 2 and 3 schematically illustrate an embodiment of the pressurized delivery device of the present invention that includes a cover having an interior diffusing surface and a set of openings for delivering fluid components and a pressurized carrier fluid to the diffusing surface. FIG. 1 describes the device in expanded view and FIG. 2 describes the interior diffusing surface of the cover.

Detailed description of the invention I. Definitions and Nomenclature Before describing the present invention in details, it should be understood that, unless otherwise indicated, this invention is not limited to particular forms of composition; cross-linked components, cross-linking techniques, or methods of use, as such may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. It should be noted that, as used in this specification and appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, "a multifunctional compound" refers not only to a simple multifunctional compound, but also to a combination of two or more of the same or different multifunctional compounds, "a reactive group" refers to a combination of groups reagents as well as a simple reactive group, and so on. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by someone ordinarily experienced in the technique to which the invention belongs. Although any methods and materials similar or equivalent to those described herein may be useful in the practice or testing of the present invention, preferred methods and materials are described below. Specific terminology of particular importance for the description of the present invention is defined below. The terms "inter-react" and "inter-reaction" as used herein refer to the formation of covalent bonds, non-covalent bonds, or both. The term therefore includes cross-linking formation, which includes crossed intermolecular bonds and optionally crossed intramolecular bonds as well, arising from the formation of covalent bonds. Interlacing is another example of non-covalent bond that can result after inter-reaction between two or more reactive groups. Covalent encases between two reactive groups can be direct, in which case one atom in reactive group is directly linked to one atom in the other reactive group or can be indirect through a linking group.

Non-covalent bonds include ionic bonds (electrostatic), hydrogen bonds, or the association of hydrophobic molecular segments, which may be the same or different. A matrix of cross-links can, in addition to covalent bonds, also include intermolecular and / or intramolecular non-covalent bonds. When referring to polymers, the terms "hydrophilic" and "hydrophobic" are generally defined in terms of an HLB value, that is, a lipophilic hydrophilic balance. A high HLB value indicates a hydrophilic compound, while a low HLB value denotes a hydrophobic compound. HLB values are well known in the art, and generally range from 1 to 18. Preferred nuclei of multifunctional compounds are hydrophilic, although while the multifunctional compound as a whole contains at least one hydrophilic component, hydrophobic components cross-linkable they can also be present. The term "polymer" is used not only in the conventional sense to refer to molecules composed of repeating monomer units, including homopolymers, block copolymers, random copolymers, and grafted copolymers, but also refers to polyfunctional small molecules that do not contain units of repeated monomers but they are "polymeric" in the sense of being "polyfunctional", that is, they contain two or more functional groups. Consequently, it will be appreciated that when the term "polymer" is used, small difunctional and polyfunctional molecules are included. Such halves include, by way of example: the electrophiles difunctional disuccinimidyl suberate (DSS), bis (sulfosuccinimidyl) suberate (BS3), dithiobis (succinimidylpropionate) (DSP), bis (2-succinimidooxy-carbonyloxy) ethyl sulfone (BSOCOES), 3,3'-dithiobis (sulfosuccinimidylpropionate (DTSSP); and the di- and polyfunctional nucleophiles ethylene diamine (H2N-CH2-CH2-NH2), tetramethylene diamine (H2N- [CH2] 4-NH2), pentamethylene diamine (cadaverine) (H2N- [CH2] 5-NH2), hexamethylene diamine ( H2N- [CH2] 6-NH2), bos (2-aminoethyl) amine (HN- [CH2-CH2-NH2] 2), and tris (2-aminoethyl) amine (N- [CH2-CH2-NH2] 3) , as well as the thiol analogues thereof All of the polymers suitable herein are biocompatible and non-immunogenic Polymers can be degradable or non-degradable In a preferred mode, the polymers will be essentially non-degradable in vivo during a period of at least several months The term "synthetic" is used to refer to polymers, compounds and other such materials that are "synthesized" s chemically. "For example, a synthetic material in the present compositions may have a molecular structure that is identical to a natural stock, but the material per se, as incorporated in the compositions of the invention, has been chemically synthesized in the laboratory or industrially.

"Synthetic" materials also include semi-synthetic materials, that is, materials of natural existence, obtained from a natural source, which have been chemically modified in some way. Generally, however, the synthetic materials herein are purely synthetic, that is, they are not semi-synthetic they have a structure identical to that of natural existence materials. The term "effective amount" refers to the amount of composition required to obtain the desired effect. For example, an "amount that promotes tissue growth" of a composition refers to the amount necessary to stimulate tissue growth to a detectable degree. Tissue, in this context, includes connective tissue, bone, cartilage, epidermis and dermis, blood, and other tissues. The actual amount that is determined to be an effective amount will vary depending on factors such as the size, condition, sex and age of the patient and can be more easily determined by the health professional. The term "in situ" as used herein means at the site of administration. Therefore, compositions of the invention can be injected or otherwise applied to a specific place within the body of a patient, for example, a place in need. of increase, and left to form cross-links at the injection site. Appropriate sites will generally be intradermal or subcutaneous regions to increase dermal support, at the site of a fracture, that is, for bone repair, within sphincter tissue for sphincter augmentation (e.g., for continence restoration), within a wound or suture, to promote tissue re-growth; and within or adjacent to vessel anastomoses, to promote vessel re-growth. The term "aqueous medium" includes solutions, suspensions, dispersions, colloids, and so forth that contain water. The term "aqueous environment" means an environment containing an aqueous medium. Similarly, the term "dry environment" means an environment that does not contain an aqueous medium. The terms "active agent," "biologically active agent," "therapeutic agent," "pharmacologically active agent," and "drug" are used interchangeably herein to refer to a material or chemical compound suitable for administration to a patient and which induces the desired effect. The terms include agents that are therapeutically effective as well as prophylactically effective. Also included are derivatives and analogues of those compounds or classes of compounds specifically mentioned that also induce the desired effect.

As used herein, the terms "active agent," "biologically active agent," "therapeutic agent," "pharmacologically active agent," and "drug" refer to an organic molecule that exerts biological effects in vivo. For the purposes of this discussion, the term "biologically active agent" is used, with the understanding that the use of this term does not exclude the application of the remaining terms. Examples of biologically active agents include, by way of example and without limitation, enzymes, antagonists or agonists of receptors, hormones, growth factors, autogenous bone marrow, antibiotics, antimicrobial agents and antibodies. The term "biologically active agent" is also intended to encompass several types of cells and genes that can be incorporated into the compositions of the invention. Other examples of biologically active agents include those that inhibit fibrosis and those that promote fibrosis. In certain embodiments, a biologically active agent can promote adhesion between a tissue and a substrate (e.g., the surface of a medical device). "Fibrosis," "scarring," or "fibrotic response" refers to the formation of fibrous tissue in response to injury or medical intervention. Therapeutic agents that promote (also called indistinctly in the present as "induce," "stimulate," "cause," and so on) fibrosis or scarring are indistinctly referred to herein as "fibrosis-inducing agents," "scarifying agents," "fibrousing agents," "adhesion-inducing agents," "and so on, where these agents do this through one or more mechanisms including: inducing or promoting angiogenesis, stimulating migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), inducing ECM production, and / or promoting tissue remodeling. Therapeutic agents that inhibit fibrosis or scarring are referred to herein as "fibrosis inhibiting agents", "anti-scarring agents", and so on, where these agents inhibit fibrosis through one or more mechanisms including: inhibiting angiogenesis, inhibiting migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), reducing the production of ECM, and / or inhibiting tissue remodeling. "Sclerosing" refers to a tissue reaction in which an irritant is applied locally to a tissue that results in an inflammatory reaction and is followed by formation of scar tissue at the site of irritation. An agent Pharmaceutical that induces or promotes sclerosis is called as a "sclerosing," or a "sclerosing agent." Representative examples of sclerosants include ethanol, dimethyl sulfoxide, surfactants (e.g., Triton X, sorbitan monolaurate, sorbitan sesquioleate, glycerol monostearate and polyoxyethylene, polyoxyethylene cetyl ether, and so forth), sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tertadecyl sulfate, sodium morruate, ethanolamine, phenol, sarapin and sotradecol. "Anti-microtubule agent" should be understood to include any protein, peptide, chemical, or other molecule that impedes the function of microtubules, for example, through the prevention or stabilization of polymerization. Compounds that stabilize microtubule polymerization are referred to herein as "microtubule stabilizing agents." A wide variety of methods can be used to determine the anti-icrotubule activity of a particular compound, including for example, assays described by Smith et al. (Cancer Lett 79 (2): 213-219, 1994) and Mooberry et al., (Cancer Lett 96 (2): 261-266, 1995). The terms "medical device," "implant," "medical implant," and so on are used synonymously to refer to any object that is intended to be placed partially or wholly within the scope of the invention. body of a patient for one or more therapeutic or prophylactic purposes, such as to restore physiological function, alleviate symptoms associated with disease, administer therapeutic agents, and / or repair or replace or augment damaged or diseased organs and tissues. Although normally biologically compatible synthetic materials (for example, medical grade stainless steel, titanium and other metals, polymers such as polyurethane, silicon, PLA, PLGA and other materials) are exogenous, some medical devices and implants include derived materials of animals (eg, "xenografts" such as complete organs of animals; animal tissues such as heart valves; natural or chemically modified molecules such as collagen, hyaloronic acid, proteins, carbohydrates, and others), human donors (e.g., " allografts "such as whole organs; tissues such as bone grafts, skin grafts and others), or from the patients themselves (for example," autografts "such as saphenous vein grafts, skin grafts, tendon / ligament transplants / muscle). With respect to the nomenclature pertaining to molecular structures, the following definitions apply: The term "alkyl" as used herein refers to a branched or non-branched saturated hydrocarbon group branched typically, although not necessarily containing from 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and so on, as well as alkyl cylogroups such as cyclopentyl, cyclohexyl and so on. Generally, although again not necessarily, group alkyls in the present contain 1 to about 12 carbon atoms. The term "lower alkyl" refers to an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups. "Alkylene," "lower alkylene," and "substituted alkylene" refer to divalent alkyl, lower alkyl, and substituted alkyl groups, respectively. The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring (monocyclic) or multiple aromatic rings that are fused together, covalently linked, or bonded to a common group such as a methylene or ethylene moiety. The common binding group can also be a carbonyl as in benzophenone, an oxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine. Preferred aryl groups contain an aromatic ring or two melted or bonded aromatic rings, for example, phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and so on. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl in which at least one carbon atom is substituted with a heteroatom The terms "arylene" and "substituted arylene" refer to divalent aryl and substituted aryl groups as defined herein. The term "heteroatom-containing" as in the "heteroatom-containing hydrocarbyl group" refers to a molecule or molecular fragment in which one or more carbon atoms are substituted with an atom other than carbon, eg, nitrogen, oxygen , sulfur, phosphorus or silicon. "Hydrocarbyl" refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, more preferably 1 to about 12 carbon atoms, including branched or non-branched, saturated or non-saturated, such as alkyls, alkenyl groups, aryl groups, and so on. The term "lower hydrocarbyl" refers to a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. The term "hydrocarbylene" is refers half divalent hydrocarbyl containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, more preferably 1 to about 12 carbon atoms, including branched or non-branched, saturated or unsaturated species, or similar. The term "lower hydrocarbylene" refers to a hydrocarbylene group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted hydrocarbyl" refers to hydrocarbyl substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbyl" and "heterohydrocarbyl" refer to hydrocarbyl in which at least one carbon atom is substituted with a heteroatom. Similarly, "substituted hydrocarbylene" refers to hydrocarbylene substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbylene" and "heterohydrocarbylene" refer to hydrocarbylene in which at least one carbon atom is substituted with a heteroatom . Unless otherwise indicated, "hydrocarbyl" denotes unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and heteroatom-containing substituted hydrocarbyl. Unless otherwise indicated, the terms "hydrocarbyl" and "hydrocarbylene" include substituted hydrocarbylene and substituted hydrocarbylene, heteroatom-containing hydrocarbyl and heteroatom-containing hydrocarbylene, and heteroatom-containing substituted hydrocarbyl and heteroatom-containing substituted hydrocarbylene, respectively. By "substituted" as in "substituted hydrocarbyl," "substituted alkyl," and so on, as alluded to in some of the above-mentioned definitions, this means that in the hydrocarbyl, alkyl, or other moiety, at least one Hydrogen bonded to a carbon atom is substituted with one or more substituents which are functional groups such as alkoxy, hydroxy, halo, nitro, and so on. Unless otherwise indicated, it should be understood that specified molecular segments can be substituted with one or more substituents that do not compromise the usefulness of the compound. For example, "succinimidyl" is intended to include unsubstituted succinimidyl as well as sulfosuccinimidyl and other succinimidyl substituted groups on a ring carbon atom, for example, with alkoxy substituents, polyether substituents, or the like. II. The Components According to the present invention, a composition is presented that contains at least two biocompatible, non-immunogenic components having reactive groups therein, with the functional groups selected to allow inter-reaction between the components, that is, formation of cross-links to form a three-dimensional matrix. Each component has a core substituted with reactive groups. Typically, a composition will contain a first component with a core substituted with nucleophilic groups and a second component with a core substituted with electrophilic groups. The invention also encompasses compositions with more than two components, where additional components may have electrophilic or nucleophilic groups. The reactive groups are selected so that the components are essentially non-reactive in a dry environment. When exposed to an aqueous medium, the components are reactive tornadoes and a plurality of components is then able to inter-react in the aqueous medium to form a three-dimensional matrix. This matrix is preferably formed without the input of any external energy, for example, at room temperature or at a slightly elevated temperature. A composition is particularly suitable for application involving contact between a biological system and a composition and the three-dimensional matrix formed therefrom. The biological system can be a biological tissue, and in a preferred embodiment, it is living tissue.

The resulting three-dimensional matrix is useful in a variety of contexts, and is particularly useful as a biomaterial for medical applications, such as for bioadhesion, administration of biologically active agents, tissue augmentation, tissue sealing, vascular sealing, needle hole sealing, hemostasis, prevention of adhesions after surgical procedure or injury, and so on. The core and reactive groups can also be selected so as to provide components having one of more of the following characteristics: they are biocompatible, are non-immunogenic, and do not leave any toxic, inflammatory or immunogenic reaction product at the site of administration. Similarly, the core and reactive groups may also be selected so as to provide a resulting matrix having one or more of these characteristics. In one embodiment of the invention, substantially immediately or immediately upon exposure to the aqueous medium, the reactive groups on the components of a composition start inter-reacting and form a three-dimensional matrix. The term "substantially immediately" is intended to mean within less than five minutes, preferably within less than two minutes, and the term "immediately" is directed to mean within less than one minute, preferably within less than 30 seconds. Typically, the three-dimensional composition will be fully formed within about 30 minutes. In one embodiment, the components and the resulting matrix are not subject to enzymatic cleavage by matrix metalloproteinases such as collagenase, and are therefore not readily degradable in vivo. In addition, a composition can be easily adapted, in terms of the selection and quantity of each component, to enhance certain properties, for example, compressive strength, bulking ability, change of direction capability, hydrophilic capacity, optical clarity, and so on A homogeneous dry powder composition of the present invention is composed of: a first component with a core substituted with nucleophilic groups and a second component with a core substituted with electrophilic groups. The nucleophilic and electrophilic groups are non-reactive with another when the first and second components are mixed in a dry environment but become reactive when exposed to an aqueous medium so that the components inter-react in the aqueous medium to form a matrix three-dimensional For a three-dimensional matrix to be formed, it is preferable that it be present a plurality of reactive groups in each of the first and second components. In a preferred embodiment, a component has a nucleus substituted with m nucleophilic groups, where m = 2, and the other components have a nucleus substituted with n electrophilic groups, where n > 2 and m + n > 4. Therefore, in one embodiment, a composition can be described as having components of formulas (I) and (II): (I) [X- (Ll) p] mR (II) [Y- (L2 ) q] nR 'where myn are integers of 2-12 and m + n > 4; R and R 'are independently selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C2-14 hydrocarbyls, and C2-14 hydrocarbyls containing heteroatoms; X is a nucleophilic group; And it's an electrophilic group; Ll and L2 are union groups; and p and q are integers of 0-1. When p is 0, then a specific nucleophilic group is directly attached to the core R, however when p is 1, then a specific nucleophilic group is indirectly linked to the nucleus via a linker group L. Each X group can be the same or different, and each group can be the same or different. Any additional components could have a formula such as [Z- (L3) r] s -R, "where s is an integer of 2- 6; R "is selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C2-14 hydrocarbyls, and C2-14 hydrocarbyls containing heteroatoms, Z is a nucleophilic or electrophilic group, L3 is a linking group, and r is an integer of 0- 1. In the components of formulas (I) and (II), each side chain typically has a reactive group, however, the invention also encompasses components where the side chains may contain more than one reactive group, therefore, for example, , the first component can have the formula (I '): (I1) [X' - (L4) aX "- (L5) b] cR '«' where: a and b are integers of 0-1; c is an integer of 2-6; R '' 'is selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C2-14 hydrocarbyls, and C2-14 hydrocarbyls containing heteroatoms; X 'and X "are electrophilic groups, and L4 and L5 are linking groups X' and X" may be the same or different. The components are commercially available or are readily synthesized by techniques that are well known in the art from commercially available materials. 1. reactive groups. Before use, a composition is stored in a dry environment that ensures that the components remain essentially non-reactive until use. When exposed to an aqueous medium, the reactive groups on the components are reactive tornadoes and a plurality of components will then inter-react to form the desired matrix. The chemical composition is preferably stored under an inert atmosphere so that the components do not react with oxygen. In general, the concentration of the components will be in the range of about 1 to 50 t%, usually about 2 to 40 wt%. The preferred concentration will depend on a number of factors, including the type of component (ie type of molecular core and reactive groups), its molecular weight, and the final use of the resulting three-dimensional matrix. For example, the use of high concentrations of the components, or using highly functionalized components, will result in the formation of a network with tighter crosslinks, producing a more rigid and robust composition, such as for example a gel. In general, the mechanical properties of the three-dimensional matrix must be similar to the mechanical properties of the tissue to which the matrix (or components that make up the matrix) will be applied. Therefore, when the matrix is used for an orthopedic application, the gel matrix should be relatively firm, for example, a firm gel; However, when the matrix is used on soft tissue, as for example in tissue augmentation, the gel matrix should be relatively soft, for example, a soft gel. The reactive groups are electrophilic and nucleophilic groups, which pass a nucleophilic substitution reaction, a nucleophilic addition reaction, or both. The term "electrophilic" refers to a reactive group that is susceptible to nucleophilic attack, i.e., susceptible to reaction with an incoming nucleophilic group. Electrophilic groups herein are positively charged or electron-deficient, typically electron-deficient. The term "nucleophilic" refers to a reactive group that is rich in electrons, has a non-shared electron pair acting as a reactive site, and reacts with positively charged or electron-deficient sites. X can be virtually any nucleophilic group, provided that the reaction can occur with the electrophilic group Y and also with Z, when Z is present and is electrophilic. Analogously, Y can be virtually any electrophilic group, provided that the reaction can take place with X and also with Z, when Z is present and is nucleophilic. The only limitation is practical, in that reaction between X and Y (and Z when present), it must be quite fast and take place automatically when mixed with an aqueous medium, without the need for the input of any external energy, for example, heat, or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although it is not essential that the reaction occurs without the need for ultraviolet or other radiation. In one embodiment, the reactions between X and Y (and Z when present), are complete in less than 60 minutes, preferably less than 30 minutes. More preferably, the reaction occurs in about 5 to 15 minutes or less. Examples of suitable nucleophilic groups such as X include, but are not limited to, -NH2, -NHR1, -N (R1) 2, -SH, -OH, -COOH, -C6H4-OH, -H, -PH2, -PHR1 , -P (R1) 2, -NH-NH2, -CO-NH-NH2, -C5H4N, etc. where R1 is a hydrocarbyl group and each R1 can be the same or different. R1 is typically alkyl or monocyclic aryl, preferably alkyl, and more preferably lower alkyl. Organometallic halides are also nucleophilic groups useful for the purposes of the invention, particularly those that act as carbanion donors. Examples of organometallic moieties include: Grignard functionalities -R2MgHal where R2 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromine, iodine or chlorine, preferably bromine; Y functionalities containing lithium, typically alkyl lithium groups; functionalities containing sodium. It will be appreciated by those ordinarily skilled in the art that certain nucleophilic groups must be activated with a base to be able to react with an electrophilic group. For example, when there are nucleophilic groups sulfhydryl and hydroxyloene the multifunctional compound, the compound must be mixed with an aqueous base to remove a proton and provide a -S- or -O- species to allow reaction with the electrophilic group. Unless it is desirable for the base to participate in the reaction, a non-nucleophilic base is preferred. In some embodiments, the base may be present as a component of a buffer solution. Suitable bases and corresponding reactions of cross-linking formation are described herein. The selection of electrophilic groups provided on the multifunctional compound must be done so that the reaction is possible with the specific nucleophilic groups. Therefore, when the reactive groups X are amino groups, the Y groups are selected so that they react with amino groups. Similarly, when the reactive groups X are sulfhydryl moieties, the corresponding electrophilic groups are sulfhydryl reactive groups, and so on. In general, examples of Suitable electrophilic groups such as Y include, but are not limited to, -C0-C1, - (CO) -0- (CO) -R (where R is an alkyl group), -CH = CH-CH = 0 and -CH = CH-C (CH3) = 0, halo, -N = C = 0, -N = C = S, -S02CH = CH2, -O (CO) -C = CH2, -0 (C0) -C (CH3 ) = CH2, -SS- (C5H4N), -O (CO) -C (CH2CH3) = CH2, -CH = CH-C = NH, -COOH, - (CO) O- (C0CH2) 2, -CHO, - (C0) 0-N (COCH2) 2-S (0) 20H, and -N (C0CH) 2. When X is amino (generally although not necessarily primary amino), the electrophilic groups present in Y are amino-reactive groups. Exemplary amino-reactive groups include, by way of example and without limitation, the following groups, or radicals thereof: (1) carboxylic acid esters, including cyclic esters and "activated" esters; (2) acid chloride groups (-C0-C1); (3) anhydrides (- (CO) -O- (CO) -R, where R is an alkyl group); (4) ketones and aldehydes, including α, β-unsaturated aldehydes and ketones such as -CH = CH-CH = 0 and -CH = CH-C (CH 3) = 0; (5) halo groups; (6) isocyanate group (-N = C = 0); (7) thioisocyanate group (-N = C = S); (8) epoxides; (9) activated hydroxyl groups (eg, activated with conventional activating agents such as carbonyldiimidazole or sulfonyl chloride); and (10) olefins, including conjugated olefins, such as ethenesulfonyl (-S02CH = CH2) and analogous functional groups, including acrylate (-0 (CO) -C = CH2), methacrylate (-0 (CO) -C (CH3) = CH2), ethyl acrylate (-O (CO) -C (CH2CH3) = CH2), and ethylene-ene (~ CH = CH-C = NH). In one embodiment the amino-reactive groups contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine, for example the carboxylic acid esters and aldehydes noted above, as well as carboxyl groups (-COOH). As a carboxylic acid group per se is not susceptible to reaction with a nucleophilic amine, components containing carboxylic acid groups must be activated so that they are amine-reactive. Activation can be performed in a variety of ways, but frequently involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU). For example, a carboxylic acid can be reacted with an alkoxy-substituted N-hydroxy-succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form electrophilic reactive groups, the N-hydroxysuccinimide ester and the N-hydroxysulfosuccinimide ester, respectively. Carboxylic acids can also be activated by reaction with an acyl halide such as an acyl chloride (eg, acetyl chloride), to give reactive anhydride groups. In more an example, an acid The carboxylic acid can be converted to an acid chloride group using, for example, thionyl chloride or an acyl chloride capable of an exchange reaction. Reagents and specific procedures used to execute these activation reactions will be known to those ordinarily skilled in the art and are described in the relevant texts and literature. Accordingly, in one embodiment, the amino-reactive groups are selected from succinimidyl ester (-O (CO) -N (C0CH2) 2), sulfoester succinimidyl (-O (CO) -N (COCH2) 2-S ( ) 20H), maleimido (-N (C0CH) 2), epoxy, isocyanate, thioisocyanate, and ethenesulfonyl. Analogously, when X is sulfhydryl, the electrophilic groups present in Y are groups that react with a sulfhydryl moiety. Such reactive groups include those which form thioester bonds upon reaction with a sulfhydryl group, such as those described in WO 00/62827 to Wallace et al. As explained in detail therein, reactive sulfhydryl groups include, but are not limited to: mixed anhydrides; phosphorus ester derivatives; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters; Esters of 1- hydroxybenzotriazole; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; Ketenes; and isocyanates. With these reactive sulfhydryl groups, auxiliary reagents can also be used to facilitate the formation of bonds, for example, l-ethyl-3- [3-dimethylaminopropyl] carbodiimide can be used to facilitate the coupling of sulfhydryl groups to carboxyl-containing groups. In addition to the reactive sulfhydryl groups that form thioester linkages, several other sulfhydryl reactive functionalities can be used that form other types of linkages. For example, compounds containing methyl imidate derivatives form thioester imido bonds with sulfhydryl groups. Alternatively, reactive sulfhydryl groups can be employed which form bisulfide bonds with sulfhydryl groups; such groups generally have the structure -SS-Ar where Ar is a heteroaromatic moiety containing substituted or unsubstituted nitrogen or a non-heterocyclic aromatic group substituted with a moiety that removes an electron, such that Ar can be, for example, 4-pyridinyl , o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc. In such cases, auxiliary reagents, ie agents Moderate oxidants such as hydrogen peroxide can be used to facilitate the formation of bisulfide bonds. Another case of reactive sulfhydryl groups forms thioether bonds with sulfhydryl groups. Such groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and α, β-unsaturated aldehydes and ketones. When X is -OH, the functional electrophilic groups in the remaining components must react with hydroxyl groups. The hydroxyl group can be activated as described above with respect to the carboxylic acid groups, or can react directly in the presence of base with a sufficiently reactive electrophilic group such as an epoxide group, an aziridine group, an acyl halide, an anhydride, and thus successively. When X is an organometallic nucleophilic group such as a Grignard functionality or an alkyl lithium group, electrophilic functional groups suitable for reaction in that case are those containing carbonyl groups, including, by way of example, ketones and aldehydes. It will also be appreciated that certain functional groups can react as nucleophilic groups or as electrophilic groups, depending on the reaction partner selected and / or the reaction conditions. For example, a carboxylic acid group can act as a nucleophilic group in the presence of a fairly strong base, but generally acts as an electrophilic group allowing nucleophilic attack on the carbonyl carbon and concomitant substitution of the hydroxyl group with the incoming nucleophilic group. These, as well as other embodiments that are illustrated below, where the covalent bonds in the matrix resulting in the covalent bonding of specific nucleophilic reactive groups to specific electrophilic reactive groups in the multifunctional compound include, by way of example only, the following : Table 1 The homogeneous dry powder can be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or minced into smaller particulates. 2. Binding groups The reactive groups can be directly attached to the nucleus, or can be indirectly linked through a linking group, with longer linking groups also called "chain extenders." In the formulas (I) and (II) shown above, the optional group connectors are represented by Ll and L2, where the linking groups are present when p and q are equal to 1. Suitable linking groups are well known in the art. See, for example, WO 97/22371 to Rhee et al. Binding groups are useful to avoid wide barrier problems that may sometimes appear associated with the formation of direct bonds between molecules. Binding groups can additionally be used to join various multifunctional compounds together to obtain larger molecules. In one embodiment, a linking group can be used to alter the degradative properties of compositions after administration and resulting gel formation. For example, union groups can be used to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation. Examples of linking groups that provide hydrolyzable sites, include, inter alia: ester linkages; anhydride bonds, such as those obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide bonds; Phosphorus bonds er; α-hydroxy acid linkages, such as those obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as those obtained by incorporation of caprolactone, valerolactone,? -butyrolactone and p-dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly (amino acid) segment. Examples of non-degradable linking groups include succinimide, pionic acid and carboxymethylate linkages. See, for example, WO 99/07417 to Coury et al. Examples of enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin. Binding groups can also be included to enhance or suppress the reactivity of several reactive groups. For example, groups that extract electrons within one or two carbons of a sulfhydryl group could be expected to decrease their effectiveness in coupling, due to the decrease in nucleophilic character. Double links Carbon-carbon and carbonyl groups will also have this effect. Conversely, groups that extract electrons adjacent to a carbonyl group (for example, the glutaryl-N-hydroxysuccinimidyl carbonyl reagents) could increase the reactivity of the carbonyl carbon with respect to an incoming nucleophilic group. By contrast, broadly bulky groups in the vicinity of a reactive group can be used to decrease reactivity and thereby reduce the coupling rate as a result of the broad barrier. By way of example, particular binding groups and corresponding formulas are indicated in Table 2: Table 2 In Table 2, x is generally in the range of 1 to about 10; R2 is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and more preferably lower alkyl; and R3 is hydrocarbylene, hydrocarbylene containing heteroatom, substituted hydrocarbylene, or hydrocarbylene containing substituted heteroatom) typically alkylene or arylene (again, optionally substituted and / or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene , n-butylene, etc.), phenylene, or amidoalkylene (e.g., - (CO) -NH-CH2). Other general principles that can be considered with respect to union groups are the following. If a multifunctional compound of higher molecular weight is to be used, it will preferably have biodegradable bonds as described above, so that fragments greater than 20,000 mol. t. they are not generated during resorption in the body. Additionally, to promote miscibility and / or water solubility, it may be desired to add sufficient electrical charge or hydrophilic capacity. Hydrophilic groups can be easily introduced using known chemical synthesis, provided that they do not give rise to unwanted swelling or unwanted decrease of compressive strength. In particular, polyalkoxy segments can weaken the strength of the gel. 3. The nucleus The "nucleus" of each component is composed of the molecular structure to which the reactive groups are linked. The molecular core can be a polymer, which includes synthetic polymers and naturally occurring polymers. The polymers may be hydrophilic, hydrophobic, or amphiphilic. The molecular core can also be a low molecular weight component such as a C2-14 hydrocarbyl or a heteroatom-containing C2-14 hydrocarbyl. The heteroatom-containing C2-14 hydrocarbyl may have 1 or 2 heteroatoms selected from N, O and S. In a preferred embodiment, the molecular core is a synthetic hydrophilic polymer. A. Hydrophilic Polymers The term "hydrophilic polymer" as used herein refers to a polymer having an average molecular weight and composition that naturally gives, or is selected to give the polymer as a "hydrophilic" whole. Preferred polymers are highly pure or are purified to a highly pure state such that the polymer is or is treated to become pharmaceutically pure. Most hydrophilic polymers can be water-soluble tornadoes incorporating a sufficient number of oxygen atoms (or less frequently nitrogen) available to form bonds by hydrogen in aqueous solutions. Hydrophilic synthetic polymers can be homopolymers, block copolymers, random copolymers, or grafted copolymers. Additionally, the polymer may be linear or branched, and if branched, it may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer. The polymer can include biodegradable segments and blocks, either distributed throughout the molecular structure of the polymer or present as a single block, as in a block copolymer. Biodegradable segments are those that degrade to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and / or enzymatically cleaved in situ. Biodegradable segments can be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. "Older biodegradable" blocks will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer. Exemplary oligomeric and polymeric segments that are biodegradable include, by way of example, poly (amino acid) segments, segments poly (orthoester), poly (orthocarbonate) segments, and so on. Hydrophilic synthetic polymers which are useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol (PEG) and poly (ethylene oxide) -poly (propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (PG) and particularly highly branched polyglycerol, propylene glycol; poly (oxyalkylene) -substituted diols, and poly (oxyalkylene) -substituted polyols such as mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; poly (acrylic acids) and analogs and copolymers thereof, such as polyacrylic acid per se, methacrylic polyacid, poly (hydroxyethyl methacrylate), poly (hydroxyethyl acrylate), poly (methylalkylsulfoxide methacrylates), poly (methylalkylsulfoxide acrylates) and copolymers of any of the above, and / or with additional acrylate species such as aminoethyl acrylate and mono-2- (acryloxy) -ethyl succinate; polymaleic acid; poly (acrylamides) such as polyacrylamide per se, poly (methacrylamide), poly (dimethylacrylamide), poly (N-) isopropyl acrylamide), and copolymers thereof; poly (olefinic alcohols) such as poly (vinyl alcohols) and copolymers thereof; poly (N-vinyl lactam) such as poly (vinyl pyrrolidones), poly (N-vinyl caprolactams), and copolymers thereof; polyoxazolines, including poly (methyloxazoline) and poly (ethyloxazoline); and polyvinylamines; as well as copolymers of any of the foregoing. It should be emphasized that the aforementioned list of polymers is not exhaustive, and a variety of other hydrophilic synthetic polymers can be used, as will be appreciated by those skilled in the art. Those ordinarily skilled in the art will appreciate that synthetic polymers such as polyethylene glycol can not be practically prepared to have exact molecular weights, and that the term "molecular weight" as used herein refers to the average molecular weight of a number of molecules in any given sample, as commonly used in the art. Therefore, a PEG 2,000 sample may contain a statistical mixture of polymer molecules ranging in weight from, for example, 1,500 to 2,500 daltons with one molecule differing slightly from the other in a range. Specification of a range of molecular weights indicates that the average molecular weight can be any value between the specified limits, and may include molecules outside those limits. Therefore, a molecular weight range of about 800 to about 20,000 indicates an average molecular weight of at least about 800, going up to about 20 kDa. Other suitable hydrophilic synthetic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and / or amino acids containing thiol groups (such as cysteine). Poly (lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly (lysine) s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000. Poly (lysine) s for use in the present invention preferably have molecular weight in the range of about 1,000 to about 300,000, more preferably in the range of about 5,000 to about 100,000, and more preferably, within the range of about from 8,000 to about 15,000. Poly (lysine) s of various molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).

Although a variety of different hydrophilic synthetic polymers can be used in the present compositions, as indicated above, preferred hydrophilic synthetic polymers are PEG and PG, particularly highly branched PG. Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (ie, is biocompatible), can be formulated so that they have a wide range of solubilities, and does not interfere typically interfere with enzymatic activities and / or peptide conformations. A particularly preferred synthetic hydrophilic polymer for certain applications is a PEG with a molecular weight in the range of about 100 to about 100,000, although for highly branched PEG, very high molecular weight polymers can be employed, up to 1,000,000 or more. more, by making biodegradable sites incorporated by ensuring that all degradation products have a molecular weight of less than about 30,000. For most P? Gs, however, the preferred molecular weight is from about 1,000 to about 20,000, more preferably in the range of about 7,500 to about 20,000. More preferably, the polyethylene glycol has a molecular weight of about 10,000.

Hydrophilic polymers found naturally include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, fibrin and thrombin, with particularly preferred collagen; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; amino polysaccharides, particularly glycosaminoglycans, for example, hyaloronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives. Collagen and glycosaminoglycans are preferred hydrophilic polymers naturally found for use herein. The term "collagen" as used herein refers to all forms of collagen, including those, that have been processed or otherwise modified. Therefore, collagen from any source can be used in the compositions of the invention; for example, collagen can be extracted and purified from human or other mammalian sources, such as bovine or porcine dermis and human placenta, or it can be recombinantly or otherwise produced. The preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. For example, US Pat. No. 5,428,022 to Palefsky et al. discloses methods of extracting and purifying collagen from human placenta, and US Pat. No. 5,667,839 to Berg discloses methods of producing recombinant human collagen in transgenic animals milk, including transgenic cows. Expression of non-transgenic collagen, recombinant in yeast and other cell lines) is described in US Pat. No. 6,413,742 to Olsen et al., 6,428,978 to Olsen et al., And 6,653,450 to Berg et al. Collagen of any type, including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred. Even atelopeptide collagen or telopeptide-containing collagen can be used; however, when collagen from a source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, due to its reduced immunogenicity compared to telopeptide-containing collagen. Collagen that has not previously had its cross-links by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the invention, although collagen having its previously crosslinked bonds may be used.

Collagen for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg / ml to about 120 mg / ml, preferably between about 30 mg / ml to about 90 mg / ml. Although intact collagen is preferred, denatured collagen, commonly known as gelatin, can also be used. Gelatin can have the additional benefit of being degradable faster than collagen. Non-fibrillar collagen is generally preferred for use in compositions of the invention, although fibrillar collagens may also be used. The term "non-fibrillar collagen" refers to any modified or non-modified collagen material that is in substantially non-fibrillar form, ie, molecular collagen that is not closely associated with other collagen molecules to form fibers. Typically, a non-fibrillar collagen solution is more transparent than a fibrillar collagen solution. Types of collagen that are non-fibrillar (or microfibrillar) in a native form include types IV, VI, and VII. Chemically modified collagens that are in non-fibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in US Pat. No. 4,164,559 to Miyata et al. Methylated collagen, which contains reactive amine groups, is a preferred component that contains nucleophile in the compositions of the present invention. In another aspect, methylated collagen is a component that is present in addition to the first and second components in the matrix-forming reaction of the present invention. Methylated collagen is described, for example, in U.S. Pat. No. 5,614,587 to Rhee et al. Collagen for use in the compositions of the present invention may begin in fibrillar form, then may be non-fibrillar tornadoes by the addition of one or more fiber stripping agents. The fiber stripping agent must be present in an amount sufficient to render the substantially non-fibrillar collagen at pH 7, as described above. Fiber stripping agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts and carbohydrates, with biocompatible alcohols being particularly preferred. Preferred biocompatible alcohols include glycerol and propylene glycol. Non-biocompatible alcohols, such as ethanol, methanol, and isopropanol, are non-preferred for use in the present invention, because of their potentially deleterious effects on the body of the receiving patient. Preferred amino acids include arginine. Preferred inorganic salts include sodium chloride and potassium chloride. Even though carbohydrates, such as various sugars including sucrose, can be used in the practice of the present invention, they are not as preferred as other types of fiber stripping agents because they can have cytotoxic effects in vivo. Collagen for use in the compositions of the present invention may begin in fibrillar form, then may be non-fibrillar tornadoes by the addition of one or more fiber stripping agents. B. Hydrophobic Polymers The core of the components can also comprise a hydrophobic polymer, including low molecular weight polyfunctional species; although for most hydrophilic polymeric uses are preferred. Generally, "hydrophobic polymers" herein contain a relatively small proportion of oxygen and / or nitrogen atoms. Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no greater than about 14 carbons. Polymers with carbon chain substantially greater than 14 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing multiple nucleophilic groups. Therefore, the use of short chain oligomers can avoid problems linked to solubility during the reaction. Acid polylactic and polyglycolic acid are examples of two particularly suitable hydrophobic polymers. C. Amphiphilic Polymers Generally, amphiphilic polymers have a hydrophilic and a hydrophobic (or lipophilic) moiety. The hydrophilic portion may be at one end of the core and the hydrophobic portion at the opposite end, or the hydrophilic and hydrophobic portions may be randomly distributed (random copolymer) or in the form of sequences or grafts (block copolymer) to form the core amphiphilic polymer of the components. The hydrophilic and hydrophobic portions can include any of the aforementioned hydrophobic and hydrophilic polymers. Alternatively, the amphiphilic polymer core can be a hydrophilic polymer that has been modified with hydrophobic moieties (eg, alkylated PEG or a hydrophilic polymer modified with one or more fatty chains), or a hydrophobic polymer that has been modified with hydrophilic moieties ( for example, "PEGylated" phospholipids such as glycolylated polyethylene phospholipids). D. Low molecular weight components As indicated above, the molecular core of the component can also be a low weight compound molecular, defined herein as being a C2-14 hydrocarbyl or a heteroatom-containing C2-14 hydrocarbyl, containing 1 to 2 heteroatoms selected from N, O, S and combinations thereof. Such a molecular nucleus can be substituted with any of the reactive groups described herein. Alkanes are appropriate C2-14 hydrocarbon molecular nuclei. Exemplary alkanes, for a primary amino group substituted with a nucleophilic and an Y electrophilic group, include, ethyleneamine (H2N-CH2CH2-Y), tetramethyleneimine (H2N- (CH4) -Y), pentamethyleneamine (H2N- (CH5) -Y) , and hexamethyleneamine (H2N- (CH6) -Y). Low molecular weight diols and polyols are also C2-14 suitable hydrocarbyls and include trimethylolpropane, di (trimethylol propane), pentaerythritol, and diglycerol. Polyacids are also C2-14 suitable hydrocarbyls, and include triacidal carboxylic based on trimethylolpropane, tetraacid carboxylic based on di (trimethylol propane), heptanedioic acid, octanediic acid (suberic acid), and hexadecanedioic acid (tapsic acid). Di- and low molecular weight poly-electrophiles are suitable C2-14 hydrocarbyl nuclei containing heteroatoms. They include, for example, disuccinimidyl suberate (DSS), bis (sulfosuccinimidyl) suberate (BS3), dithiobis (succinimidylpropionate) (DSP), bis (2-) succinimidoxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-dithiobis (sulfosuccinimidylpropionate (DTSPP), and its analogues and derivatives.) Low molecular weight materials comprising a plurality of acrylate moieties are present in one aspect of the invention Low molecular weight materials comprising a plurality of groups thiol are present in another aspect of the present invention 4. Preparation The components are easily synthesized to contain a hydrophilic, hydrophobic polymer core or an amphiphilic molecular weight core, functionalized with the desired functional groups, i.e., electrophilic or nucleophilic groups , which allow the formation of cross-links For example, the preparation of the first and second components with a polyethylene glycol (PEG) core is discussed below and in the examples; however, it should be understood that the following discussion is for illustration purposes and analogous techniques can be employed with other polymers. With respect to PEG, first, several functionalized P? Gs have been effectively used in fields such as protein modification (see Abuchowski et al., Enzymes as Drugs, John Wiley &Sons: New York, NY (1981) pp. 367-383; and Dreborg et al. (1990) Crit. Rev.

Therap. Drugs Carrier Syst. 6: 315), peptide chemistry (see Mutter et al., The Peptides, Academic: New York, NY 2: 285-332, and Zalipsky et al. (1987) Int. J. Peptide Protein Res. 30: 740) , & the synthesis of polymeric drugs (see Zalipsky et al (1983) Eur. Polim. J. 19: 1177; and Ouchi et al. (1987) J. Macro ol. Sci. Chem. A24: 1011). Functionalized forms of PEG, including multifunctional PEG, are commercially available, and are also readily prepared using known methods. For example, see Chapter 22 of Poly (ethylene Glycol) Chemistry: Biotechnical & Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992). Multi-functionalized forms of PEG are of particular interest and include, PEG succinimidyl glutarate, PEG succinimidyl propionate, succinimidyl butylate, PEG succinimidyl acetate, PEG succinimidyl succinamide, PEG succinimidyl carbonate, PEG propionaldehyde, PEG glycidyl ether, PEG-isocyanate, and PEG- vinylsulfone. Many such forms of PEG are described in US Pat. Nos. 5,328,955 and 6,534,591, both to Rhee et al. Similarly, various forms of multi-amino PEG are commercially available from sources such as PEG Shop, a division of SunBio of South Korea (www.sunbio.com), Nippon Oil & Fats (Yebisu Garden Place Tower, 20-3 Ebisu 4-chome, Shibuya-ku, Tokyo), Nektar Therapeutics (San Carlos, California, formerly Shearwater Polymers, Huntsville, Alabama) and Huntsman's Performance Chemicals Group (Houston, Texas) under the name Jeffamine® polyoxyalkylene amines. Multi-amino PEGs useful in the present invention include the Jeffamine diamines ("D" series) and triamines ("T" series), which contain two and three amino groups per molecule. PEGs of poly (sulfhydryl) analogs are also available from Nektar Therapeutics, for example, in the form of pentaerythritol poly (ethylene glycol) tetra-sulfhydryl ether (molecular weight 10,000). Reaction with succinimidyl groups to convert terminal hydroxyl groups to reactive esters is a technique for preparing a nucleus with electrophilic groups suitable for reaction with nucleophilic groups such as primary amines, thiols, and hydroxyl groups. Other agents for converting hydroxyl groups include carbonyldiimidazole and sulfonyl chloride; however, as discussed herein, a wide variety of electrophilic groups can be sold for use in reaction with corresponding nucleophilic groups. Examples of such electrophilic groups include acidic chloride groups; anhydrides, ketones, aldehydes, isocyanate, isothiocyanate, epoxides, and olefins, including conjugated olefins such as ethenesulfonyl (-S02CH = CH2) and analogous functional groups.

III. The compositions or components of the invention can be included in a pharmaceutical composition. A pharmaceutically acceptable carrier can also be included. To enhance the matrix strength, it may generally be desirable to add a "stress resistance enhancer" to a composition. These tensile strength enhancers preferably comprise fibers of high tensile strength of micron size, preferably 5 to 40 microns in diameter and 20 to 5000 microns in length, usually with glass transition temperatures well above 37 ° C. Stress resistance enhancers suitable for use with the multifunctional compound of the present invention include, inter alia, collagen fibers, synthetic polymer fibers, as well as other organic tensile strength enhancers and inorganic tensile strength enhancers. Synthetic polymer fibers can be degradable or non-degradable. In a preferred embodiment, the synthetic polymer fibers are degradable. These degradable polymer fibers may comprise polyesters, polyamides, poly (ortho esters), poly (anhydrides), poly (phosphazines), poly (urethanes), poly (carbonates) and poly (dioxanones) as well as copolymers and mixtures thereof. An enhancer Particularly useful tensile strength is Vicril® (90:10 glycolide copolymer and lactide). The use of tensile strength enhancers, which are part of the broader category of "fillers," are well known. For example, silicone gums, when cross-linked with peroxides, are weak gels with tensile strength of the order of only about 34 N / cm2. When properly composited with reinforcement fillers, the tensile strength of these gums can increase up to fifty times. Lichtenwalner et al., Eds., Encyclopedia of Polymer Science & Technology, Vol. 12, p. 535, John Wiley, New York, 1970. Appropriate stress resistance enhancers are those that have a high inherent resistance to stress and can also interact through covalent or non-covalent bonds with the three-dimensional matrix. The voltage resistance enhancer must be linked to the matrix, either mechanically or covalently, to provide voltage support. Resistance to the tension of resorbable polyglycolide sutures is approximately 89,000 N / cm2; those of the collagen fibers is 5000-10,000 N / cm2 (Tsuruta & Hayashi, Eds., Biomedical Aplications of Polimeric Materials, CRC Press, Boca Raton, Fia., 1993).

The components can also be prepared to contain various imaging agents such as iodine, derivatives of iodine soluble in water, or barium sulfate, or fluorine, to aid in the visualization of the compositions after administration via X-rays or 19 F-MRI, respectively. For use in tissue adhesion as discussed below, it may also be desirable to incorporate proteins such as albumin, fibrin or fibrinogen into the multifunctional compound to promote cell adhesion. Additionally, the introduction of hydrocolloids such as carboxymethylcellulose can promote tissue adhesion and / or bulking capacity. A crosslinkable composition can be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected of the group consisting of amino acids comprising primary amino groups and amino acids comprising thiol groups, the second component comprises a polyethylene glycol moiety, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and furthermore where the link formation Crosses of a composition result in a biocompatible, non-immunogenic, cross-linked matrix. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. In a preferred embodiment, the selected amino acid residues are lysine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. In another preferred embodiment, the amino acid residues selected are cysteine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. A crosslinkable composition can also be composed of a crosslinkable composition composed of: (a) a first crosslinkable component having m nucleophilic groups, where m 2; and (b) a second componentsusceptible to cross-links having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected from the group consisting of amino acids comprising groups primary amino acids and amino acids comprising thiol groups, the second component comprises a polyethylene glycol moiety, the electrophilic moieties are succinimidyl moieties, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and furthermore where the cross-linking of a composition results in a biocompatible, non-immunogenic, cross-linking matrix. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. In a preferred embodiment, the selected amino acid residues are lysine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, groups electrophilic are succinimidyl moieties, all n are identical, and all m are identical. In another preferred embodiment, the amino acid residues selected are cysteine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, and all m are identical. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected of the group consisting of amino acids comprising primary amino groups and amino acids comprising thiol groups, the second component comprises a polyethylene glycol multifunctionally activated, and each of the first and second crosslinkable components is biocompatible, synthetic, and non-immunogenic, and also where the cross-linking of a composition results in a biocompatible matrix, non-immunogenic, cross-linked. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, the multifunctionally activated polyethylene glycol is tetrafunctionally activated polyethylene glycol, and the polyethylene glycol is multifunctionally activated It is a star-branched polyethylene glycol. In a preferred embodiment, the selected amino acid residues are lysine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, and the multifunctionally activated polyethylene glycol is tetrafunctionally activated polyethylene glycol or the polyethylene glycol multifunctionally activated it is a star-branched polyethylene glycol. In another preferred embodiment, the amino acid residues selected are cysteine. Within this embodiment, any of the following is preferred: m > 3, m = 3, m = 4, n = 4, groups electrophilic are succinimidyl moieties, all n are identical, all m are identical, and the multifunctionally activated polyethylene glycol is tetrafunctionally activated polyethylene glycol or the multifunctionally activated polyethylene glycol is a star-branched polyethylene glycol. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected of the group consisting of lysine and cysteine, the second component comprises half polyethylene glycol, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible matrix, non-immunogenic, cross-linked. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are halves succinimidil, all n are identical, all m are identical, the first component consists of three lysine residues, and the first component consists of three cysteine residues. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where ta = 2; and (b) a second cross-linkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more lysine residues, the second component comprises half polyethylene glycol, and each of the first and second crosslinkable components is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible, non-immunogenic matrix of cross links. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, and the first component consists of three lysine residues.

A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m > 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component consists of lysine residues, the second The component comprises a polyethylene glycol moiety, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible, non-immunogenic, cross-linked matrix. . Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, and the first component consists of three lysine residues. Another aspect of the invention relates to a crosslinkable composition composed of: (a) a first crosslinkable component having m nucleophilic groups, where m > 2; and (b) a second cross-linkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more cysteine residues, the second component comprises one half polyethylene glycol, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible, non-immunogenic, cross-linked matrix. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, and the first component consists of three cysteine residues. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, where the first component consists of residues of cysteine, the second component comprises a polyethylene glycol moiety, and each of the first and second crosslinkable components is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible, non-immunogenic matrix , cross-linked. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m >; 3, m = 3, m = 4, n = 4, the electrophilic groups are succinimidyl moieties, all n are identical, all m are identical, and the first component consists of three cysteine residues. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more amino acid residues selected of the group consisting of lysine and cysteine, the second component comprises a polyethylene glycol moiety, the electrophilic moieties are succinimidyl moieties, and each of the first and second components cross-linked is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible, non-immunogenic, cross-linked matrix. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, all n are identical, all m are identical, the first component consists of three lysine residues, and the first component consists of three cysteine residues. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second cross-linkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component comprises two or more lysine residues, the second component comprises a polyethylene glycol moiety, the electrophilic moieties are succinimidyl moieties, and each of the first and second crosslinkable components is biocompatible, synthetic, and non-immunogenic, and linkage formation Crosses of a composition result in a biocompatible, non-immunogenic, cross-linked matrix. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, all n are identical, all m are identical, and the first component consists of three lysine residues. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m = 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component consists of lysine residues, the second component comprises a polyethylene glycol moiety, the electrophilic moieties are succinimidyl moieties, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible matrix, non-immunogenic, cross-linked. Any of the following are preferred embodiments of a linkable composition crossed ones described immediately above: m > 3, m = 3, m = 4, n = 4, all n are identical, all m are identical, and the first component consists of three lysine residues. A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m > 2; and (b) a second crosslinkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n 5, the first component comprises two or more cysteine residues, the second component comprises a polyethylene glycol moiety, the electrophilic moieties are succinimidyl moieties, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and cross-linking of a composition results in a biocompatible matrix , non-immunogenic, cross-linked. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, all n are identical, all m are identical, and the first component consists of three cysteine residues.

A crosslinkable composition can also be composed of: (a) a first crosslinkable component having m nucleophilic groups, where m >;2; (b) a second cross-linkable component having n electrophilic groups capable of reacting with the m nucleophilic groups to form covalent bonds, where n = 2 and m + n = 5, the first component consists of cysteine residues, the second component comprises a polyethylene glycol moiety, the electrophilic moieties are succinimidyl moieties, and each of the crosslinkable first and second components is biocompatible, synthetic, and non-immunogenic, and crosslinking of a composition results in a biocompatible matrix, not - Immunogenic, cross-linked. Any of the following are preferred embodiments of a crosslinkable composition described immediately above: m > 3, m = 3, m = 4, n = 4, all n are identical, all m are identical, and the first component consists of three cysteine residues. IV. Administration and Formation of the three-dimensional matrix The invention is also directed to a method of formulating an in-situ cure composition. This method involves an activation / triggering / initiation of the reaction between the reactive groups, generating a cured composition with consistent and uniform strength. A composition can be administered before, during or after the inter-reacting components in the aqueous medium to form a three-dimensional matrix. Certain uses, which are discussed in more detail below, such as tissue augmentation, may require that the matrix be formed prior to administration, while other applications, such as tissue adhesion, require compositions to be administered prior to administration. interreaction have reached "equilibrium." The point at which an interreaction has reached equilibrium is defined herein as the point at which a composition does not feel more damp or sticky to the touch. A composition of the present invention is generally administered to the site of administration so that individual reactive groups of compounds are exposed to the aqueous medium for the first time at the site of administration, or immediately prior to administration. Therefore, a composition is preferably administered at the site of administration using an apparatus that allows a composition to be administered in a dry environment, where the compounds are essentially non-reactive.

In an embodiment of the invention, a three-dimensional array is formed by the steps of: (a) providing a composition of the invention; and (b) making the reactive nucleophilic and electrophilic groups by exposing a composition to an aqueous medium to effect interreaction; wherein said exposure comprises: (i) dissolving a composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution with a pH within the range of about 6.0 to 11.0 to the homogeneous solution; and (c) allow a three-dimensional matrix to be formed. Typically, the matrix is formed, for example, by polymerization, without input of any external energy. The first and second components of a composition are typically combined in amounts such that the number of nucleophilic groups in the mixture is approximately equal to the number of electrophilic groups in the mixture. As used in this context, the term "about" refers to a 2: 1 to 1: 2 ratio of moles of nuclesfyl groups to moles of electrophilic groups. A 1: 1 molar ratio of nucleophilic groups to electrophilic groups is generally preferred. The first and second components are mixed together to form a homogeneous dry powder. This powder is then combined with a buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous aqueous acidic solution, and this solution is then combined with a buffer solution with a pH within the range of about 6.0 to 11.0 to form a reactive solution. For example, 0.375 grams of the dry powder can be combined with 0.75 grams of the acid buffer to give, after mixing, a homogeneous solution, where this solution is combined with 1.1 grams of the basic buffer to give a reactive mixture that substantially, immediately, forms a three-dimensional matrix. 1. Buffers The buffer solutions are aqueous and can be any pharmaceutically acceptable basic or acidic composition. The term "buffer" is used in a general sense to refer to an acidic or basic aqueous solution, where the solution may or may not be functional to give a buffer effect (i.e., resistance to change in pH with the addition of acid or base) in the compositions of the present invention. Acidic buffer solutions with a pH within the range of about 1.0 to 5.5, include by way of illustration and without limitation, solutions of: citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, AMPSO (3- [(1, l- dimethyl-2-hydroxyethyl) amino] 2-hydroxypropane- sulfonic acid), acetic acid, lactic acid and combinations thereof. In a preferred embodiment, the acidic buffer solution is a solution of citric acid, hydrochloric acid, phosphoric acid, sulfuric acid and combinations thereof. Independently of the precise acidifying agent, the acidic buffer preferably has a pH such that it retards the reactivity of the nucleophilic groups in the first component. For example, a pH of 2.1 is generally sufficient to retard the nucleophilic character of thiol groups. A lower pH is typically preferred when the first component contains amino groups as nucleophilic groups. In general, the acidic buffer is an acidic solution which, when contacted with nucleophilic groups that are present as part of the first component, renders those nucleophilic groups relatively non-nucleophilic. An exemplary acidic buffer is a hydrochloric acid solution, with a concentration of about 6.3 mM and a pH in the range of 2.1 to 2.3. This buffer can be prepared by combining concentrated hydrochloric acid with water, that is, diluting concentrated hydrochloric acid with water. Similarly, this buffer A can also be conveniently prepared by diluting 1.23 grams of concentrated hydrochloric acid to a volume of 2 liters, or diluting 1.84 grams of concentrated hydrochloric acid to a volume of 3 liters, or diluting 2.45 grams of concentrated hydrochloric acid to a volume of 4 liters, or diluting 3.07 grams of concentrated hydrochloric acid to a volume of 5 liters, or diluting 3.68 grams of hydrochloric acid concentrated to a volume of 6 liters. For safety reasons, the concentrated acid is preferably added to water. Basic buffer solutions with a pH in the range of about 6.0 to 11.0, include, by way of illustration and without limitation, solutions of: glutamate, acetate, carbonate and carbonate salts (e.g., sodium carbonate, sodium carbonate monohydrate) and sodium bicarbonate), borate, phosphate and phosphate salts (e.g., monobasic sodium phosphate monohydrate and dibasic sodium phosphate), and combinations thereof. In a preferred embodiment, the basic buffer solution is a solution of carbonate salts, phosphate salts, and combinations thereof. In general, the basic buffer is an aqueous solution that neutralizes the effect of the acidic buffer, when it is added to the homogeneous solution of the first and second components and the acid buffer, so that the nucleophilic groups of the first component recover their nucleophilic character (which they had been masked by the action of the acidic buffer), thus allowing the nucleophilic groups to inter-react with the electrophilic groups of the second component. An exemplary basic buffer is an aqueous solution of carbonate and phosphate salts. This buffer can be prepared by combining a base solution with a salt solution. The salt solution can be prepared by combining 34.7 g of monobasic sodium phosphate monohydrate, 49.3 g of sodium carbonate monohydrate, and enough water to give a volume of solution of 2 liters. Similarly, a 6-liter solution can be prepared by combining 104.0 g of monobasic sodium phosphate monohydrate, 147.94 g of sodium carbonate monohydrate, and enough water to give 6 liters of salt solution. The basic buffer can be prepared by combining 7.2 g of sodium hydroxide with 180.0 g of water. The basic buffer is typically prepared by adding the base solution as necessary to the salt solution, finally to give a mixture having the pH pH, for example, a pH of 9.65 to 9.75. In general, the basic species present in the basic buffer must be sufficiently basic to neutralize the acidity offered by the acidic buffer, but they should not be so nucleophilic in themselves that they will react substantially with the electrophilic groups of the second component. For this reason, relatively "soft" bases such as carbonate and phosphate are preferred in this embodiment of the invention. To illustrate the preparation of a three-dimensional matrix of the present invention, a mixture of a first component (for example, a polyethylene glycol core with four thiol nucleophilic groups, such as pentaerythritol tetrakis [mercaptoethyl poly (oxyethylene) ether] ("HS") can be combined. -PEG ") available from Aldrich Chemical Co. (Milwaukee, Wl), and a second component (eg, a polyethylene glycol core with four N-hydroxysuccinimide electrophilic groups, such as pentaerythritol tetrakis [1- (1'-oxo-5- succimidylpentanoate) -2-poly (oxyethylene) ether] ("NHS-PEG," 10,000 MW, available from Aldrich Chemical Co.), with a first acidic buffer (eg, an acid solution, eg, a dilute acid solution) hydrochloric) to form a homogeneous solution.This homogenous solution is mixed with a second basic buffer (for example, a basic solution, for example, an aqueous solution containing phosphate and carbonate salts) in consecu The first and second components substantially immediately interreact with each other to form a three-dimensional matrix. 2. Management Systems A. Multi-compartment devices Suitable administration systems for a homogeneous dry powder composition and the two buffer solutions may involve a multi-compartment device, where one or more compartments contain the powder and one or more compartments contain the buffer solutions necessary to enable the aqueous medium, so that a composition is exposed to the aqueous medium as it leaves the compartment. Many devices that are adapted for administration of multi-component sealants / hemostats to fabrics are well known in the art and can also be used in the practice of the present invention. Alternatively, a composition can be administered using any type of controllable extrusion system, or it can be administered manually in the form of a dry powder, and exposed to the aqueous medium at the site of administration. A homogeneous dry powder composition and the two buffer solutions can be conveniently formed under aseptic conditions by placing each of the three ingredients (dry powder, acidic buffer solution and basic buffer solution) in separate syringe barrels. For example, a composition, first buffer solution and second buffer solution can be housed separately in a multi-compartment syringe system having multiple drums, a mixing head, and a multi-compartment orifice. departure. The first buffer solution can be added to the cylinder that houses a composition to dissolve a composition and form a homogeneous solution, which is then extruded to the mixing head. The second buffer solution can be simultaneously extruded to the mixing head. Finally, a resulting composition can then be extruded through the hole on a surface. For example, syringe barrels containing the dry powder and the basic buffer can be part of a double-syringe system, for example, a double-drum syringe as described in US Pat. 4,359,049 to Redi et al. In this embodiment, the acid buffer can be added to the syringe barrel which also contains the dry powder, so that the homogeneous solution is produced. In other words, the acid buffer can be added (eg, injected) into the syringe barrel containing the dry powder to thereby produce a homogeneous solution of the first and second components. This homogeneous solution can then be extruded in a mixing head, while the basic buffer is simultaneously extruded to the mixing head. Inside the mixing head, the homogeneous solution and the basic buffer are mixed together to thereby form a reactive mixture. Subsequently, the mixture Reactive is extruded through a hole and onto a surface (eg, fabric), where a film is formed, which can function as a sealant or a barrier, or the like. The reactive mixture begins to form a three-dimensional matrix immediately as it is formed by the mixture of the homogeneous solution and the basic buffer in the mixing head. Accordingly, the reaction mixture is preferably extruded from the mixing head in the fabric very quickly after being formed so that the three-dimensional matrix is formed on, and is capable of adhering to, the tissue. A preferred embodiment of the multi-compartment syringe system of the present invention is shown in FIG. 1. The device is composed of three syringes, two containing each of the two buffers of the present invention with the third syringe containing the dry powder composition 1. The two syringes containing the solutions 1 are preassembled in a syringe housing 2 with a transfer door lock 3 attached to the housing assembly 2 to allow the dry powder mixture to enter the correct syringe. A syringe clip 4 is attached to the plunger rod of the syringe that does not require mixing with the dry powder composition. Other systems for combining two liquid reagents are well known in the art, and include systems described in US Pat. No. 6,454,786 to Holm et al .; 6,461,325 to Delmotte et al .; 5,585,007 to Antanavich et al .; 5,116,315 to Capozzi et al .; 4,631,055 to Redi et al .; and US Patent Application Publication No. 2004/0068266 to Delmotte. B. Pressurized delivery devices Other delivery systems for dispensing the multicomponent compositions of the invention may include pressurized delivery devices, examples of which are described in US Pat. Application No. 10 / 957,493 commonly pertaining to co-pending, filed on October 1, 2004, and entitled "Mixing and Managing a Multicomponent Composition." Such a pressurized delivery device may include a diffusing surface with an outlet extending through which is positioned downstream of a plurality of inlets. While at least one input is adapted to communicate with a source of a pressurized carrier fluid, each of a plurality of inputs is adapted to communicate with a source of different fluid components. Using this device, the dry powder solution is premixed with the first buffer to form a homogeneous solution as previously described and this solution is subsequently communicated with a first fluid component. The second fluid component will communicate with the second buffer solution previously described. Once the diffusing surface receives fluid components from inlets, each received fluid component is pushed towards the outlet to mix and dispense through itself by the pressurized carrier fluid, typically a gas such as air, from the carrier inlet fluid. The diffusing surface and the inlets can represent components of a mixing nozzle. In general, there are two categories of gas-enhanced nozzles for dispensing reactive components of a multicomponent composition-those that concern internal mixing and those that concern external mixing. When the diffusing surface is part of the nozzle, the nozzle can be considered an internal mixing nozzle. In deference to other internal mixing technologies, the internal mixing nozzle of the pressurized delivery device of the present invention has several characteristics that serve individually and collectively to eliminate clogging. For example, a diffusing surface typically has an effective way to direct and maintain each received fluid component in a different flow path on the diffusing surface toward the outlet to mix there and dispense therethrough.

Due to the minimum residence time of the mixture within the nozzle, reactive components do not have time to settle and clog the nozzle, before the mixture is forced out of the nozzle by the pressurized carrier fluid. Additionally, the outlet may be aligned with any or all of the fluid carrier entries that may be present in the nozzle to direct the pressurized carrier fluid in a manner that improves mixing of the fluid components and expel the mixture in the form of a jet. With the orientation of the diffusing surface relative to the inputs affects the performance of the device, the diffusing surface can be permanently fixed or immobilized with respect to the inputs; however, when the diffusing surface is removable from entries, the nozzle can be disassembled to facilitate cleaning and / or replacement of parts. For example, the diffusing surface may be replaceable and / or disposable. However, when the pressurized delivery device of the present invention has a diffusing surface that is removable from inlets, the device can be constructed to allow components to be mounted only in configurations that align the diffusing surface to the inlets so that the Device performance is optimized.

FIGS. 2 and 3 illustrate an example of the pressurized delivery device of the present invention in the form of a nozzle including all of the features discussed above that serve to eliminate the problems associated with nozzle clogging. As in the case of all the figures referenced herein, in which like parts are referenced by like numbers, FIGS. 2 and 3 are necessarily in scale, and certain dimensions can be exaggerated for clarity of presentation. As represented in FIG. 2, the nozzle 1 includes a cover 10 with a slot-shaped exit hole 12 extending through the center of the distal end 14 of the cover 10. The cover 10 is shown having a cylindrical outer surface 16 and an inner surface 18 ending in opening 20, but additional cover shapes are also available for use with the pressurized delivery device of the present invention. As shown in FIG. 3, the inner surface 18 of the cover 10 at the end 14 serves to receive fluid components therein. Also provided is a generally elongated cylindrical connector 30 in the form of a unitary member with a first terminal 32 and a second terminal 34. A plurality of inlet openings 36A, 36B, and 36C running through the Connector length defined by terminals 32 and 34. As described, the connector 30 is detached from the cover 10. Each entry opening 36A and 36B communicates the second terminal 34 with a different source of a fluid component, for example, the first buffer mixed with the dry powder in one source and the second buffer in the other source (not shown). Similarly, inlet openings 36C provide fluid communication in the second terminal 34 with a source of pressurized carrier gas (not shown). The fluid carrier inlet openings 36C define a plane that is perpendicular to a plane defined by the fluid component inlet openings 36A and 36B. As represented in FIGS. 2 and 3, the first terminal 32 of the connector 30 has appropriate dimensions to form a fluid tight seal against the inner surface 18 of the cover 10 at its near end 20. In operation, the cover 10 is placed on the first terminal 32 of the connector 30 so that the fluid carrier inlet openings 36C are aligned with the outlet port 12. Additionally, each of a plurality of different sources of fluid components is provided fluid communication with the fluid component inlet openings 36A and 36B and at least one Pressurized carrier gas source is provided fluid communication with the fluid carrier input 36C. As discussed above, the inner surface 18 of the cover 10 at the distal end 14 serves as a diffusing surface 18 which is adapted to receive fluid components therein. As represented in FIG. 2, the diffusing surface 18 exhibits bi-axial symmetry. The dashed lines indicate the position of openings 36A, 36B, and 36C relative to the diffusing surface 18. Similarly, in FIG 2, the dashed lines shown within the connector 30 indicate the separate flow paths of emerging fluid components from openings of fluid component inlet 36A and 36B, respectively, and directed by the diffusing surface 18 in an interior direction generally toward the central outlet orifice 12. Once the fluid components reach the outlet orifice 12, pressurized gas from the openings of carrier fluid 36C mixes the fluid components and forces the mixture out of the exit orifice 12. In the pressurized delivery device of the present invention, the geometries of and spatial relationships between the various components of the diffusing surface 18 represent an important aspect of the pressurized administration device. For example, the pressurized delivery device can be used to effect the mixing of a plurality of reactive components. Typically, nozzles for mixing reactive components are of the external mixing category because previously known internal mixing designs are prone to clogging. Obstruction results when reactive components are mixed before being introduced into the gas stream. In contrast, the pressurized delivery device provides a high pressure area between the inlets 36A-36C and the diffusing surface 18 which serves to mix reactive fluids while simultaneously urging the mixture out of the orifice 12. Additionally, the diffusing surface 18 is located downstream from inlets 36A-36C and is effective to direct fluid components to the outlet to mix and dispense therethrough by a pressurized carrier fluid; therefore, the diffusing surface 18 must exhibit an appropriate shape to perform its intended function while minimizing the chances of device obstruction. For example, while the diffusing surface 18 shown in FIGS. 2 and 3 is located within a cylindrical cover 10 having a flat circular outer end surface and containing a centrally located slot-shaped hole 12, this geometry is not required.

As represented in FIGS. 2 and 3, the outer surface of the cover is parallel to the diffusing surface. While such a parallel configuration of the outer surface of the cover is preferred, it is understood to be merely exemplary and not a requirement of the pressurized delivery system of the present invention. Similarly, while both FIGS. 2 and 3 show covers exhibiting axial symmetry, such axial symmetry is merely preferred and not indispensable. Where the covers of the present invention are symmetrical, the symmetry can be axial or mirror symmetry. It is expected that variations in the shapes of the diffuser surface and nozzle configurations can be developed through routine experimentation. With respect to the inputs, the pressurized delivery device of the present invention generally requires a plurality of fluid component inputs for communication with an equal or lesser number of sources of fluid components. While a single fluid carrier entry can be provided, the pressurized delivery device typically provides a plurality of fluid carrier entries. Often the fluid carrier entries are provided for communication with a single source of carrier fluid via a bifurcator or manifold, although a plurality of sources of carrier fluid can be advantageously used also in certain cases. Additionally, inputs are typically located at the terminals of the corresponding opening. In some cases, the openings may be coextensive through an elongated cylindrical connector 30, as shown in FIG. 2 (with 36A-36C describing the openings). Alternatively, the openings may extend through separate tubes. Additionally, pipes and / or pipe members can be constructed to form a set of openings. For example, several lengths of multi-opening administration tubing for use in specific surgical and non-surgical applications. Particularly in laparoscopic applications, it may be useful to use flexible tubing. The pipe serves to maintain the separation of the two fluid components and provides a path for the administration of pressurized gas to the diffusing surface. Additional features also serve to enhance the mixing performance. and administration of the pressurized delivery device of the present invention. As discussed above, two or more fluid components can be individually administered through inputs to impact the diffusing surface. Typically, the components first impact on the diffuser plate near the outlet to reduce the residence time of the components in the device. Any number of media can be used to provide motive power to introduce fluid components through inlets and outlets. Exemplary means of motive power include pumps, compressors, pistons, and so on. Then, as the diffuser plate directs the components towards the outlet 12, and the pressurized carrier fluid simultaneously provides a force to mix and expel the components through the outlet. Accordingly, one or more fluid carrier inputs are positioned so that a high pressure zone is created between the component inlet and the diffuser surface while comparatively a low pressure zone is created downstream from the outlet. "Dead spaces" that serve to trap waste are generally avoided. As a result, a fluid mixture is forced through the outlet in the form of a jet, thereby reducing any potential or actual accumulation of debris that serves to clog the pressurized delivery device. In general, any number of fluid carriers can be employed with the pressurized delivery device of the present invention. For example, him carrier fluid can be gaseous and / or natural liquid. Typically, however, the carrier fluid is chemically inert with respect to the fluid components. Suitable inert gases include, without limitation, air, carbon dioxide, nitrogen, argon, helium, perfluorinated gaseous alkanes and ethers, gaseous chlorofluorocarbons and so forth. Suitable inert liquids include, without limitation, polysiloxanes, perfluroinated polyethers, and so forth. Pressurized air represents an economical and practical fluid carrier for use with the pressurized delivery device. Equipment associated with pressurized air is well known in the art and may include pressurized tanks or cylinders as well as compressors. In some cases, one or more check valves, for example, unidirectional valves, may be provided to prevent fluid component reflux resulting from increased pressure associated with the use of the pressurized delivery device. Such check valves can be positioned upstream of the diffuser surface, for example, within openings associated with the inlets. Such check valves are particularly useful when the inlet openings are cut, for example, about 2 to about 5 centimeters in length, as the potential for reflux tends to be inversely proportional to the length of the openings. openings; however, check valves can be used with longer openings as well. The portions of the device that contact the multicomponent composition and the fluid components thereof must be inert and preferably repellent to the contacted materials. Therefore, portions of the device that contact the fluids in operation must be selected according to the fluids themselves. For example, the device or components thereof can be made of plastic such as polycarbonates, polyurethane, polyesters, acrylics, ABS polymers, polysulfone, and so forth. Adhesion inhibitor coatings such as polysiloxanes, perfluorinated polymers, and so on may also be used. Therefore, the diffusing surface is typically inert and optionally repellent of the fluid components. Similarly, surfaces of openings that can contact the fluid components or the carrier fluid are typically inert and optionally repellent to the corresponding fluids as well. The pressurized delivery device of the present invention is particularly useful for dispensing multicomponent compositions. Although some gaseous components may be used, the pressurized delivery device is particularly useful for liquids. Therefore, at least one fluid component is usually a liquid. Often, each fluid component includes a liquid. For example, the pressurized delivery device is useful for dispensing compositions such as fluid mixtures, where mixing a plurality of fluids results in an increase in viscosity sufficient to affect the mixing flow.

Such compositions can be formed of fluid components that are chemically reactive with respect to each other. In some cases, a cross linking agent can be provided. In practice, then, a diffusing surface having an outlet that extends through itself so that the diffusing surface is downstream of a plurality of fluid component inlets and at least one fluid carrier inlet. A different fluid component is directed from each of the fluid component inlets towards the diffusing surface. In some cases, fluid components are directed to substantially the same flow velocity toward the diffusing surface. Alternatively, the fluid components are directed at different flow rates towards the diffusing surface. Typically, the flow rate of the carrier fluid is greater than that for the fluid components. The diffuser surface maintains and directs each component fluid received in a different flow path to the exit. Pressurized carrier fluid from at least one fluid carrier inlet is also directed through the outlet, thereby mixing the fluid components present in the outlet and dispensing a composition through the outlet. V. Kits The compositions of the invention can also be packaged in kits and used in a variety of medical applications. The kit could include buffer solutions, as well as instructions for use written or otherwise illustrated. A typical kit for use in medical applications comprises: (a) a homogeneous dry powder composition composed of: (i) a first component having a core substituted with m nucleophilic groups, where m = 2; and (ii) a second component having a core substituted with n electrophilic groups, where n = 2 and m + n > 4; where the nucleophilic and electrophilic groups are not reactive in a dry medium but become reactive when exposed to an aqueous medium so that the components interreact in the aqueous medium to form a three-dimensional matrix; (b) a first buffer solution with a pH within the range of about 1.0 to 5.5; and (c) a second buffer solution with a pH within the range of about 6.0 to 11.0; where each component is packed separately and mixed immediately before use. As is clear to those ordinarily skilled in the art, before use, each component must remain in a separate sterilized package. In another embodiment, the kit can further comprise a delivery system that will allow a composition to be administered as a spray. The spray can be generated by manually mixing the components and passing them through a spray nozzle. Spray generation can also be achieved using a gas flow (for example, air, nitrogen, carbon dioxide). Kits contemplated under the present invention will preferably include a delivery system for the compositions of the present invention. Delivery devices that may be included in the kits will preferably be a multicomponent syringe device and / or the pressurized delivery devices described herein. In one embodiment of the kit, a multi-component syringe device is included in the kit. As previously described, the multi-component spray device can be a multi-compartment syringe system with multiple cylinders, a mixing head, and an exit orifice, where the dry powder composition, the first buffer, and the second buffer are housed separately in the multi-compartment syringe system. FIG. 1 describes a preferred embodiment of the multi-compartment device. When provided in a kit, the device is provided with three bags. The first bag is a bag of liquid components, consisting of two syringes that are preassembled in a housing. A transfer door closure is attached to the housing assembly to allow mixing of the dry powders in the correct syringe. A clip is attached to the plunger rod of the syringe that does not require mixing with dry powders. The second bag is a powder component bag, which consists of a syringe containing the dry powder (s) and a desiccant packet. The third bag is an applicator bag, which contains two applicators. To use the preferred kit of FIG. 1, each bag is opened using aseptic techniques and the contents of each bag is transferred to a sterile field. In the sterile field, the liquid and component in powders are prepared in the following manner. Without removing the clip from the syringe, the luer cover on the transfer door lock is removed. The cover is removed from the powder syringe and the powder syringe is connected to the opening of the transfer door closure. The liquid is transferred towards the powder by squeezing the plunger tightly. The content between the two syringes is mixed back and forth between the two syringes until the solid is completely dissolved (eg, 18-20 times). All the contents are then pushed towards the syringe that is in the syringe housing. The powder syringe is decoupled by separating the transfer door lock by grasping the drum of the powder syringe; pressing the levers on the syringe housing; and pulling the empty powder syringe and the transfer door lock from the housing. To expel all the air from the syringe, the tips of the syringes are held, the pistons of the syringes are leveled, the syringe clip is rotated to connect to the other pistons; and holding the syringe upright, all air is expelled from the syringe. As a final step, the applicator is fitted into the end of the syringe housing making the composition ready for use. A clear gel should be seen approximately three minutes after mixing the components. In another embodiment of the kit, a pressurized delivery device is included in the kit. As previously described, the pressurized delivery device of the present invention includes a plurality of fluid component entries each adapted to communicate with a source of different fluid components; at least one carrier fluid inlet adapted to communicate with a source of a pressurized carrier fluid; a diffusing surface located downstream from a plurality of fluid component inlets and at least one fluid carrier inlet; and an outlet extending through the diffusing surface, where the diffusing surface is adapted to receive fluid components therein and has an effective way to direct and maintain each received fluid component in a different flow path to the outlet for mixing and dispensing through itself by the pressurized carrier fluid from at least one fluid carrier inlet. Kits contemplated under the present invention are not limited to the devices described herein and may also include any other suitable delivery device known in the art of drug delivery. Exemplary medical applications include, by way of illustration and without limitation, adhering or sealing biological tissue, administering a biologically active agent (in which case, the kit could further comprise a biologically active agent, for example, mixed with the components to form a mixture homogeneous or packed separately), administering cells and genes (in which case, the kit could further comprise living cells or genes, for example, mixed with the components to form a homogeneous or separately packaged mixture), bioadhesion, in ophthalmic applications, for tissue augmentation , to prevent adhesion, form synthetic implants and coat synthetic implants, and for the treatment of aneurysms. In a preferred embodiment, the mixture of biologically active agents with the components is a homogeneous mixture; however, this feature is not required. Whether packed together or separately, each of the components and the biological agent must be in sterile packaging before use. For purposes of description only, the surgical use of the multi-compartment syringe kit of FIG. 1 is described. As a preliminary step, blood circulation to the surgical site is re-established to expand the graft by opening the site and after the circulation is restored, the site is clamped again to stop circulation. Excess blood is aspirated and all surfaces are air dried after the application of a composition. Holding the applicator approximately 3 cm from the site (touching the site or keeping it more than 6 cm from the site is not recommended), sealant is forcefully applied to the site. To enhance the mix, the applicator is moved quickly along the anastomotic site. If a composition is to be applied to more than one site, the tip of the applicator should be cleaned with gauze and the device should be placed straight to avoid obstruction. If a composition does not become gel within 30 seconds, that is, a composition now remains in place, the site should be rinsed with saline and the material aspirated. If the treated site fails to seal, the surface must be dried; it may be essential to re-clamp the vessel to dry the field for reapplication of a composition. If the applicator becomes blocked, it must be replaced with a new applicator. SAW . Uses The compositions of the present invention can be used in a variety of different applications. In general, the compositions can be adapted for use in any tissue engineering application where synthetic gel matrices are currently used. For example, the compositions are useful as tissue sealants, vascular sealants, in tissue augmentation, in tissue repair, as hemostatic agents, in prevention of tissue adhesion, in favoring surface modifications, and in drug / cell administration applications. / genes and they can be used in a variety of open, endoscopic and laparoscopic surgical procedures. One skilled in the art can easily determine the appropriate administration protocol for use with any particular composition having known gel strength and gel time. A more detailed description of several specific applications is given below. 1. Tissue Sealants and Adhesives In one application, the compositions described herein may be used for medical conditions that require a coating or sealing layer to prevent the escape of gases, liquids or solids. The method involves applying a composition to the damaged tissue or organ to be sealed 1) vascular tissue and / or other tissues or organs to stop or minimize blood flow; 2) chest tissue to stop or minimize air leakage; 3) digestive tube or pancreatic tissue to stop or minimize the escape of fecal contents or tissues; 4) bladder or urethra to stop or minimize the escape of urine; 5) hard to stop or minimize CSF escape; and 6) skin or serous tissue to stop the leakage of serous fluid. These compositions can also be used to adhere tissues together such as small vessels, nerves or dermal tissue. The compositions can be used 1) by applying them to the surface of a fabric and then a second tissue can be quickly pressed against the first tissue or 2) by placing the tissues in close juxtaposition and then applying the compositions. Additionally, the compositions can be used to fill spaces in soft and hard tissues that are created by disease or surgery. Thus, one embodiment of the invention is a method of sealing tissue of a patient comprising the steps of: (a) providing a composition of the invention; and (b) making the reactive nucleophilic and electrophilic groups by exposing a composition to an aqueous medium to effect interreaction; wherein said exposure comprises: (i) dissolving a composition in a first buffer solution with a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution with a pH within the range of about 6.0 to 11.0 to the homogeneous solution to form a mixture; and (c) placing the mixture in contact with tissue and allowing a three-dimensional matrix to form and seal the tissue. In another embodiment, the compositions can be applied in conjunction with an implanted medical device such as to prevent the escape of gases, liquids or solids from the device or from the device-tissue interface. For example, after implantation of a vascular graft (either synthetic or biological), There is often leakage of blood through the suture holes in the graft or at the interface between the graft and the tissue. A composition of the invention can be applied to this area to prevent further leakage of blood. In certain aspects of the invention, a composition can be further combined with a fibrosing agent to further enhance the properties of the sealant or adhesive. In one aspect of the present invention, a fibrosing (ie, healing) can be included in a polymeric sealant spray that solidifies in a film or coating to promote fibrosis and seal air leaks. In an illustrative application, a fibrosing agent may be included with the composition of the polymer for use as a pulmonary sealant during open or endoscopic lung reduction surgeries, for example, for pulmonary ampullae in open or endoscopic lung destruction procedures. The addition of a fibrosis inducing agent as a pulmonary sealant can induce the formation of a stable, fibrous scar that permanently seals the parietal surface of the lung in the surgical site (or the alveolar surface of the lung if administered endoscopically during lung reduction surgery). , reduces hospitalization time and prevents recurrence of air leakage. Clinically an inducing pulmonary sealant of fibrosis can be useful to improve the results in open lung surgery, endoscopic surgery for lung reduction due to emphysema (severe COPD), esophageal leaks after endoscopy or resection, complications of treatment of other intra-thoracic malignancies, pleural effusion, hemothorax, pneumothorax, chylothorax, aspiration complications, and tuberculosis. It should be apparent to one skilled in the art that potentially any adhesion promoting agent or fibrosis described above can be used alone, or in combination with the present composition, in the practice of this embodiment. Exemplary fibrosing agents for use in sealants and adhesives include talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin, and connective tissue growth factor (CTGF), as well as analogs and derivatives of the aforementioned. The exact dose administered may vary with the composition of the sealant or adhesive; however, certain principles can be applied in the application of this technique. Dosage of drug can be calculated as a function of dose per unit area (of the amount of sealant being applied), total dose of drug administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of incorporation of the drug into the sealant or adhesive, exemplary fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines: Using talc as an exemplary agent for fibrosis induction, the total dose of talc administered from a sealant, or coated on the surface of One lung, should not exceed 100 mg (range from 1 μg to 100 mg). In one embodiment, the total amount of talc released from sealant should be in the range of 10 μg to 50 mg. The dose per unit area (ie, the dosage of talc as a function of the surface area of the lung to which the drug is applied) should fall within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In another embodiment, talc should be applied to the surface of a lung at a dose of 0.05 μg / mm2 -10 μg / mm2 of coated surface area. Using silk as an exemplary agent of fibrosis induction, the total dose of silk administered from a pulmonary sealant, or coated on the surface of a lung, should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount of silk released from sealant should be in the range of 10 μg to 50 mg. The dose per unit area (ie, the dosage of silk as a function of the surface area of the lung to which the drug is applied) must fall within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In another embodiment, silk should be applied to the surface of a lung at a dose of 0.05 μg / mm2 -10 μg / mm2 of coated surface area. Since specific drug delivery vehicles (polymeric and non-polymeric) and specific lung sealants can administer silk at different rates, the above dosage parameters should be used in combination with the rate of administration of the drug from sealant such that a minimum concentration of 0.01 nM to 1000 μM of silk is administered to the tissue. Using chitosan as an exemplary agent of fibrosis induction, the total dose of chitosan administered from a pulmonary sealant, or coated on the surface of a lung, should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount of chitosan released from sealant should be in the range of 10 μg to 50 mg. The dose per unit area (ie, the dosage of chitosan as a function of the surface area of the lung to which the drug is applied) should fall within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In another embodiment, chitosan must be applied to the surface of a lung at a dose of 0.05 μg / mm2 -10 μg / mm2 of coated surface area.

As specific drug delivery vehicles (polymeric and non-polymeric) and specific lung sealants can administer chitosan at different speeds, the above dosage parameters should be used in combination with the rate of administration of the drug from sealant such that a Minimum concentration of 0.01 nM to 1000 μM of chitosan is administered to the tissue. Using polylysine as an exemplary agent of fibrosis induction, the total dose of polylysine administered from a pulmonary sealant, or coated on the surface of a lung, should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount of polylysine released from sealant should be in the range of 10 μg to 50 mg. The dose per unit area (ie, the dosage of polylysine as a function of the surface area of the lung to which the drug is applied) should fall within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In another embodiment, polylysine must be applied to the surface of a lung at a dose of 0.05 μg / mm 2 -10 μg / mm 2 of coated surface area. As specific drug delivery vehicles (polymeric and non-polymeric) and specific lung sealants can administer polylysine at different speeds, the parameters of Prior dosages should be used in combination with the rate of administration of the drug from sealant such that a minimum concentration of 0.01 nM to 1000 μM of polylysine is administered to the tissue. Using fibronectin as an exemplary agent of fibrosis induction, the total dose of fibronectin administered from a pulmonary sealant, or coated on the surface of a lung, should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount of fibronectin released from sealant should be in the range of 10 μg to 50 mg. The dose per unit area (ie, the dosage of fibronectin as a function of the surface area of the lung to which the drug is applied) must fall within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In another embodiment, fibronectin should be applied to the surface of a lung at a dose of 0.05 μg / mm2 -10 μg / mm2 of coated surface area. Since specific drug delivery vehicles (polymeric and non-polymeric) and specific lung sealants can administer fibronectin at different rates, the above dosage parameters should be used in combination with the rate of administration of the drug from sealant such that a Minimum concentration of 0.01 nM to 1000 μM fibronectin is administered to the tissue.

Using bleomycin as an exemplary agent of fibrosis induction, the total dose of bleomycin administered from a pulmonary sealant, or coated on the surface of a lung, should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount of bleomycin released from sealant should be in the range of 0.010 μg to 50 mg. The dose per unit area (ie, the dosage of bleomycin as a function of the surface area of the lung to which the drug is applied) must fall within the range of 0.005 μg - 10 μg per mm.2 of coated surface area. In another embodiment, bleomycin should be applied to the surface of a lung at a dose of 0.05 μg / mm2 -10 μg / mm2 of coated surface area. As specific drug delivery vehicles (polymeric and non-polymeric) and specific lung sealants can administer bleomycin at different rates, the above dosage parameters should be used in combination with the rate of administration of the drug from sealant such that a Minimum concentration of 0.001 nM to 1000 μM of bleomycin is administered to the tissue. Using GTGF as an exemplary agent of fibrosis induction, the total dose of GTGF administered from a pulmonary sealant, or coated on the surface of a lung, should not exceed 100 mg (range of 1 μg to 100 mg).

In one embodiment, the total amount of GTGF released from sealant should be in the range of 0.10 μg to 50 mg. The dose per unit area (ie, the dosage of GTGF as a function of the surface area of the lung to which the drug is applied) must fall within the range of 0.005 μg - 10 μg per mm2 of coated surface area. In another embodiment, GTGF should be applied to the surface of a lung at a dose of 0.05 μg / mm2 -10 μg / mm2 of coated surface area. As specific drug delivery vehicles (polymeric and non-polymeric) and specific lung sealants can administer GTGF at different rates, the above dosage parameters should be used in combination with the rate of administration of the drug from sealant such that a Minimum concentration of 0.001 nM to 1000 μM of GTGF is administered to the tissue. The fibrosing agent (eg, talc, silk, chitosan, polylysine, fibronectin, bleomycin, CTGF) can be released from lung sealant such that fibrosis in the tissue is promoted for a period ranging from a few hours to several months. For example, the fibrosing agent can be released in effective concentrations for a period ranging from 1 hour to 30 days. It should be easily evident given the discussions shown in the present that analogues and derivatives of the fibrosing agent (eg, analogues and derivatives of talc, silk, chitosan, polylysine, fibronectin, bleomycin, CTGF, as previously described) with similar functional activity can be used for the purposes of this invention; the above dosage parameters are then adjusted according to the relative potency of the analog or derived derivative compared to the parent compound (for example, a compound twice as potent as the agent is administered at half of the above parameters, a compound half as powerful as the agent is administered twice the previous parameters, etc.). Optionally, the sealant may alone or additionally comprise an inflammatory cytokine (eg, TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-α, IL-1, IL-β-β, IL-8, IL-6, and growth hormone) or an analogue or derivative thereof. Inflammatory cytokines are to be used in formulations at concentrations ranging from 0.0001 μg / ml to approximately 20 mg / ml depending on the specific clinical application, type of formulation (eg, gel, liquid, solid, semi-solid), chemical the formulation, duration of the indispensable application, type of medical device interface and volume of formulation and / or coverage of the required surface area.

Preferably, the inflammatory cytokine is released in effective concentrations for a period ranging from 1 to 180 days. The total dose for a single application typically does not exceed 500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a device coating, the dose is per unit area of 0.0001 μg -500 μg per mm2; with a preferred dose of 0.001 μg / mm2 -200 μg / mm2. Minimum concentration of 10-10 - 10-4 g / ml of inflammatory cytokine should be maintained on the surface of the device. Additionally, the sealant can alone or additionally comprise an agent that stimulates cell proliferation. Examples include: dexamethasone, isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, la-25 dihydroxyvitamin D3, diethylstibesterol, cyclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analogs and derivatives thereof. Used doses are those concentrations that are shown to stimulate cell proliferation. The proliferating agents are to be used in formulations at concentrations ranging from 0.0000001 to 25 mg / ml depending on the specific clinical application, type of formulation (eg, gel, liquid, solid, semi-solid), chemical formulation, indispensable application duration, type of medical device interface and formulation volume and or coverage of required surface area. Preferably, the proliferative agent is administered in effective concentrations for a period ranging from 1 to 180 days. The total dose for a single application typically does not exceed 500 mg (range of 0.0001 μg to 200 mg); preferred 0.001 μg to 100 mg. When used as a device coating, the dose is per unit area of 0.00001 μg - 500 μg per mm2; with a preferred dose of 0.0001 μg / mm2 - 200 μg / mm2. Minimum concentration of 10-11 - 10-6 g / ml of proliferating agent must be maintained on the surface of the device. 2. Administration of biologically active agent The compositions can also be used for localized administration of various drugs and other biologically active agents. The biologically active agent can be mixed with the compositions of the invention or chemically coupled to one of the individual components in a composition, for example, by binding to one of the reactive groups. For example, processes for covalent attachment of biologically active agents such as growth factors using functionally activated polyethylene glycols are described in US Pat. 5,162,430 to Rhee et al. Such compositions preferably include linkages that can be readily biodegraded, for example as a result of enzymatic degradation, resulting in the release of the active agent to the target tissue, where it will exert its desired therapeutic effect. In certain aspects, the biologically active agent can be incorporated with a polymeric or non-polymeric carrier to facilitate incorporation of the agent into a composition. In certain aspects, the carrier may facilitate the sustained administration of the agent of a composition for a prolonged period of time (for example, in the course of several days, weeks, or months). For many embodiments, localized administration as well as sustained localized administration of the agent may be desired. For example, a therapeutic agent can be mixed with, conjugated with, bound to, or otherwise modified to contain a polymeric composition (which can be biodegradable or non-biodegradable) or non-polymeric composition for administering the therapeutic agent during a treatment. time frame. Representative examples of biodegradable biopolymers suitable for the administration of therapeutic agents include albumin, collagen, gelatin, hyaloronic acid, starch, cellulose and cellulose derivatives (eg, regenerated cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose, fthalate), casein, dextrans, polysaccharides, fibrinogen, poly (ester ester) block multicopolymers, based on poly (ethylene glycol) and poly (butylene terephthalate), polycarbonates derived from tyrosine (for example, US Patent No. 6,120,491), poly (hydroxy acid), poly (D, L-lactide), poly (D, L-lactide-co-glycolide), poly (glycolide), poly (hydroxybutyrate), polydioxanone, poly (alkylcarbonate) and poly (orthoesters), polyesters, poly (hydroxyvaleric acid) ), polydioxanone, polyesters, poly (malic acid), poly (tartronic acid), poly (acrylamides), polyanhydrides, polyphosphazenes, poly (amino acids), poly (alkylene oxide) -poly (ester) block copolymers (for example, XY , XYX, YXY, R- (YX) n, or R- (XY) n, where X is a polyalkylene oxide (for example, poly (ethylene glycol), poly (propylene glycol) and poly (oxide) block copolymers ethylene) and poly (propylene oxide) (for example, PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive , NJ) and Y is a polyester, wherein the polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta -butyrolactone, gamma-butyrolactone, gamma-valerolactone,? -decanolactone, d-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1, 5-dioxepan-2one (eg, PLGA, PLA, PCL, polydioxanone and copolymers thereof) and R is a multifunctional initiator), and the copolymers as well as mixtures thereof (see generally, Illum, L., Davids, SS (eds.) "Polymers in Controlled Drug Delivery" Wright, Bristol, 1987; Arshady, J. Controlled Relay 17: 1-22, 1991; Pitt, Int. J. Phar. 59: 173-196, 1990; Holland et al., J. Controlled Release 4: 155-0180, 1986). Representative examples of degradable non-polymers suitable for the administration of therapeutic agents include poly (ethylene-co-vinyl acetate) ("EVA") copolymers, aromatic polyesters, such as poly (ethylene terephthalate), silicone rubber, acrylic polymers ( polyacrylate, polyacrylic acid, polymethylacrylic acid, polymethylmethacrylate, poly (butyl methacrylate)), poly (alkyl-acrylate) (for example, poly (ethyanocyanoacrylate), poly (butylcyanoacrylate) poly (hexylcyanoacrylate) poly (octylcyanoacrylate)), acrylic resin, polyethylene, polypropylene, polyamides (nylon 6,6), polyurethanes (for example, CHRONOFLEX AL and CHRONOFLEX AR (both from CardioTech International Inc., Woburn, MA), TECOFLEX, and BIONATE (Polymer Technology Group, Inc., Emeryville, CA )),, poly (ester urethanes), poly (ether urethanes), poly (ester urea), polyethers (poly (ethylene oxide), poly (propylene oxide), polyoxyalkylene ether) block copolymers based on ethylene oxide and propylene oxide such as PLURONIC polymers (eg, F-127 or F87) from BASF Corporation (Mount Olive, NJ), and poly (tetramethylene glycol), polymers based on styrene (polystyrene) , poly (stirene sulphonic acid), poly (stirene) -block-poly (isobutylene) -block-poly (stirene), poly (stirene) -poly (isoprene) block copolymers), and vinyl polymers (polyvinylpyrrolidone, poly (vinyl) alcohol), poly (vinyl acetate phthalate) as well as copolymers and mixtures thereof Polymers can also be developed that are anionic (eg, alginate, carrageenans, carboxymethyl cellulose, poly (acrylamido-2-methyl propane sulfonic acid) and copolymers thereof, poly (methacrylic acid and copolymers thereof and poly (acrylic acid) and copolymers thereof, as well as mixtures thereof, or cationic (e.g., chitosan, poly-L-lysine, polyethylene imine, and poly (allil amine)) and of them (see generally, Dunn et al., J. Applied Polymer Sci. 50: 353-365, 1993; Cascone et al., J. Materials Sci .: Materials in Medicine 5: 770-774, 1994; Shiraishi et al., Biol. Pharm. Bull. 16 (11): 1164-1168, 1993; Thacharodi & Rao, Int'l J. Pharm. 120: 115-118, 1995; Miyazaki et al., Int'l J. Pharm. 118: 257-263, 1995).

Some examples of preferred polymer carriers for the practice of this invention include poly (ethylene-co-vinyl acetate), polyurethanes, poly (D, L-lactic acid) oligomers and polymers, poly (L-lactic acid) oligomers and polymers, poly (glycolic acid), copolymers of lactic acid and glycolic acid, copolymers of lactide and glycolide, poly (caprolactone), poly (valerolactone), polyanhydrides, copolymers of poly (caprolactone) or poly (lactic acid) with polyethylene glycol (for example , MePEG), block copolymers of the form XY, XYX, YX- Y, R- (YX) n, or R- (XY) n, where X is a polyalkylene oxide (for example, poly (ethylene glycol, poly (propylene glycol) and block copolymers of poly (ethylene oxide) and poly (propylene oxide) (for example, PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a polyester, where the polyester can comprise the waste of one or more of the monomers sele of lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, β-decanolactone, d-decanolactone, trimethylene carbonate, , 4-dioxane-2-one or 1,5-dioxepan-2one and R is a multifunctional initiator), silicone gums, poly (styrene) block-poly (isobutylene) -block poly (styrene), poly (acrylate) polymers and mixtures, combinations, or co-polymers of any of the foregoing. Other preferred polymers include collagen, poly (alkylene oxide) -based polymers, polysaccharides such as hyaloronic acid, chitosan and fucans, and polysaccharide copolymers with degradable polymer. Other representative polymers capable of sustained local administration of therapeutic agents described herein include carboxylic polymers, polyacetates, polycarbonates, polyethers, polyethylenes, polyvinyl butyrals, polysilanes, polyureas, polyoxides, polystyrenes, polysulfides, polysulfones, polysulfonides, polyvinylalides, pyrrolidones, gums, polymers. thermal drying, acrylic and crosslinkable methacrylic polymers, ethylene acrylic acid copolymers, acrylic styrene copolymers, vinyl acetate polymers and copolymers, vinyl acetal polymers and copolymers, epoxies, melamines, other amino resins, phenolic polymers, and copolymers thereof, water-insoluble cellulose ester polymers (including cellulose acetate propionate, cellulose acetate, cellulose acetate butyrate, cellulose nitrate, cellulose acetate phthalate, and mixtures thereof), polyvinylpyrrolidone, polyethylene glycols, polyethylene oxide, polyvinyl alcohol, polyethers, polysaccharides, hydrophilic polyurethane, polyhydroxyacrylate, dextran, xantan, hydroxypropyl cellulose, and homopolymers and copolymers of N-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinyl caprolactam, other vinyl compounds with pendant polar groups, acrylate and methacrylate with hydrophilic esterifying groups, hydroxyacrylate , and acrylic acid, and combinations thereof; cellulose esters and ethers, ethyl cellulose, hydroxyethyl cellulose, cellulose nitrate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, natural and synthetic elastomers, gum, acetal, styrene polybutadiene, acrylic resin, polyvinylidene chloride, polycarbonate, homopolymers and copolymers vinyl, polyvinylchloride, and polyvinylchloride acetate compounds. Representative examples of patents relating to drug delivery polymers and their preparation include PCT Publication Nos. WO 98/19713, WO 01/17575, WO 01/41821, WO 01/41822, and WO 01/15526 (as well as the corresponding applications). USA), US Patents 4,500,676; 4,582,865 5,143,724 4,113,743 5,069,899 5,099,013 5,128,326 5,143,724 5,153,174 5,246,698 5,266,563 5,399,351 5,525,348 5,800,412 5,837,226 5,942,555 5,997,517 6,007,833 6,071,447 6,090,995 6,106,473 6,110,483 6,121,027 6,156,345 6,214,901 6,368,611 6,630,155; 6,528,080; RE37,950 , 46.1631; 6,143,314 5,990,194 5,792,469 5,780,044, 759,563; 5,744,153 5,739,176 5,733,950 5,681,873 ,599,552; 5,340,849 5,278,202; 5,278,201; 6,589,549 6,287,588; 6,201,072 6,117,949; 6,004,573; 5,702,717 6,413,539; 5,714,159; 5,612,052; and Publications of Patent Applications US 2003/0068377, 2002/0192286, 2002/0076441, and 2002/0090398. It should be obvious to anyone skilled in the art that the polymers as described herein can also be mixed or copolymerized into various compositions as indispensable to administer therapeutic doses of biologically active agents. Drug administration vehicles can take a variety of forms. For example, the carrier can be in the form of microspheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly (alkylcyanoacrylate)), nanospheres (PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly ( alkylcyanoacrylate)) (see, for example, Hagan et al., Proc. Intern Symp. Control Reí. Bioact. Mater. 22, 1995; Kwon et al., Pharm Res. 12 (2): 192-195; Kwon et al. al., Pharm Res. 10 (7): 970-974, Yokoyama et al., J. Contr. Re. 32: 269-277, 1994; Gref et al., Science 263: 1600-1603, 1994; Bazile et al. al., J. Pharm. Sci. 84: 493-498, 1994), emulsions (see, for example, Tarr et al., Pharm Res. 4: 62-165, 1987), microemulsions, micelles (SDS, block copolymers of the form XY, YXY, R- (YX) n, R- (XY) n and XYX (where X is a polyalkylene oxide (for example, poly (ethylene glycol, poly (propylene glycol)) and block copolymers of poly (ethylene oxide) and poly (propylene oxide) (for example, PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, wherein the polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone,? -decanolactone , d-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2one (eg, PLG-PEG-PLG) and R is a multifunctional initiator), and zeolites. which can be used to contain and administer therapeutic agents described in the pres include: cyclodextrins, such as hydroxypropyl cyclodextrin (Cserhati and Holló, Int. J. Pharm. 108: 69-75, 1994), liposomes (see, for example, Sharma et al., Cancer Res. 53: 5877-5881, 1993; Sharma and Straubinger, Pharm. Res. 11 (60): 889-896, 1994;; WO 93/18751; US Patent No. 5,242,073), liposo a / gel (WO 94/26254), nanocapsules (Bartoli et al., J. Microencapsulation 7 (2) A91-197, 1990), implants (Jampel et al., Invest. Ophthalm., Vis. Science 34 (11): 3076-3083, 1993; Walter et al., Cancer Res. 54: 22017-2212, 1994), nanoparticles (Violante and Lanzafame PAACR), nanoparticles - modified (US Patent No. 5,145,684), nanoparticles (modified surfaces) (US Patent No. 5,399,363), micelles such as sn described in Alkan-Onyuksel et al., Pharm. Res. 11 (2): 206-212, 1994), micelle (surfactant) (US Patent No. 5,403,858), synthetic phospholipid compounds (US Patent No. 4,534,899), gas dispersion (US Pat. No. 5,301,664), liquid emulsions, foam, spray, gel, lotion, cream, ointment, dispersed vesicles, solid or liquid aerosol particles or droplets, microemulsions (US Patent No. 5,330,756), polymer shell (nano) - and microcapsule) (US Patent No. 5,439,686), and implants (US Patent No. 4,882,168). Within certain aspects of the present invention, therapeutic agents can be modeled in the form of microspheres, microparticles and / or nanoparticles with any size ranging from 50 nm to 500 μm, depeg on the particular use. These compositions can be formed by spray drying methods, milling methods, accumulation methods, W / O emulsion methods, W / O / W emulsion methods, and solvent evaporation methods. In other aspects, these compositions may include microemulsions, emulsions, liposomes and micelles. Compositions comprising a drug-laden carrier can also be easily applied as a "spray", which solidifies in a film or coating for use as a device / implant surface coating or for coating the tissues of the implantation site. Such sprays can be prepared from microspheres of a wide variety of sizes, including for example, from 0.1 μm to 3 μm, from 10 μm to 30 μm, and from 30 μm to 100 μm. In one aspect, biologically active agents such as growth factors or fibrotic inducing agents can be administered from a composition to a local tissue site to facilitate scar formation, tissue healing, and / or regeneration. Therefore, in one aspect, a method is provided for administering a biologically active agent, wherein a composition also includes the biologically active agent (e.g., a fibrosing agent) to be administered, and steps (a) and (b) are described for the method of sealing tissue. Step (c) could involve allowing a three-dimensional matrix to form and administering the biologically active agent. As described above, a composition can include an agent that promotes fibrosis. Compositions that include a fibrosis inducing agent can be used in a variety of applications, including, without limitation, tissue augmentation, bone growth, treatment of aneurysms, filling and blocking of voids in the body, coatings of medical devices, and for use in sealant compositions. In certain embodiments, the fibrosis or adhesion inducing agent is silk. Silk refers to a fibrous protein, and can be obtained from a number of sources, typically spiders and silkworms. Typical silks contain about 75% real fiber, called as fibroin, and about 35% sericin, which is one is a sticky protein that holds the filaments together. Silk filaments are usually very thin and long - about 300-900 meters in length. There are several species of domesticated silkworms that are used in commercial silk production, however, Bo byx mori is the most common, and most of the silk comes from this source. Other suitable silkworms include Philosamia cynthia ricini, Antheraea yamamai, Antheraea pernyi, and Antheraea mylitta. Spider silk is relatively more difficult to obtain, however, recombinant techniques are promising as a means of obtaining spider silk at economic prices (see, for example, US Patents No. 6,268,169, 5,994,099, 5,989,894, and 5,728,810, which they are exemplary only). Biotechnology has allowed Researchers develop other sources for silk production, including animals (eg, goats) and vegetables (eg, potatoes). Silk from any of those sources can be used in the present invention. A silk protein is commercially available from Croda, Inc., of Parsippany, NJ, and is sold under the trade names CROSILK LIQUID (silk amino acids), CROSILK 10,000 (hydrolyzed silk), CROSILK POWDER (powdered silk), and CROSILKQUAT ( cocodiamonium hydroxypropyl amino acid silk). Another example of a commercially available silk protein is SERICIN, available from Pentapharm, LTD, a division of ordia, BV, of the Netherlands. More details of these silk protein blends can be found in US Pat. No. 4,906,460, to Kim, et al., Assigned to Sorenco. Silk useful in the present invention includes natural (raw) silk, hydrolyzed silk, and modified silk, that is, silk which underwent chemical, mechanical, or steam treatment, for example, acid treatment or acylation (see, for example, Patent EE). No. 5,747,015). Raw silk is typically twisted into a thread strong enough to weave or spin. Four different types of silk thread can be produced by this procedure: organza, crepe, weft and simple thrown. Organza is a thread made by giving the raw silk a preliminary twist in one direction and then twisting two of these threads together in the opposite direction. Crepe is similar to organza but is twisted to a much greater extent. Twisting in only one direction two or more raw silk threads makes the plot.

Simple thrown are single strands of raw silk that are twisted in only one direction. Any of these types of silk threads can be used in the present invention. The silk used in the present invention can be in any suitable form that allows the silk to be attached with the medical implant, for example, the silk may be in wire or powder-based forms. Silk can be prepared in the pulverized form by several different methods. For example, silk can be milled (for example, criomolienda) in the powdered form. Alternatively the silk can be dissolved in a suitable solvent (for example, HFIP or 9M LiBr) and then sprayed (electrospray, dry spray) or added to a non-solvent to produce a powder. Additionally, the silk may have any molecular weight, where several molecular weights are typically obtained by the hydrolysis of natural silk, where the extent and hardness of the hydrolysis conditions determine the molecular weight of the product. By example, silk may have an average molecular weight (number or weight) from about 200 to 5,000. See, for example, JP-B-59-29199 (Japanese Patent Examined Publication) for a description of conditions that can be used to hydrolyze silk. A silk discussion can be found in the following documents, which are exemplary only: Hinman, M.B., et al. "Synthetic spider silk: a modular fiber" Trends in Biotechnology, 2000, 18 (9) 374-379; Vollrath, F. and Knight, D.P. "Liquid crystals spinning spider silk" Nature, 2001, 410 (6828) 541-548; and Hayashi, C.Y. , et al. "Hypotheses that correlate the sequence, structure, and mechanical properties of spider silk proteins" Int. J. Biol. Macromolecules, 1999, 24 (2-3), 265-270; and US Patent No. 6,427,933. Other representative examples of fibrosis and adhesion-inducing agents include irritants (eg, talcum powder, talcum powder, copper, beryllium metal (or its oxides), wool (eg, animal wool, plant wool, and synthetic wool), quartz powder , silica, crystalline silicates), polymers (e.g., polylysine, polyurethanes, poly (ethylene terephthalate), polytetrafluoroethylene (PTFE), poly (alkylcyanoacrylates), and poly (ethylene-co-vinylacetate)); vinyl chloride and vinyl chloride polymers; peptides with high lysine content; growth factors and inflammatory cytokine involved in angiogenesis, fibroblast migration, fibroblast proliferation, ECM synthesis and tissue remodeling, such as epidermal growth factor (EGF) family, transformation-a growth factor (TGF-.a), transforming growth factor-ß (TGF-ß- 1, TGF-ß-2, TGF-ß-3), platelet-derived growth factor (PDGF), fibroblast growth factor (acidic - aFGF; and basic - bFGF), fibroblast-1 stimulating factor, activins, vascular endothelial growth factor (including VEGF-2, VEGF-3, VEGF-A, VEGF-B, VEGF-C, growth factor of placenta - PIGF), angiopoietins, insulinogenic growth factors (IGF), hepatocyte growth factor (HGF), connective tissue growth factor (CTGF), myeloid colony stimulating factor (CSFs), monocyte chemoattractant protein, granulocyte-macrophage colony stimulating factor (GM-CSF) ), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), erythropoietin, interleukins (particularly IL-1, IL-8, and IL-6), tumor necrosis factor-a (TNF-a), nerve growth factor (NGF), interferon-D- ... Xnterferon-D ~ ..histamine, endothelin-1, angiotensin II, growth hormone (GH), and synthetic peptides, analogs or derivatives thereof factors are also suitable for administration from implants and specific devices to be described later. Other examples include CTGF (connective tissue growth factor); inflammatory microcrystals (e.g., crystalline minerals such as crystalline silicates); bromocriptine, metilsergide, methotrexate, chitosan, N-carboxybutyl chitosan, carbon tetrachloride, thioacetamide, fibrosin, ethanol, bleomycin, natural or synthetic peptides containing the sequence Arg-Gly-Asp (RGD), generally in one or both terminals (see for example , US Patent No. 5,997,895), and tissue adhesives, such as cyanoacrylate and poly (ethylene glycol) -methylated collagen crosslinked compositions, as described below. Other examples of fibrosis inducing agents include agents that promote bone growth, such as, for example, bone morphogenic proteins. Examples of bone morphogenic proteins include the following: BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9 , BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Of these, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. Bone morphogenic proteins are described, for example, in US Pat. No. 4,877,864; 5,013,649; 5,661,007; 5,688,678; 6,177,406; 6,432,919; and 6,534,268, and Wozney, J.M., et al. (1988) Science, 242 (4885): 1528-1534.

Other representative examples of fibrosis inducing agents include components of the extracellular matrix (e.g., fibronectin, fibrin, fibrinogen, collagen (e.g., bovine collagen), fibrillar and non-fibrillar collagen, glycoprotein adhesive, proteoglycan (e.g., heparin sulfate). , chondroitin sulfate, dermatan sulfate), hyaluronan, cysteine-rich and secreted protein acid (SPARC), thrombospondin, tenascin, and cell adhesion molecules (including integrins, vitronectin, fibronectin, laminin, hyaluronic acid, elastin, bitronectin), proteins found in base membranes, and fibrosin) and metalloproteinase matrix inhibitors, such as TIMPs (metalloproteinase matrix inhibitor tissues) and synthetic TIMPs, eg, marimistat, bathimistate, doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS 27023A, and BMS-275291. Within various configurations of the invention, the composition incorporates a compound that acts to stimulate cell proliferation. In certain configurations, the composition may incorporate a compound that acts to stimulate cell proliferation in addition to a fibrosing agent. Representative examples of agent that stimulate cell proliferation include pyruvic acid, naltrexone, leptin, D-glucose, insulin, a lodipin, alginate oligosaccharides, minoxidil, dexamethasone, isotretinoin (13-cis retinoic acid), 17-ß-estradiol, estradiol, la-25 dihydroxyvitamin D3, diethylstilbestrol, cyclosporin A, L-NAME (L-NG-nitroarginine methyl ester (hydrochloride)), all-trans retinoic acid (ATRA), and analogs and derivatives thereof. Other examples of agents that stimulate cell proliferation include: sphingosine 1-phosphate receptor fighter (e.g., FTY-720 (1,3-propanediol, 2-amine-2- (2- (4-octylphenyl) ethyl) -, hydrochloride; immunostimulants, such as Imupedone (methanone, [5-amine-2- (4-methyl-1-piperidinyl) phenyl] (4-chlorophenyl) -, DiaPep227 synthetic peptide (Peptor Ltd., Israel)); nerve growth factor, for example, NG-012 (5H, 9H, 13H, 21H, 25H, -dibenzo [k, u] [1,5,9,15,19] pentaoxacicotetracosine-5, 9, 13, 1, 25-pentone, 7.8, 11, 12,15,16,23,24,27,28-decahydro-2,4,88,20-tetrahydroxy-11- (hydroxymethyl) -7, 15.23, 27-tetramethyl-, NG-121, SS-701 (2,2 ': 6', 2"-terpyridine, '- (4-methylphenyl) -, trihydrochloride, AMPAlex (piperidine, 1- (6- quinoxalinylcarbonyl) - , RGH-2716 (8- [4,4-bis (4-fluorophenyl) butyl] -3- (1, 1-dimethylethyl) -4-methylene-1-oxa-3, 8-diaza-spiro [4.5] decan -2-one, and TDN-345 (l-oxa-3,8-diazaspiro [4.5] decan-2-one, 8- [4,4-bis (4- f luorophenyl) butyl] -3- (1,1-dimethylethyl) -4-methylene-).

Biologically active agents particularly useful for use in the compositions of the present invention are cytokines, which are biologically active molecules that include growth factors and active peptides, which aid in the healing or re-growth of normal tissue. The function of the cytokines is twofold: 1) they can incite the local cells to produce new collagen or tissue, or 2) they can attract cells to the site in need of correction. As such, cytokines, as well as appropriate combinations of cytokines, serve to support "biological anchoring" of an implant within the host tissue, by facilitating re-growth and remodeling of the implant within normal bone tissue. Cytokines can also be used in the treatment of injuries. Examples of cytokines include, for purposes of illustration and not limitation, the transformation of growth factors (TGFs); fibroblast growth factors (FGFs), including FGF and basic FGF acids; platelet-derived growth factors (PDGFs) such as PDGF-AA, PDGF-AB, and PDGF-BB; epidermal growth factors (EGFs); peptides activated by connective tissues (CTAPs); colony stimulation factors (CSFs); erythropoietin (EPO); nerve growth factor (NGF); osteogenic factors; β-thromboglobulin; necrosis factors of tumors (TNFs); interleukins; interferons (IFNs); bone morphogenic protein (BMP); and analogues, fragments and biologically active derivatives of such growth factors. Members of the supergroup family of transforming growth factor (TGF), which are multifunctional regulatory proteins, are particularly preferred. Members of the TGF super gene family include TGF-α and beta-transforming growth factor (e.g., TGF-β1, TGF-β2, TGF-β3); bone morphogenetic proteins (e.g., BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9); heparin binding growth factors, eg, FGFs; EGFs; PDGFs; growth factors such as insulin (IGFs); inhibins such as Inhibin A and Inhibin B; growth-differentiating factors, for example, GDF-1); and activins such as Activin A, Activin B, Activin AB. Growth factors can be isolated from native or natural sources, such as from mammalian cells, or they can be prepared synthetically, such as by means of recombinant DNA techniques or by means of various chemical processes. In addition, analogues, fragments or derivatives of these factors can be used, since they exhibit at least some biological activity of the native molecule. For example, analogs can be prepared by the expression of genes altered by site-specific mutagenesis or other genetic engineering techniques. By varying the relative molar amounts of the different reactive groups in the components, it is possible to alter the liquid charge of the resulting three-dimensional matrix, with the aim of preparing a matrix for the distribution of a charged compound such as an ionizable protein or drug. As such, the distribution of charged drugs or proteins, which would normally spread rapidly out of a neutral carrier matrix, can be controlled. For example, if a molar excess of nucleophilic groups is used, the resulting matrix has a positive liquid charge and can be used to ionically connect and distribute negatively charged compounds. In a similar way, if a molar excess of electrophilic groups is used, the resulting matrix has a negative liquid charge and can be used to ionically connect and distribute positively charged compounds. Examples of negatively and positively charged compounds that can be distributed from these matrices include various drugs, cells, proteins and polysaccharides. Negatively charged collagens, such as succinylated collagen, and glycosaminoglycan derivatives such as sodium hyaluronate, keratan sulfate, keratosulfate, sodium chondroitin sulfate A, dermatan B sodium sulfate, chondroitin C sodium sulfate, heparin, esterified chondroitin C sulfate, and esterified heparin can also be effectively incorporated into the matrix as described above. Positively charged collagens, such as methylated collagen, and glycosaminoglycan derivatives such as deacetylated esterified hyaluronic acid, chondroitin sulfate A de-sulfated deacetylated ester, deaceulfated deacetylated ester chondroitin C, des-sulphated deacetylated keratin sulfate, deacetylated keratosulfate -sulphated, de-sulfated esterified heparin, and chitosan, can also be incorporated in a similar manner. In another aspect, biologically active agents such as fibrosis inhibiting agents can be distributed from the composition to a tissue site with the aim of inhibiting scar formation, tissue healing and / or regeneration. Thus, in one aspect, a method is provided for the distribution of a biologically active agent, wherein the composition also includes the biologically active agent (e.g., a fibrosis inhibiting agent) to be distributed, and steps (a) and (b) are in accordance with those described for the method of tissue sealing. The phase (c) would involve allowing the formation of a three-dimensional matrix to distribute the biologically active agent. Compositions that include a fibrosis inhibiting agent can be used in a variety of applications, including, without limitation, the prevention of surgical adhesion and the coating of medical devices. Numerous therapeutic compounds were identified and are useful in the invention including: 3. Angiogenesis inhibitors In one embodiment, the pharmacologically active compound is an inhibitor of angiogenesis, such as, for example, 2-ME (NSC-659853), PI- 88 (D-mannose), O-6-O-phosphono-alpha-D-mannopyranosyl- (1-3) -O-alpha-D-mannopyranosyl- (1-3) -O-alpha-D- acid sulfate mannopyranosyl- (1-3) -O-alpha-D-mannopyranosyl- (1-2)), thalidomide (lH-isoindol-1,3 (2H) -dione, 2- (2,6-dioxo-3-piperidinyl) ) -), CDC-394, CC-5079, ENMD-0995 (S-3-amine-phthalideglutarimide), AVE-8062A, vatalanib, SH-268, halofuginone hydrobromide, atiprimoda dimaleate (2-azaspivo [4.5] decano- 2-propanamine, N, N-diethyl-8,8-dipropyl, dimaleate), ATN-224, CHIR-258, combretastatin A-4 (phenol, 2-methoxy-5- [2- (3,4, 5- trimethoxyphenyl) ethenyl] -, (Z) -) f GCS-100LE, or an analogue or derivative thereof. Other examples of angiogenesis inhibitors for use in the compositions of the invention include: 2- methoxyestradiol, A6, ABT-510, ABX-IL8, actimide, Ad5FGF-4, AG3340, integrin alphabebe antibody, AMGOOl, anecortava acetate, angiocol, angiogenix, angiostatin, angiozyme, antiangiogenic antithrombin 3, anti-VEGF, anti-VEGF Mab , aplidine, aptosine, ATN-161, avastin, AVE8062A, Bay 12-9566, benefina, BioBypass CAD, MS275291, CAI, carboxy idotriazole, CC 4047, CC 5013, CC7085, CDC801, Celebrex, CEP-7055, CGP-41251 / PKC412, cilengitide, CM101, col-3, combretastatin, combretastatin A4P, CP-547, 632, CP-564, 959, Del-1, dexrazoxane, didemnin B, DMXAA, EMD 121974, endostatin, FGF (AGENT 3), flavopiridol , GBC-100, polysaccharide concentrated in genistein, green tea extract, HIF-1 alpha, human chorio-gonadotrophin, IM862, INGN 201, interferon alfa-2a, interleukin-12, iressa, ISV-120, LY317615, LY-333531 , Mab huJ591-DOTA- 0 ftrio, marimastate, Medi-522, metareta, neoretna, neovastata, NM-3, NPe6, NV1FGF, octreotide, oltipraz, paclitaxel, pegaptanib sodium, penicillamine, pent osana polysulfate, prinomastat, PSK, psorvastat, PTK787 / ZK222584, ranibizumab, razoxane, replistatatin, revimida, RhuMab, Ro317453, squalamine, SU101, SU11248, SU5416, SU6668, tamoxifen, tecogalan sodium, temptostatin, tetrathiomol, tetrathiomolybdate, thalomide, TNP- 470, UCN-01, VEGF, VEGF trap, Vioxx, vitaxin, vitaxin-2, ZD6126, ZD6474, angiostatin (plasminogen fragment), a TIMPs, antiangiogenic antithrombin III, epithelial derived factor pigment (PEDF), canstatin, placental ribonuclease inhibitor, cartilage-derived inhibitor (CDI), plasminogen activator inhibitor, complement fragment CD59, platelet factor -4, endostatin (fragment of collagen XVIII ), 16kD prolactin fragment, fibronectin fragment, proliferin-related protein, gro-beta, a retinoid, a heparinase, tetrahydrocortisol-S, hexa-saccharide heparin fragment, thrombospondin-1, human chorionic gonadotropin, transformation growth factor beta, interferon alpha, interferon beta, or interferon gamma, tumistatin, interferon-inducible protein, vasculostatin, interleukin-12, vasostatin (fragment of calreticulin), kringle 5 (fragment of plasminogen), angioarrestine, or 2-methoxyestradiol. Inhibitors of angiogenesis also include angiogenin antagonists, placental growth factor, angiopoietin-1, platelet-derived endothelial cell growth factor, Del-1, platelet-derived growth factor-BB, aFGF, bFGF, pleiotrophin, follistatin, proliferin, colony-stimulating factor by granulocyte, alpha-transforming growth factor, hepatocyte growth factor, beta-transforming growth factor, interleukin-8, tumor necrosis factor alpha, leptin, vascular endothelial growth factor, midchin, progranulin, 2-methoxyestradiol (PANZEM) (EntreMed), A6, ABT-510, ABX-IL8 (Abgenix), active, Ad5FGF-4 (Collateral Therapeutics), AG3340 (Agouron Pharmaceuticals Inc. LaJolla, Calif.), Alfadbetal integrin antibody, AMGOOl (AnGes / Daichi Pharmaceuticals), anecortava acetate (Retaane, Alcon), angiocol, angiogenix (Endovasc Ltd), angiostatin (EntreMed), angiozyme, antiangiopenic antithrombin 3 (Genzyme Molecular Oncology), anti-VEGF (Genentech), anti-VEGF Mab, aplidine, aptosine, ATN-161, avastin (bevacizumab), AVE8062A, Bay 12-9566 (Bayer Corp. West Haven, Conn.), Benefina, BioBypass CAD ( VEGF-121) (GenVec), MS275291, CAI (carboxy-starch imidazole), carboximidotriazole, CC 4047 (Celgene), CC 5013 (Celgene), CC7085, CDC 801 (Celgene), Celebrex (Celecoxib), CEP-7055, CGP -41251 / PKC412, cilengitide, CM101 (Carborned Brentwood, Tenn.), Col-3 (CollaGenex Pharmaceuticals Inc. Newton, Pa.), Combretastatin, co mbretastatin A4P (Oxigene / Bristol-Myers Squibb), CP-547, 632, CP-564, 959, Del-1 (VLTS-589) (Valentis), dexrazoxane, didemnin B, DMXAA, EMD 121974, endostatin (EntreMed), FGF (AGENT 3) (Berlex (Krannert Institute of Cardiology)), flavopiridol, GBC-100, polysaccharide concentrated in genistein, green tea extract, HIF-1 alpha (Genzyme), chorio-gonadotropin human, IM862 (Cytran), INGN 201, interferon alfa-2a, interleukin-12, iressa, ISV-120 (Batimastat), LY317615, LY-333531 (Eli Lilly and Company), Mab huJ591-DOTA-90 Itrio (90Y), marimastate (British Biotech Inc. Annapolis, Md.), Medi-522, metareta (suramin), neoretna, neovastat (AEtema Laboratories), NM-3, NPe6, NV1FGF (Gencell / Aventis), octreotide, oltipraz, paclitaxel (for example, taxol, docetaxel or paxene), pegaptanib sodium (Eyetech), penicillamine, pentosana polysulfate, PI-88, prinomastat (Agouron Pharmaceuticals), PSK, psorvastat, PTK787 / ZK222584, ranibizumab (Lucentis, Genentech), razoxane , Repistastatin (Platelet factor-4), Revived, RhuMab, Ro317453, Squalamine (Magainin Pharmaceuticals, Inc. Ply Outh Meeting, Pa.), SU101 (Sugen Inc. Redwood City, Calif.), SU11248, SU5416 (Sugen), SU6668 (Sugen), tamoxifen, tecogalan sodium, temptostatin, tetrathiolol, tetrathiomolybdate, Antiangiogenesis compounds found in vivo can be used in the compositions and methods described including angiostatin (plasminogen fragment), metalloproteinase inhibitors (TIMPs), antiangiogenic antithrombin III (aaATIII), epithelium-derived pigment factor (PEDF), canstatin, placental ribonuclease inhibitor, cartilage-derived inhibitor (CDI), activated plasminogen r inhibitor, complement fragment CD59, factor platelet 4 (PF4), endostatin (fragment of collagen XVIII), fragment of prolactin 16kD, fragment of fibronectin, protein related to proliferin, gro-beta, retinoid s, heparinases, tetrahydrocortisol-S, heparin hexa-saccharide fragment, thrombospondin-1, human chorionic gonadotropin (hCG), beta-transforming growth factor, interferon alpha / beta / gamma, tumistatin, interferon-inducible protein (IP-10), vasculostatin, interleukin-12 (IL-12), vasostatin ( fragment of calreticulin), kringle 5 (fragment of plasminogen), angioarrestine, and 2-methoxyestradiol. Compounds that inhibit, block or antagonize the angiogenic activity of the following species in vivo can be used in the methods and compositions described herein including angiogenin, placental growth factor, angiopoietin-1, endothelial cell growth factor platelet-derived (PD-ECGF), Del-1, platelet-derived BB growth factor (PDGF-BB), fibroblast growth factors: acid (aFGF) and basic (bFGF), pleiotrophin (PTN), follistatin, proliferin , granulocyte colony stimulating factor (G-CSF), alpha transforming growth factor (TGF-alpha), hepatocyte growth factor (HGF) / dispersion factor (SF), beta-transforming growth factor (TGF- beta), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha), leptin, vascular endothelial growth factor (VEGF) / vascular permeability factor (VPF), midiquina, and progranulin. Other examples of angiogenesis inhibitor for use in the present compositions include 2-methoxyestradiol, prinomastat, batimastat, BAY 12-9566, carboxyamidotriazole, CC-1088, dextromethorphan acetic acid, dimethylxanthenone acetic acid, EMD 121974, endostatin, IM-862, marimastat, matrix metalloproteinase, penicillamine, PTK787 / ZK 222584, RPI.4610, squalamine, squalamine lactate, SU5416,. { . + -.) - thalidomide, S-thalidomide, R-thalidomide, TNP-470, combretastatin, paclitaxel, tamoxifen, COL-3, neovastat, BMS-275291, SU6668, interferon-alpha, anti-VEGF antibody, Medi-522 (Vitaxin II), CAI, celecoxib, Interleukin-12, IM862, Amylorete, Angiostatin.RTM protein. , Angiostatin Kl-3, Angiostatin Kl-5, Captopril, DL-alpha-Difluoromethylomitine, DL-alpha-Difluoromethylomitine HCl, His-Tag.RTM protein. Endostatin. M., Fumagillin, Herbimycin A, 4-Hydroxyphenylretinamide, gamma-interferon, Juglone, Laminin, Hexapeptide Laminin, Laminin Pentapeptide, Lavendustine A, Medroxyprogesterone, Medroxyprogesterone Acetate, Minocycline, Minocycline HCl, Placental Ribonuclease Inhibitor, Suramine, Sodium Salt of Suramina, Human Platelet of Thrombospondin, Tissue Metalloproteinase 1 Inhibitor, Neutrophilic Granulocyte Granulocyte Inhibitor of Metalloproteinase 1, and Metalloproteinase 2 Synovial Synovial Fibroblast Inhibitor. 4. 5 - Lipoxygenase Inhibitors and Antagonists. In another configuration, the pharmacologically active compound is an inhibitor or antagonist. -lipoxygenase (for example, Wy-50295 (2-naphthalene acetic acid, alpha-methyl-6- (2-quinolinylmethyl) -, (S) -), ONO-LP-269 (2,11,14-eicosatrienamide, N- (4-hydroxy-2- (lH-tetrazol-5-yl) -8-quinolinyl) -, (E, Z, Z) -), licofelone (lH-pyrrolizine-5-acetic acid, 6- (4 -chlorophenyl) -2,3-dihydro-2, 2-dimethyl-7- phenyl-, CMI-568 (urea, N-butyl-N-hydroxy-N1 - (4- (3- (methylsulfonyl) -2- propoxy-5- (tetrahydro-5- (3,4,5-trimethoxyphenyl) -2-furanyl) phenoxy) butyl) -, trans-), IP-751 ((3R, 4R) - (delta 6) -THC acid -DMH-ll-oico), PF-5901 (benzenemethanol, alpha-pentyl-3- (2-quinolinylmethoxy) -), LY-293111 (benzoic acid, 2- (3- (3- ((5-ethyl-4) '-fluoro-2-hydroxy (1, 1 '-biphenyl) -4-yl) oxy) propoxy) -2-propylphenoxy) -), RG-5901-A (benzenemethanol, alpha-pentyl-3- (2-quinolinylmethoxy) -, hydrochloride), rilopirox (2 ( ÍH) - pyridinone, 6- ((4- (4-chlorophenoxy) phenoxy) ethyl) -l-hydroxy-4-methyl-), L-674636 (acetic acid, ((4- (4-chlorophenyl) -1- (4- (2-quinolinylmethoxy) phenyl) butyl) thio) -AS)), 7- ((3- (4-methoxy-tetrahydro-2H-pyran-4-yl) phenyl) methoxy) -4-phenylnapht (2 ,3- c) furan-1 (3H) -one, MK-886 (ÍH-indole-2-propanoic acid, 1- ((4-chlorophenyl) methyl) -3- ((1,1-dimethylethyl) thio) -alpha, alpha-dimethyl-5- (1-methylethyl) -), quiflapon acid (lH-indol-2-propanoic, 1- ((4-chlorophenyl) methyl) -3- ((1,1-dimethylethyl) thio) -alpha , alpha-dimethyl-5- (2-quinolinylmethoxy) -), quiflapon (ÍH-Indol-2-propanoic acid, 1- ((4-chlorophenyl) methyl) -3- ((1,1-dimethylethyl) thio) - alpha, alpha-dimethyl-5- (2-quinolinylmethoxy) -), docebenone (2,5-cyclohexadiene-1,4-dione, 2- (12-hydroxy-5,10-dodecadiinyl) -3,5,6- trimethyl-), zileuton (urea, N- (1-benzo (b) thien-2-ylethyl) -N-hydroxy-), or an analogue or derivative thereof). 5. CCR Chemotherapy Receptor Antagonists (1, 3, and 5) In another configuration, the pharmacologically active compound is a chemokine receptor antagonist that inhibits one or more CCR subtypes (1, 3, and 5) (e.g., ONO-4128 (1,4, 9-triazaspiro (5.5) undecano-2, 5-dione, l-butyl-3- (cyclohexylmethyl) -9- ((2,3-dihydro-l, 4-benzodioxin-6- il) methyl-), L-381, CT-112 (L-arginine, L-threonyl-L-threonyl-L-seryl-L-glutaminyl-L-valyl-L-arginyl-L-prolyl-), AS- 900004, SCH-C, ZK-811752, PD-172084, UK-427857, SB-380732, vMIP II, SB-265610, DPC-168, TAK-779 (N, N-dimethyl-N- (4- (2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-ylcarboxamido) benyl) tetrahydro-2H-pyran-4-aminium), TAK-220, KRH-1120), GSK766994, SSR-150106 , or an analogue or derivative thereof). Other examples of Chemokine receptor antagonists include α-Immunoquina-NNS03, BX-471, CCX-282, Sch-350634; Sch-351125; Sch-417690; SCH-C, and analogs and derivatives thereof. 6. Cell cycle inhibitors In a further configuration, the pharmacologically active compound is a cell cycle inhibitor. Representative examples of such agents include the taxanes (e.g., paclitaxel (discussed in more detail below) and docetaxel) (Schiff et al., Nature 277: 665-667, 1979; Long and Fairchild, Cancer Research 54: 4355-4361, 1994; Ringel and Horwitz, J. Nat'l Cancer Inst. 83 (4): 288-291, 1991; Pazdur et al., Cancer Treat., Rev. 19 (40): 351-386, 1993), etanidazole, nimorazole (BA Chabner and DL Longo, Cancer Chemotherapy and Biotherapy - Principles and Practice, Lincincott-Raven Publishers, New York, 1996, p.554), perfluoro chemicals with hyperbaric oxygen, transfusion, erythropoietin, BW12C, nicotinamide, hydralazine, BSO, WR-2721, IudR, DUdR, etanidazole, WR-2721, BSO, mono-substituted keto-aldehyde compounds (LG Egyud, keto-aldehyde-amine addition products and methods for making same. .650, January 3, 1978), nitroimidazole (KC Agrawal and M. Sakaguchi.) Nitroimidazole radiosensitizers for Tum Cells Hypoxic Oils and Compositions for the same. US Patent No. 4,462,992, July 31, 1984), 5- substituted-4-nitroimidazoles (Adams et al., Int. J. Radiat, Biol. Relat.Stud.Phys., Phys.-Chem. Med. 40 (2): 153-61, 1981), SR-2508 (Brown et al. , Int. J. Radiat Oncol., Biol. Phys. 7 (6): 695-703, 1981), 2H-isoindolediones (JA Myers, 2H-Isoindolediones, synthesis and use as radiosensitizers Patent 4,494,547, of January 22, 1985), chiral ((((2-bromoethyl) -amine) methyl) -nitro-1H-imidazole-1-ethanol (VG Beylin, et al., Process for the preparation of (((2-bromoethyl) ) -amine) methyl) -nitro-1H-imidazole-1-chiral ethanol and related compounds US Patent No. 5,543,527, 6 August 1996; US Patent No. 4,797,397; of January 10, 1989; US Patent No. 5,342,959, August 30, 1994), nitroaniline derivatives (WA Denny, et al .. Nitroaniline derivatives and the use with anti-tumor agents. No. 5,571,845, November 5, 1996), hypoxia-selective cytotoxins with DNA affinity (MV Papadopoulou-Rosisnzweig, selective cytotoxins of hypoxia with affinity for DNA. US Patent No. 5,602,142, February 11, 1997), halogenated DNA sealant (RF Martin, halogenated DNA sealants for cancer therapy, US Patent No. 5,641,764, June 24, 1997). , 1,2,4-benzotriazine oxides (WW Lee et al., 1, 2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents.

US Patent No. 5,616,584, of April 1, 1997; US Patent No. 5,624,925, of April 29, 1997; Process for the preparation of 1,2,4-Benzotriazine oxides. US Patent No. 5,175,287, of December 29, 1992), nitric oxide (JB Mitchell et al., Use of compounds that release nitric oxide as hypoxic sensitizers of cellular radiation, US Patent No. 5,650,442, of 22 July 1997), 2-nitroimidazole derivatives (MJ Suto et al., 2-Nitroimidazole Derivatives Useful as Radiosensitizers for Hypoxic Tumor Cells, US Patent No. 4,797,397, January 10, 1989; Suzuki, 2-Nitroimidazole derivative, production thereof, and radiosensitizer containing the same as an active ingredient, US Patent No. 5,270,330, of December 14, 1993, T. Suzuki et al. Nitroimidazole, production thereof, and radiosensitizer containing the same as active ingredient US Patent No. 5,270,330, of December 14, 1993; T. Suzuki, Derivative of 2-Nitroimidazole, production thereof and radiosensitizer containing the same as an active ingredient; Patent EP 0 513 351 Bl, of January 24, 1991), nitroazole derivatives containing fluorine (T. Kagiya Derivatives of nitroazole containing fluorine and radiosensitizer comprising same. US Patent No. 4,927,941, May 22, 1990), copper (M.J. Abrams.

Copper radiosensitizers. US Patent No. 5,100,885, March 31, 1992), combination of modalities of cancer therapies (DH Picker et al.) Combination of modalities of cancer therapies US Patent No. 4,681,091, July 21 of 1987). 5-CldC or (d) H4U or derivatives of 5-halo-2'-halo-2'-deoxy-cytidine or -uridine (SB Greer.) Method and Materials for the sensitization of neoplastic tissues to radiation. No. 4,894,364 of January 16, 1990), Platinum Complexes (KA Skov, Platinum Complexes with a Radiosensitization Sealer, US Patent No. 4,921,963, May 1, 1990, KA Skov. Platinum complexes with a radiosensitization sealer Patent EP 0 287 317 A3), nitroazole containing fluorine (T. Kagiya, et al .. Nitroazole fluoro-containing derivatives and radiosensitizer comprising same US Patent No. 4,927,941. of May 22, 1990), benzamide (WW Lee, Benzamide-substituted radiosensitizers, US Patent No. 5,032,617, July 16, 1991), autobio- tics (LG Egyud, Autobiotics and the use in the elimination of no auto-cells in vivo, US Patent No. 5,147,652 of September 15, 1992), benzamide and nicotinamide (WW Lee et al. Adiosensitizers based on Benzamide and Nictoinamide. US Patent No. 5,215,738, June 1, 1993), acridine intercalator (M. Papadopoulou-Rosisnzweig.

Hypoxia-selective cytotoxins based on Acridine Interlayer. US Patent No. 5,294,715, March 15, 1994), fluorine-containing nitroimidazole (T. Kagiya et al., Fluorine-containing nitroimidazole compounds, US Patent No. 5,304,654, April 19, 1994), texaphyrins. Hydroxylated (JL Sessler et al., Hydroxylated Texaphyrins, US Patent No. 5,457,183, October 10, 1995), Hydroxylated Compound Derivative (T. Suzuki et al., Heterocyclic Compound Derivative, Heterocyclic Compound Production, and Radiosensitizer and antiviral agent containing said derivative as an active ingredient Publication Number 011106775 A (Japan), of October 22, 1987; T. Suzuki et al. Derivative of heterocyclic compound, production thereof and radiosensitizer, antiviral agent and anticancer agent containing said derivative as an active ingredient Publication Number 01139596 A (Japan), November 25, 1987; S. Sakaguchi et al. Derivative of heterocyclic compound, its production and radiosensitizer containing said derivative as active ingredient; Publication Number 63170375 A (Japan), January 7, 1987), 3-nitro-l, 2,4-triazole containing fluorine (T. Kagitani et al., Novo 3-nitro-l, 2,4-triazole containing fluorine and radiosensitizer containing the same compound Publication Number 02076861 A (Japan), March 31, 1988), derivative of 5- tiotretrazole or its salts (E. Kano et al.

Radiosensitizer for Hypoxic Cells. Number of Publication 61010511 A (Japan), of June 26, 1984), Nitrothiazole (T. Kagitani et al., Radiation sensitizing agent, Publication number 61167616 A (Japan) of January 22, 1985), imidazole derivatives (S. Inayma et al.

Imidazole derivatives. Publication Number 6203767 A (Japan) of August 1, 1985; Publication Number 62030768 A (Japan) of August 1, 1985; Publication Number 62030777 A (Japan) of August 1, 1985), 4-nitro-l, 2,3-triazole (T. Kagitani et al.

Radiosensitizer. Publication Number 62039525 A (Japan), August 15, 1985), 3-nitro-l, 2,4-triazole (T. Kagitani et al. Radiosensitizer Publication Number 62138427 A (Japan), December 12, 1985), Carcinostatic action regulator (H. A agasa.

Carcinostatic action regulator. Publication Number 63099017 A (Japan), November 21, 1986), 4,5-dinitroimidazole derivative (S. Inayama, 4,5-dinitroimidazole derivative, Publication number 63310873 A (Japan) of June 9, 1987), Nitrotriazole compound (T.

Kagitanil Compound Nitrotriazole. Publication Number 07149737 A (Japan) of June 22, 1993), cisplatin, doxorubin, misonidazole, mitomycin, tiripazamine, nitrosourea, mercaptopurine, methotrexate, flurouracil, bleomycin, vincristinea carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide (IF Tannock, Review article: Cancer treatment with radiation and drugs Journal of Clinical Oncology 14 (12): 3156-3174, 1996), camptothecin (Ewend MG et al., local distribution of concurrent external beam chemotherapy and radiotherapy prolongs survival in brain metastatic tumor models, Cancer Research 56 (22) -.5217-5223, 1996) and paclitaxel (Tishler RB et al., Taxol: a new sensitizer of radiation, International Journal of Radiation Oncology and Biological Physics 2 (3): 613-617, 1992). A number of the cell cycle inhibitors cited above also possess a variety of analogs and derivatives, including, but not limited to, cisplatin, cyclophosphamide, misonidazole, tiripazamine, nitrosourea, mercaptopurine, methotrexate, flurouracil, epirubicin, doxorubicin, vindesine and etoposide. Analogs and derivatives include (CPA) 2Pt (DOLYM) and (DACH) Pt (DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22 (2): 151-156, 1999), Cis- (PtCl2 (4 , 7-H-5-methyl-7-oxo) 1,2,4 (triazolo (1,5-a) pyrimidine) 2) (Navarro et al., J. Med. Chem. 41 (3): 332- 338, 1998), (Pt (cis-1, 4-DACH) (trans-C12) (CBDCA)) • ^ MeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36 (25): 5969-5971, 1997) , 4-pyridoxate diamine hydroxy platinum (Tokunaga et al., Pharm. Sci. 3 (7): 353-356, 1997), Pt (II) • • • Pt (II) (Pt2 (NHCHN (C (CH2) (CH3))) 4) (Navarro et al., Inorg, Chem. 35 (26): 7829-7835, 1996), analog of 254-S cisplatin (Koga et al., Neurol. Res. 18 (3): 244-247, 1996), o-phenylenediamine sealant endowed with cisplatin analogues (Koeckerbauer &Bednarski, J. Inorg. Biochem. 62 (4): 281-298, 1996), trans, cis- (Pt (OAc) 212 (en)) (Kratochwil et al. al., J. Med. Chem. 39 (13): 2499-2507, 1996), analogs of 1, 2-diethylethylenediamine estrogen sealant (with amino acids and glutathione containing sulfur) endowed with cisplatin (Bednarski, J. Inorg. Biochem. 62 (1): 75, 1996), cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al., J. Inorg. Biochem. 61 (4): 291-301, 1996), cis 5 'orientational isomer - (Pt (NH3) (4-aminoTEMP-O). {D (GpG).}.) (Dunham &Lippard, J. Am. Chem. Soc. 117 (43): 10702-12, 1995), Cisplatin analog chelates equipped with diamine (Koeckerbauer & Bednarski, J. Pharm. Sci. 84 (7): 819-23, 1995), cisplatin analogs endowed with 2- diacylethyleneamine sealant (Otto et al., J. Cancer Res. Clin. Oncol. 121 (1): 31-8, 1995), (ethylene diamine) platinum (II) complexes (Pasini et al., J. Chem. Soc., Dalton Trans. 4: 579-85, 1995), cisplatin analogue CI-973 (Yang et al., Int. J. Oncol., 5 (3): 597-602, 1994), cis-diaminodichloroplatin (II) and its analogs cis-1, 1- cyclobutanedicarbossilate (2R) -2-methyl-1, 4- butanodiaminoplatin (II) and cis-diamino (glycolate) platinum (Claycamp &Zimbrick, J. Inorg. Biochem., 26 (4): 257-67, 1986; Fan et al., Cancer Res. 48 (11): 3135 -9, 1988; Heiger-Bernays et al., Biochemistry 29 (36): 8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res. 12 (4): 233-40, 1993; Murray et al., Biochemistry 31 (47): 11812-17, 1992; Takahashi et al., Cancer Chemother. Pharmacol. 33 (1): 31-5, 1993), cis-amine-cyclohexylamine-dichloroplatinum (II) (Yoshida et al., Biochem Pharmacol 48 (4): 793-9, 1994), gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1,2-bis (2,6-dichloro-4-hydroxyphenyl) ethylenediamine) dichloroplatinum (II) (Bednarski et al., J. Med. Chem. 35 (23) -.4479-85, 1992), cisplatin analogs containing a dansyl teterated group (Hartwig et al., J. Am. Chem. Soc. 114 (21): 8292-3, 1992), platinum (II) polyamines (Siegmann et al., Inorg.Met.-Containing Polim. Mater., (Proc. Am. Chem.

Soc. Int. Symp.), 335-61, 1990), cis- (3H) dichloro (ethylenediamine) platinum (II) (Eastman, Anal.

Biochem. 197 (2): 311-15, 1991), trans-diaminodichloroplatin (II) and cis- (Pt (NH3) 2 (N3-cytosine) Cl) (Bellon &Lippard, Biophys. Chem. 35 (2-3) : 179-88, 1990), 3H-cis-1, 2-diaminocyclohexanediolophoplatinum (II) and 3H-cis-1, 2-diaminocyclohexanomalonate platinum (II) (Oswald et al., Res. Commun. Chem. Pathol. Pharmacol. 64 (1) -.41-58, 1989), diaminocarboxylateplatinum (EPA 296321), analogs of transporter or trans- (D, 1) -1,2-diaminocyclohexane vehicle equipped with platinum-based sealant (Wyrick &Chaney, J. Labelled Compd. Radiopharm. 25 (4): 349-57, 1988), analogues of cisplatin aminoalkylaminoanthraquinone derivatives (Kitov et al., Eur. J. Med. Chem. 23 (4): 381-3, 1988), spiroplatin, carboplatin, iproplatin and platinum analogs JM40 (Schroyen et al., Eur. J. Cancer Clin Oncol 24 (8): 1309-12, 1988), cisplatin derivatives containing bidentate tertiary diamine (Orbell et al., Inorg. Chim. Acta 152 (2) -.125-34, 1988), platinum ( II), platinum (IV) (Liu &Wang, Shandong Yike Daxue Xuebao 24 (1): 35-41, 1986), cis-diamine (1,1-cyclobutanedicarboxylate-) platinum (II) (carboplatin, JM8) and ethylenediamine malonate platinum (II) (JM40) (Begg et al., Radiother Oncol 9 (2): 157-65, 1987), cisplatin analogues JM8 and JM9 (Harstrick et al., Int. J. Androl. (1); 139-45, 1987), (NPr4) 2 ((PtCL4). Cis- (PtCl2- (NH2Me) 2)) (Brammer et al., J. Chem. Soc., Chem. Commun. 6: 443-5, 1987), platinum complexes with aliphatic triacid carboxylic acid (EPA 185225), cis-dichloro (amino acid) (tert-butylamine) platinum (II) complexes (Pasini &Bersanetti, Inorg. Chim. Acta 107 ( 4) -.259-67, 1985); 4- hydroperoxy cyclophosphamide (Ballard et al., Cancer Chemother, Pharmacol 26 (6): 397-402, 1990), acyclopridine derivatives cyclophosphamide (Zakerinia et al., Helv. Chim.

Acta 73 (4): 912-15, 1990), analogs of 1,3,2-dioxa-e -oxazaphosforinana cyclophosphamide (Yang et al., Tetrahedron 44 (20): 6305-144), analogs of cyclophosphamide C5 -substituted (Spada, University of Rhode Island Dissertation, 1987), analogues of tetrahydrooxazine cyclophosphamide (Valente, Dissertation of the University of Rochester, 1988), phenyl ketone analogs cyclophosphamide (Hales et al., Teratology 39 ( l): 31-7, 1989), analogs of phenylkethophosphamide cyclophosphamide (Ludeman et al., J. Med. Chem. 29 (5): 716-27, 1986), analogs of ASTA Z-7557 (Evans et al., Int. J. Cancer 34 (6): 883-90, 1984), 3- (1-oxy-2,2,6,6-tetramethyl-4-piperidinyl) cyclophosphamide (Tsui et al., J. Med. Chem. 25 (9): 1106-10, 1982), 2-oxobis (2-chloroethylamino) -4-, 6-dimethyl-1,3,2-oxazaphosforinana cyclophosphamide (Carpenter et al., Phosphorus Sulfur 12 (3 ): 287-93, 1982), 5-fluoro-5-chlorocyclofosfamide (Foster et al., J. Med. Chem. 24 (12): 1399-403, 1981), cis- and trans-4- pheny Lycopephosphamide (Boyd et al., J. Med. Chem. 23 (4): 372-5, 1980), 5-bromocyclophosphamide, 3,5-dehydrocyclofosfamide (Ludeman et al., J. Med. Chem. 22 (2) : 151-8, 1979), analogs of 4-ethoxycarbonyl cyclophosphamide (Foster, J. Pharm. Sci. 67 (5): 709-10, 1978), analogs of arylaminotetrahydro-2H-1, 3, 2-oxazaphosphorine 2-oxide cyclophosphamide (Hamacher, Arch. Pharm. (Weinheim, Ger.) 310 (5): J , 428-34, 1977), analogs of NSC-26271 cyclophosphamide (Montgomery &Struck, Cancer Treat. Rep. 60 (4): J381-93, 1976), annulled benzo analogs cyclophosphamide (Ludeman &Zon, J. Med. Chem. 18 (12): 1251-3, 1975), 6-trifluoromethyl cyclophosphamide (Farmer &Cox, J. Med. Chem. 18 (11): 1106-10, 1975), analogs of 4-methyl cyclophosphamide and 6-methyl cyclophosphamide (Cox et al., Biochem. Pharmacol. 24 (5): J599- 606, 1975); derivative of FCE 23762 doxorubicin (Quaglia et al., J. Liq Chromatogr., 17 (18): 3911-3923, 1994), ana icine (Zou et al., J. Pharm. Sci. 82 (11): 1151- 1154, 1993), ruboxil (Rapoport et al., J. Controlled Reléase 58 (2): 153-162, 1999), an analogue of the anthracycline disaccharide doxorubicin (Pratesi et al., Clin. Cancer Res. 4 (11): 2833-2839, 1998), N- (trifluoroacetyl) doxorubicin and 4'-O-acetyl-N- (trifluoroacetyl) doxorubicin (Berube &Lepage, Synth Commun. 28 (6): 1109-1116, 1998), 2 pyrrolinodoxorubicin (Nagy et al., Proc. Nat'l Acad. Sci. USA 95 (4): 1794-1799, 1998), disaccharide analogs of doxorubicin (Arcamone et al., J. Nat'l Cancer Inst. (16): 1217-1223, 1997), analogue of 4-demethoxy-7-0- (2,6-dideoxy-4-0- (2,3,6-trideoxy-3-amine-DL-lixo-hexopyrano) -DL-lixo-hexopyrano adriamycinone doxorubicin disaccharide (Monteagudo et al., Carbohydr Res. 300 (1) -.11-16, 1997), 2- pyrrolinodoxorubicin (Nagy et al., Proc. Nat'l Acad. Sci.

USES. 94 (2): 652-656, 1997), morpholinyl doxorubicin analogues (Duran et al., Cancer Chemother, Pharmacol. 38 (3): 210-216, 1996), enaminomalonyl-O-alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett 36 (9): 1413-16, 1995), cephalosporin derivatives doxorubicin (Vrudhula et al., J. Med. Chem. 38 (8): 1380-5, 1995), hydroxyirubicin (Solary et al., Int. J. Cancer 58 (1): 85-94, 1994), derivative of methoxymorpholino doxorubicin (Kuhl et al., Cancer Chemother, Pharmacol 33 (1): 10-16, 1993), derivative of (6-maleimidocaproyl) hydrazone doxorubicin (Willner et al., Bioconjugate Chem. 4 (6): 521-7, 1993), N- (5, 5-diacetoxipent-1-yl) doxorubicin (Cherif &Farquhar, J. Med. Chem. 35 (17 ): 3208-14, 1992), derivative of FCE 23762 methoxymorpholinyl doxorubicin (Ripamonti et al., Br. J. Cancer 65 (5): 703-7, 1992), derivatives of N-hydroxysuccinimide ester of doxorubicin (Demant et al. Biochim, Biophys, Acta 1118 (1): 83-90, 1991), polideoxynucleotide derivatives doxorubicin (Ruggiero et al., Biochim Biophys, Acta 1129 (3): 294-302, 1991), morpholinyl doxorubicin derivatives (EPA 434960), mitoxantrone analogue doxorubicin (Krapeho et al., J. Med. Chem. 34 (8): 2373-80, 1991), analogue of AD198 doxorubicin (Tráganos et al., Cancer Res. 51 (14): 3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al., Drug Des. Delivery 6 (2): 123-9, 1990), 4 '-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40 (2): 159-65, 1988; Weenen et al., Eur. J. Cancer Clin. Oncol. 20 (7): 919- 26, 1984), derivative of doxorubicin cyanomorpholino alkylating agent (Scudder et al., J. Nat'l Cancer Inst. 80 (16): 1294-8, 1988), deoxy-dihydro-iodo-oxorubicin (EPA 275966), adriblastin (Kalishevskaya et al., Vestn., Mosk. Univ., 16 (Biol. 1): 21-7, 1988), 4'-deoxidoxorubicin (Schoelzel et al., Leuk. Res. 10 (12): 1455-9, 1986), 4-demethyloxy-4 '-o-methyldoxorubicin (Giuliani et al., Proc. Int.Congr.Chemmother., 16: 285-70-285-77, 1983), 3'-deamin-3' -hydroxydexorubicin ( Horton et al., J. Antibiot, 37 (8): 853-8, 1984), analogues of 4-demethyloxy doxorubicin (Barbieri et al., Drugs Exp. Clin. Res. 10 (2): 85-90, 1984), N-L-leucyl doxorubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81, 1983), 3'-deamino-3 '- (4-methoxy-1-piperidinyl) doxorubicin derivatives (4,314,054), 3'-deamino derivatives -3 '- (4-mortolinil) doxorubicin (4,301,277), 4'-deoxidoxorubicin and 4' -o-methyldoxorubicin (Giuliani et al., Int. J. Cancer 27 (1): 5-13, 1981), aglycone derivatives doxorubicin (Chan &Watson, J. Pharm. Sci. 67 (12): 1748-52, 1978), SM 5887 (Pharma Japan 1468: 20, 1995), MX-2 (Pharma Japan 1420: 19, 1994), 4'-deoxy-13 (S) -dihydro-4 '-iododoxorubicin (EP 275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3' - (4-methoxy-1-) derivatives piperidinyl) doxorubicin (4,314,054), doxorubicin-14-valerats, morpholinodoxorubicin (5,004,606), 3 '-deamin-3' - (3"-cyano-4" -morpholinyl doxorubicin; 3 '-deamin-3' - (3"-cyano-4" -morpholinyl) - 13-dihydroxorubicin; (3 '-deamin-3' - (3"-cyano-4" -morpholinyl) daunorubicin; 3 '-deamin-3' - (3"-cyano-4" -morpholinyl) - 3-dihydrodaunorubicin; and 3 '-deamin-3' - (4"-morpholinyl-5-iminodoxorubicin and derivatives (4,585,859), 3'-deamin-3 '- (4-methoxy-1-piperidinyl) derivatives doxorubicin (4,314,054) and 3-deamino-3- (4-morpholinyl) doxorubicin derivatives (4,301,277); 4,5-dimethylmisonidazole (Born et al., Biochem. Pharmacol 43 (6) -1337- 44, 1992), azo and azoxy misonidazole derivatives (Gattavecchia &Tonelli, Int. J. Radiat, Biol. Relat.Stud.Phys., Chem. Med. 45 (5): 469-77, 1984); RB90740 ( Wardman et al., Br. J. Cancer, 74 Suppl. (27): S70-S74, 1996), derivatives of 6-bromo and 6-chloro-2,3-dihydro-l, 4-benzothiazines nitrosourea (Rai et al. al., Heterocycl, Commun. 2 (6): 587-592, 1996), diamino nitrosou acid derivatives rea (Dulude et al., Bioorg. Med. Chem. Lett. 4 (22): 2697-700, 1994; Dulude et al., Bioorg. Med. Chem. 3 (2): 151-60, 1995), nitrosourea amino acid derivatives (Zheleva et al., Pharmazie 50 (l): 25-6, 1995), 3 ', 4' -didemethoxy-3 derivatives ', 4' -dioxo-4-deoxipodophyllotoxin nitrosourea (Miyahara et al., Heterocycles 39 (l): 361-9, 1994), ACNU (Matsunaga et al., Immunopharmacology 23 (3): 199-204, 1992), Tertiary phosphine derivatives of nitrosourea oxide (Guguva et al., Pharmazie 46 (8): 603, 1991), sulfamerizine derivatives and sulfametizole nitrosourea (Chiang et al., Zhonghua Yaozue Zazhi 43 (5): 401-6, 1991), thymidine analogs nitrosourea (Zhang et al., Cancer Commun. 3 (4): 119-26, 1991), 1,3-bis (2-chloroethyl) -1-nitrosourea (August et al., Cancer Res. 51 (6): 1586 -90, 1991), 2, 2, 6,6-tetramethyl-l-oxopiperidiunium nitrosourea derivatives (USSR 1261253), 2- and 4-deoxy sugar nitrosourea derivatives (4,902,791), nitroxyl nitrosourea derivatives (USSR 1336489 ), fotemustine (Boutin et al., Eur. J. Cancer Clin. Oncol. 25 (9): 1311-16, 1989), pyrimidine (II) nitrosourea derivatives (Wei et al., Chung-hua Yao Hsueh Tsa Chih 41 (l): 19-26, 1989), CGP 6809 (Schieweck et al., Cancer Chemother, Pharmacol. 23 (6): 341-7, 1989), B-3839 (Prajda et al., In Vivo 2 ( 2): 151-4, 1988), 5-halogenocytosine nitrosourea derivatives (Chiang &Tseng, T'ai-wan Yao Hsueh Tsa Chih 38 (l): 37-43, 1986), 1- (2-chloroethyl) -3-isobutyl-3- (D-maltosyl) -1-nitrosourea (Fujimoto &Ogawa, J. Pharmacobio-Dyn. 10 (7): 341-5, 1987), nitrosoureas containing sulfur (Tang et al., Yaoxue Xuebao 21 (7): 502-9, 1986), sucrose, derivatives of 6- (((((2-chloroethyl) nitrosoamino-) carbonyl) amine) -6-deoxysucrose (NS-1C) and 6 '- (((((2-chloroethyl) nitrosoamino) carbonyl) amine) -6'-deoxysucrose (NS-1D) nitrosourea (Tanoh et al., Chemotherapy (Tokyo) 33 (11): 969-77, 1985), CNCC, RFCNU and chlorozotocin (Mena et al. al., Chemotherapy (Basel) 32 (2): 131-7, 1986), CNUA (Edanami et al., Chemotherapy (Tokyo) 33 (5): 455-61, 1985), 1- (2-chloroethyl) - 3-isobutyl-3- (D-maltosyl) -1-nitrosourea (Fujimoto &Ogawa, Jpn. J. Cancer Res. (Gann) 76 (7): 651-6, 1985), chloro-type nitrosoalkylureas (Belyaev et al. ., Izv. Akad. NAUK SSSR, Ser. Khim. 3: 553-7, 1985), sucrose nitrosourea derivatives (JP 84219300), drug analogues sulfa nitrosourea (Chiang et al., Proc. Nat'l Sci. Counc , Republic of China, Part A 8 (l): 18-22, 1984), DONU (Asanuma et al., J. Jpn. Soc. Cancer Ther.17 (8): 2035-43, 1982), N, N β-bis (N- (2-chloroethyl) -N-nitrosocarbamoyl) cystamine (CNCC) (Blazsek et al., Toxicol, Appl. Pharmacol., 74 (2): 250-7, 1984), dimethylnitrosourea (Krutova et al. , Izv. Akad. NAUK SSSR, Ser. Biol. 3: 439-45, 1984), GANU (Sava &Giraldi, Cancer Chemother, Pharmacol., 10 (3): 167-9, 1983), CCNU (Capelli et al. ., Med., Biol., Environ. 11 (1): 111-16, 1983), analogues of 5-aminomethyl-2'-deoxyuridine nitrosourea (Shiau, Shih Ta Hsueh Pao (Taipei) 27: 681-9, 1982), TA-077 (Fujimoto & Ogawa, Cancer Chemother. Pharmacol. 9 (3): 134-9, 1982), gentianose nitrosourea derivatives (JP 82 80396), CNCC, NCCU, NPCs and chlorozotocin (CZT) (Marzin et al., INSERM Symp., 19 (Nitrosoureas Cancer Treat.) - .165-74, 1981), thioscolchicine nitrosourea analogs (George, Shih Ta Hsueh Pao (Taipei) 25: 355-62, 1980), 2-chloroethylnitrrosourea (Zeller &Eisenbrand, Oncology 38 (l): 39- 42, 1981), ACNU, (1- (4-amine-2-methyl-5-pyrimidinyl) methyl-3- (2-chloroethyl) -3-nitrosourea hydrochloride) (Shibuya et al., Gan To Kagaku Ryoho 7 (8) : 1393-401, 1980), analogs of N-deacetylmethyl thiocolkycin nitrosourea (Lin et al., J. Med. Chem. 23 (12): 1440-2, 1980), pyridine derivatives and piperidine nitrosourea (Crider et al. , J. Med. Chem. 23 (8) .848-51, 1980), methyl-CCNU (Zimber &Perk, Refu.Vet. 35 (1) -.28, 1978), fensuzimide nitrosourea derivatives (Crider et al. ., J. Med. Chem. 23 (3): 324-6, 1980), nitrosourea ergoline derivatives (Crider et al., J. Med. Chem. 22 (l): 32-5, 1979), derivatives of glucopyranose nitrosourea (JP 78 95917), 1- (2-chloroethyl) -3-cyclohexyl-1-nitrosourea (Farmer et al., J. Med. Chem. 21 (6) .514-20-1978), 4- ( 3- (2-chloroethyl) -3-nitrosoureid-o) -cis-cyclohexane-carboxylic acid (Drewinko et al., Cancer Treat. Rep. 61 (8): J1513-18, 1977), RPCNU (ICIG 1163) (Larnicol et al. al., Biomedicine 26 (3): J176-81, 1977), IOB-252 (Sorodoc et al., Rev. Roum. Med., Virol. 28 (1): J 55-61, 1977), 1, 3-bis (2-chloroethyl) -1-nitrosourea (BCNU) (Siebert &Eisenbrand, Mutat. Res. 42 (1): J45-50, 1977 ), 1-tetrahydroxycyclopentyl-3-nitroso-3- (2-chloroethyl) -urea (4,039,578), d-1-1- (0-chloroethyl) -3- (2-oxo-3-hexahydroazepinyl) -1 -nitrosourea (3,859,277) and derivatives of gentianoso nitrosourea (JP 57080396); 6-S-aminoacyloxymethyl ercaptopurine derivatives (Harada et al., Chem. Pharm. Bull. 43 (10): 793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm. Bull. 18 (11): 1492-7, 1995), 7,8-polymethyleneimidazole 1, 3, 2-diazaphosphorins (Nilov et al., Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J. Inorg. Biochem. 56 (4): 249-64, 1994), derivatives of methyl-D-glucopyranoside mercaptopurine (De la Silva et al., Eur. J. Med. Chem. 29 (2): 149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim.-Farm. Zh. 15 (8): 65-7, 1981); indoline ring and a modified ornithine or methotrexate derivatives endowed with glutamic acid (Matsuoka et al., Chem. Pharm. Bull. 45 (7): 1146-1150, 1997), alkyl-substituted benzene ring derivatives containing methotrexate C (Matsuoka et al. al., Chem. Pharm. Bull. 44 (12): 2287-2293, 1996), methotrexate derivatives containing benzoxazine or benzothiazine functional group (Matsuoka et al., J. Med. Chem. 40 (1) .105-111 , 1997), 10-deaza-aminopterin analogs (DeGraw et al., J. Med. Chem. 40 (3): 370-376, 1997), analogs of 5-deaza-aminopterin and 5, 10-dideaza-aminopterin methotrexate (Piper et al., J. Med. Chem. 40 (3): 377-384, 1997), methotrexate derivatives endowed with an indoline functional group (Matsuoka et al., Chem. Pharm. Bull. 44 (7): 1332-1337, 1996), lipophilic methotrexate starch derivatives (Pignatello et al., World Meet.Pharm., Biopharm.Pharm.Technol., 563-4, 1995), L-threo- (2S, 4S) -4 acid. - fluoroglutamic and methotrexate analogues containing DL-3, 3-difluoroglutamic acid (Hart et al., J. Med. Chem. 39 (l): 56-65, 1996), methotrexate tetrahydroquinazoline analogue (Gangjee, et al., J Heterocycl, Chem. 32 (l): 243-8, 1995), N- (D-aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3 (1-2): 101-2, 1992), derivatives of biotin methotrexate (Fan et al., Pteridines 3 (1-2) -131-2, 1992), analogs of D-glutamic acid or D-eritho acid, threo-4-fluoroglutamic methotrexate (McGuire et al., Biochem. Pharmacol. 42 (12): 2400-3, 1991) ,. GD-D-ethane methotrexate analogs (Rosowsky et al., Pteridines 2 (3) -133-9, 1991), 10-deazaaminopterin analogue (10-EDAM) (Braakhuis et al., Chem. Biol. Pteridines , Int.P. Symp.Pteridines Folie Acid Deriv., 1027-30, 1989), D-tetrazole metrotrexate analog (Kalman et al., Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folie Acid Deriv., 1154-7, 1989), N- (LD-aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 28 (2): 751-8, 1989), meta and ortho-isomers of aminopterin (Rosowsky et al., J. Med. Chem. 32 (12): 2582, 1989), hydroxymethylmethotrexate (DE 267495), D-fluoromethotrexate (McGuire et al., Cancer Res. 49 (16): 4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al., Cancer Res. 46 (10): 5020-3, 1986), analogs of gem-diphosphonate methotrexate (WO 88/06158), analogs of methotrexate .0- and D-substituted (Tsushima et al., Tetrahedron 44 (17): 5375-87, 1988), analogs of 5-methyl-5-deaza methotrexate (4,725,687), derivatives of NO-acyl-ND- (4-amine-4-deoxypteroyl) -L-Ornithine (Rosowsky et al., J. Med. Chem. 31 (7): 1332-7, 1988), analogs of 8-deaza methotrexate (Kuehl et al., Cancer Res. 48 (6): 1481-8, 1988) , acivicin analogue methotrexate (Rosowsky et al., J. Med. Chem. 30 (8): 1463-9, 1987), polymeric platinol derivative methotrexate (Carraher et al., Poly Sci. Technol. (Plenum), 35 (Adv. Biomed.Polim.): 311-24, 1987), methotrexate-D-dimyristoylphosphatidylethanolamine (Kinsky et al., Biochim Biophys. Acta 917 (2): 211-18, 1987), methotrexate polyglutamate analogs ( Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv .: Chem. Biol. Clin. Aspects: 985-8, 1986), poly-D-derivatives glutamyl methotrexate (Kisliuk et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv .: Chem., Biol. Clin. Aspects: 989-92, 1986), derivatives of deoxyuridylate methotrexate (Webber et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Sym p.Pididines Folid Acid Deriv .: Chem. Biol. Clin. Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analog (Delcamp et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv .: Chem. Biol.

Clin. Aspects: 807-9, 1986), methotrexate analogs containing 2, omega acid. -diaminoalkanoid (McGuire et al., Biochem. Pharmacol.35 (15): 2607-13, 1986), polyglutamate methotrexate derivatives (Kamen &Winick, Methods Enzymol 122 (Vitamin Coenzymes, Pt. G): 339- 46, 1986), dec5-methyl-5-deaza analogues (Piper et al., J. Med. Chem. 29 (6) -.1080-7, 1986), quinazoline analog methotrexate (Mastropaolo et al., J. Med. Chem. 29 (l): 155-8, 1986), Pyrazine Methotrexate Analog (Lever &Vestal, J. Heterocycl, Chem. 22 (1): 5-6, 1985), Analogs of Cysteic Acid and Acid homocysteic methotrexate (4,490,529), D-tert-butyl methotrexate esters (Rosowsky et al., J. Med. Chem. 28 (5): 660-7, 1985), fluorinated methotrexate analogues (Tsushima et al., Heterocycles 23 (l): 45-9, 1985), folate analogue methotrexate (Trombe, J. Bacteriol, 160 (3): 849-53, 1984), analogues of phosphonoglutamic acid (Sturtz &Guillamot, Eur. J. Med. Chem. - Ch. Ther 19 (3): 267-73, 1984), conjugates of poly (L-lysine) methotrexate (Rosowsky et al., J. Med. Chem. 27 (7) : 888-93, 1984), derivatives of dilisin and trilisin methotrexate (Forsch & Rosowsky, J. Org. Chem. 49 (7): 1305-9, 1984), 7- hydroxymethotrexate (Fabre et al., Cancer Res. 43 (10): 4648-52, 1983), poly-D-glutamyl-methotrexate analogues (Piper &Montgomery, Adv. Exp. Med. Biol., 163 (Folil Antifolil Poliglutamates): 95-100, 1983), 3 ', 5'-dichloromethotrexate (Rosowsky &Yu, J. Med. Chem. 26 (10): 1448-52, 1983), analogues of diazoketone and chloromethyl ketone methotrexate (Gangjee et al., J. Pharm. Sci. 71 (6): 717-19 , 1982), homologs of 10-propargylamino-terine and alkyl methotrexate (Piper et al., J. Med. Chem. 25 (7): 877-80, 1982), lectin derivatives of methotrexate (Lin et al., JNCI 66 (3): 523-8, 1981), polyglutamate methotrexate derivatives (Galivan, Mol.Pharmacol. 17 (1): 105-10, 1980), halogenated methotrexate derivatives (Fox, JNCI 58 (4): J955-8 , 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al., J. Med. Chem. 20 (10): J1323-7, 1977), 7-methyl methotrexate and dichloromethotrexate derivatives (Rosowsky & Chen, J. Med. Chem. 17 (12): J1308-11, 1974), lipophilic methotrexate derivatives and 3 ', 5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 16 (10): J1190-3, 1973), deaza ametopterin analogues (Montgomery et al., Ann. NY Acad. Sci. 186: J227-34, 1971), MX068 (Pharma Japan, 1658: 18, 1999) and analogs of cysteic acid and homocysteic acid methotrexate (EPA 0142220); N3-alkylated analogues of 5-fluor-uracil (Kozai et al., J. Chem. Soc., Perkin Trans. 1 (19): 3145-31-46, 1998), 5-fluor-uracil derivatives with functional groups 1 , 4-oxaheteroepane (Gómez et al., Tetrahedron 54 (43): 13295-13312, 1998), 5-fluor-uracil and nucleoside analogs (Li, Anticancer Res. 17 (AIA) -.21-27, 1997), cis- and trans-5-fluoro-5,6-dihydro-6-alcohoxyuracil (Van der Wilt et al., Br. J. Cancer 68 (4) -.702-7, 1993), cyclopentane 5-fluorouracil analogues (Hronowski &Szarek, Can. J. Chem. 70 (4): 1162-9, 1992 ), A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi 20 (11): 513-15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38 (4): 998-1003, 1990), 1-hexylcarbamoyl-5-fluoro-uracil (Hoshi et al., J. Pharmacobio-Dun. 3 (9): 478-81, 1980; Maehara et al., Chemotherapy (Basel) 34 (6): 484-9, 1988), B-3839 (Prajda et al., In Vivo 2 (2): 151-4, 1988), Uracil-1- (2-tetrahydrofuryl) -5-fluoro-uracil (Anai et al., Oncology 45 (3): 144-7, 1988), 1- (2'-deoxy-2'-fluoro-DD-arabinofuranosyl) ) -5-fluor-uracil (Suzuko et al., Mol.Pharmacol. 31 (3): 301-6, 1987), doxifluridine (Matuura et al., Hear Yakuri 29 (5) .803-31, 1985), 5'-deoxy-5-fluoruridine (Bollag &Hartmann, Eur. J. Cancer 16 (4): 427-32, 1980), l-acetyl-3-0-toluyl-5-fluor-uracil (Okada , Hiroshima J. Med. Sci. 28 (l): 49 -66, 1979), 5-fluoro-uracil-m-formylbenzenesulfonate (JP 55059173), N '- (2-furanidyl) -5-fluoro-uracil (JP 53149985) and 1- (2-tetrahydrofuryl) -5 -fluor-uracil (JP 52089680); 4 '-epidoxorubicin (Lanius, Adv. Chemother, Gastrointest. Cancer, (Int. Symp.), 159-67, 1984); N-substituted deacetylvinblastine starch (vindesine) sulfate (Conrad et al., J. Med. Chem. 22 (4): 391-400, 1979); and Cu (II) -VP-16 complex (etoposide) (Tawa et al., Bioorg.

Med. Chem. 6 (7): 1003-1008, 1998), eyoposide analogs containing pyrrole-carboxamidino (Ji et al., Bioorg. Med.

Chem. Lett. 7 (5) -.607-612, 1997), analogs of 4D-amine etoposide (Hu, Dissertation from the University of North Carolina, 1992), analogues of the arylamine etoposide with the modified D-lactone ring (Zhou et al. al., J. Med. Chem. 37 (2): 287-92, 1994), an analogue of N-glucosyl etoposide (Allevi et al., Tetrahedron Lett 34 (45): 7313-16, 1993), analogs of the A ring of the etoposide (Kadow et al. ., Bioorg, Med Chem. Lett. 2 (l): 17-22, 1992), 4-dehydroxy-4'-methyl etoposide (Saulnier et al., Bioorg, Med. Chem.

Lett. 2 (10): 1213-18, 1992), etoposide analogs with a pendulum ring (Sinha et al., Eur. J. Cancer 26 (5): 590-3, 1990) and E-ring analogues. (Saulnier et al., J. Med. Chem. 32 (7): 1418-20, 1989). Within a preferred embodiment of the invention, the cell cycle inhibitor is paclitaxel, a compound that breaks down mitosis (M-phase) by binding to tubulin to form abnormal mitotic threads or an analogue or derivative thereof. Briefly, paclitaxel is a highly derivative diterpenoid (Wani et al., J. Am. Chem. Soc. 93: 2325, 1971) which was obtained from the collected and dried trunk of the Taxus brevifolia (Pacific Tejo) and Taxomyces Andreanae and Endophytic Fungus or Pacific Tejo (Stierle et al., Science 60: 214-216, 1993). HE "Paclitaxel" (which should be considered here to include the formulations, pro-drugs, analogs and derivatives thereof, for example, TAXOL (Bristol Myers Squibb, New York, NY, USA, TAXOTERE (Aventis Pharmaceuticals, Fran? A), docetaxel , paclitaxel 10-desacetyl analogues and 3 'N-desbenzoyl-3' Nt-butoxycarbonyl analogs of paclitaxel) can be readily prepared using techniques known to those who possess skills in art (see, for example, Schiff et al., Nature 277: 665-667, 1979; Long and Fairchild, Cancer Research 54: 4355-4361, 1994; Ringel and Horwitz, J. Nat'l Cancer Inst 83 (4): 288-291, 1991; et al., Cancer Treat, Rev 19 (4) -351-386, 1993, WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076, WO94. / 00156 WO 93/24476; EP 590267; WO 94/20089; US Patent No. . 294,637 5,283,253; 5,279,949; 5,274,137; 5,202,448 5,200,534 5,229,529; 5,254,580; 5,412,092; 5,395,850 5,380,751 5,350,866; 4,857,653; 5,272,171; 5,411,984 . 248,796 5,248,796; 5,422,364; 5,300,638; 5,294,637 . 362,831 5,440,056; 4,814,470; 5,278,324; 5,352,805 . 411,984 5,059,699; 4,942,184; Tetrahedron Letters (52): 9709-9712, 1994; J. Med. Chem. 35: 4230-4237, 1992; J. Med. Chem. 34: 992-998, 1991; J. Natural Prod. 57 (10). 1404-1410, 1994; J. Natural Prod. 57 (11) .1580-1583, 1994; J. Am. Chem. Soc. 110: 6558-6560, 1988), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Missouri, USA (T7402 - from Taxus brevifolia). Representative examples of paclitaxel derivatives or analogs include 7-deoxy-docetaxol, 7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxy paclitaxel, 6,7-modified paclitaxel, 10-deacetoxytoxol, 10-deacetyltaxol (of 10-deacetylbaccatin III), phosphonoxy and carbonate derived from taxol, taxol 2 ', 7-di (sodium 1,2-benzenedicarboxylate, 10-deacetoxy-11,12-dihydrotaxol-10,12 (18) -diene derivatives, 10- Deacetoxitaxol, Protaxol (2 '- and / or 7-O-derived esters), (2 '- and / or 7-O-carbonate derivatives), asymmetric synthesis of side chain taxol, fluorine taxols, 9-deoxotaxane, (13-acetyl-9-deoxobacatine III, 9-deoxotaxol, 7-deoxy-9- deoxotaxol, 10-deoxyethoxy-7-deoxy-9-deoxotaxole, derivatives containing hydrogen or acetyl group and a hydroxy tert-butoxycarbonylamino, sulfonated 2'-acryloyltaxol and derivatives of 2'-0-acyl sulfonate taxol, succinyltaxol, 2 ' -? - aminobutyryltaxol format, 2'-acetyl taxol, 7-acetyl taxol, 7-glycine carbamate taxol, 2'-OH-7-PEG (5000) carbamate taxol, 2'-benzoyl and 2 'derivatives, 7-dibenzoyl taxol , other pro-drugs (2'-acetyltaxol; 2 ', 7-diacetyltaxol; 2' succinyltaxol; 2 '- (beta-alanyl) -taxol); 2'gama-aminobutyryltaxol; ethylene glycol derivatives; 2'-succinyltaxol; 2 '-glutariltaxol; 2 '- (N, N-dimethylglycyl) taxol; 2 '- (2- (N, -dimethylamino) propionyl) taxol; 2 'orthocarboxybenzoyl taxol; 2'-aliphatic carboxylic acid derivatives of taxol, Pro-drugs. { 2 '(N, N-diethylaminopropionyl) taxol, 2' (N, N-dimethylglycyl) taxol, 7 (N, N-dimethylglycyl) taxol, 2 ', 7-di- (N, N-dimethylglycyl) taxol, 7 ( N, N-diethylaminopropionyl) taxol, 2 ', 7-di (N, N-diethylaminopropisyl) taxol, 2' - (L-glycyl) taxol, 7- (L-glycyl) taxol, 2 ', 7-di (L glycyl) taxol, 2 '- (L-alanyl) taxol, 7- (L-alanyl) taxol, 2', 7-di (L-alanyl) taxol, 2'- (L-leucyl) taxol, 7- ( L-leucyl) taxol, 2 ', 7-di (L-leucyl) taxol, 2' - (L-isoleucyl) taxol, 7- (L-isoleucyl) taxol, 2 ', 7-di (L-isoleucyl) taxol , 2 '- (L-valil) taxol, 7- (L-valil) taxol, 2' 7-di (L-valil) taxol, 2 '- (L-phenylalanyl) taxol, 7- (L-phenylalanyl) taxol , 2 ', 7-di (L-phenylalanyl) taxol, 2' - (L-prolyl) taxol, 7- (L-prolyl) taxol, 2 ', 7-di (L-prolyl) taxol, 2' - ( L-lysyl) taxol, 7- (L-lysyl) taxol, 2 ', 7-di (L-lysyl) taxol, 2' - (L-glutamyl) taxol, 7- (L-glutamyl) taxol, 2 ', 7-di (L-glutamyl) taxol, 2 '- (L-arginyl) taxol, 7- (L-arginyl) taxol, 2', 7-di (L-arginyl) taxol} , taxol analogs modified phenylisoserine side chains, taxotere, (N-debenzoyl-N-tert- (butoxicaronyl) -10-deacetyltaxol, and taxanes (eg, baccatin III, cephalomannin, 10-deacetylbaccatin III, brevifolol, iunantaxusin, and taxusin) and other analogues and derivatives of taxanes, including 14-beta-hydroxy-10 deacetybaccatin III, debenzoyl-2-acyl paclitaxel derivatives, paclitaxel benzoate derivatives, phosphonooxy and paclitaxel carbonate derivatives, sulfonated 2'-acryloyltaxol; 2'-0-acyl sulphonated paclitaxel acid derivatives, site-substituted paclitaxel derivatives 18, chlorinated analogs of paclitaxel, C4 methoxy ether derivatives of paclitaxel, sulfonamide taxane derivatives, brominated paclitaxel analogs, Girard derivatives of taxanes, nitrophenyl paclitaxel , substituted 10-deacetylated derivatives of paclitaxel, derivatives of 14-beta-hydroxy-10-deacetylbaccatin III taxane, derivatives of C7 taxane, derivatives of CIO taxane, derivatives of 2-debenzoyl-2-acyl taxane, 2-debenzoyl derivatives and -2-acyl paclitaxel, taxane and baccatin III analogs containing new C2 and C4 functional groups, n-acyl paclitaxel analogues, 10-deacetylbaccatin III and 7-protected-10-deacetylbaccatin III derivatives of 10-deacetyl taxol A, 10-deacetyl taxol B, and 10-deacetyl taxol, benzoate derivatives of taxol, analogs of 2-aroyl-4-acyl paclitaxel, ortho-ester analogs paclitaxel, analogs of 2-aroyl-4-acyl paclitaxel and analogues of 1- deoxi pa clitaxel 1-deoxy paclitaxel. In one aspect, the cell cycle inhibitor is a taxane which has the structure of formula (III): where the portions highlighted in ash can be replaced and the portions not highlighted are the taxane nucleus. A side chain (identified as "A" in the diagram) is preferably present for the compound to have a good activity as a cell cycle inhibitor. Examples of compounds possessing this structure include paclitaxel (Merck Index entry 7117), docetaxsl (Taxotere, Merck Index entry 3458), and 3 '-desphenyl-3' - (4-ntrophenyl) -N-debenzoyl-N- (t -butoxycarbonyl) -10-deacetyltaxol. In one aspect, suitable taxanes such as paclitaxel and its analogs and derivatives are disclosed in U.S. Pat. No. 5,440,056 as having the structure of formula (IV): where X can be oxygen (paclitaxel), hydrogen (9-deoxy derivative), thioacyl, or dihydroxyl precursors; Rl is selected from side chains paclitaxel or taxotere or alkanoyl possessing the structure of formula (V) wherein R7 is selected from hydrogen, alkyl, phenyl, alkoxy, amine, phenoxy (substituted or unsubstituted); R8 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), alpha or beta-naphthyl; and R9 is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; wherein the substitutions refer to hydroxyl, sulfhydryl, all-alcohoxyl, carboxyl, halogen, thioalcohoxyl, N, N-dimethylamino, alkylamino, dialkylamino, nitro, and -OS03H, and / or may refer to groups containing such substitutions as; R2 is selected from groups containing hydrogen or oxygen, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidialkanoyloxy; R3 is selected from hydrogen or oxygen containing groups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidialkanoyloxy, and may even be a group containing silyl or a sulfur containing group; R 4 is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R5 is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R6 is selected from groups containing hydrogen or oxygen, such as hydrogen, hydroxyl, alkyl, alkanoyloxy, aminoalkanoyloxy, and peptidialkanoyloxy. In one aspect, paclitaxel analogs and derivatives useful as cell cycle inhibitors are disclosed in PCT International Patent Application No. WO 93/10076. As disclosed in that publication, the analog or derivative must possess a side chain attached to the taxane nucleus at C13, as shown in the structure with formula VI, for the purpose of conferring an anti-tumor activity on the taxane.

WO 93/10076 discloses that the taxane nucleus can be substituted in any position except for the existing methyl groups. Substitutions may include, for example, hydrogen, alkanoyloxy, alkenyloxy, aryloyloxy. In addition, the oxo groups can be attached to the carbons identified as 2, 4, 9, and / or 10. In addition, an oxetane ring can be bonded to the carbons identified as 4 and 5. And further, an oxirane ring can be be bound to the carbon identified as 4. In one aspect, a taxane-based cell cycle inhibitor useful in the present invention is disclosed in US Pat. 5,440,056, which discloses the 9-deoxo taxanos. These are compounds that have deficiency of an oxo group on the carbon identified as 9 in the structure of the taxane shown below (formula VI). The taxane ring can be substituted on the carbons identified as 1, 7 and 10 (independently) with H, OH, O-R, or o-CO-R where R is an alkyl or an aminoalkyl. In the same way, it can be substituted in the carbons identified as 2 and 4 (independently) with aryol, alkanoyl, aminoalkanoyl or alkyl groups. The side chain of formula (V) can be substituted on R7 and R8 (independently) with phenyl rings, substituted phenyl rings, linear alkanes / alkenes, and groups containing H, u or N. R9 can be substituted by H, or a substituted or unsubstituted alkanoyl group. Taxanes in general, and paclitaxel in particular, is considered to function as an inhibitor of the cell cycle by action as an anti-microtubule agent, and more specifically as a stabilizer. These compounds proved useful in the treatment of proliferative disorders, including: cancers in the lung without small cells (NSC - non-small cell); in the lung with small cell; in the breast; in the prostate; in the cervical; endometrial; in the head and in the neck. In another aspect, the anti-microtubule agent (microtubule inhibitor) is albendazole (carbamic acid, [5- (propylthio) -lH-benzimidazol-2-yl] -, methyl ester), LY-355703 (l, 4- dioxa-8, ll-diazacyclohexadec-13-ene-2, 5, 9, 12-tetrone, 10 - [(3-chloro-4-methoxyphenyl) methyl] -6,6-dimethyl-3- (2-methylpropyl) -16- [(1S) -1- [(2S, 3R) -3-phenyloxyranyl] ethyl] -, (3S, 10R, 13E, 16S) -), vindesine (vincaleucoblastin, 3- (aminocarbonyl) -04-deacetyl) -3-de (methoxycarbonyl) -), or WAY-174286 In another aspect, the cell cycle inhibitor is a vinca alkaloid. The vinca alkaloids have the following general structures of formulas (VI) and (VII). They are indole-dihydroindole dimers. dihydroindole Di idroindol (VII) As disclosed in U.S. Pat. No. 4,841,045 and 5,030,620, R 1 can be a formyl or methyl group or alternatively H. R 1 can also be an alkyl group or a substituted alkyl-aldehyde (e.g., CH 2 CHO). R2 is typically a CH3 or NH2 group; meanwhile ele can alternatively be substituted with a lower alkyl ester or the ester linkage for the dihydroindole core can be substituted with C (0) -R where R is NH2, an amino acid ester or a peptide ester. R3 is typically C (0) CH3, CH3 or H. Alternatively, a protein fragment can be ligated by a bifunctional group, such as the amino acid maleoil. R3 can also be substituted to form an alkyl ester that can still be substituted. R4 can be -CH2- or a single bond. R5 and R6 can be H, OH or a lower alkyl, typically -CH2CH3. Alternatively, R6 and R7 can form each other an oxetane ring. R7 can alternatively be H. Additional substitutions include molecules where methyl groups are substituted by other alkyl groups, and where unsaturated rings can be derived by the addition of a side group such as an alkane, alkene, alkyne, halogen, ester, amide or amine. Examples of vinca alkaloids are vinblastine, vincristine, vincristine sulfate, vindesine, and vinorelbine, with the structures of formula (VIII): R, R2 R3 R4 R5 Vinblastine: CH3 CH3 C (0) CH3 OH CH2 Vipcristine: CH20 CH3 C (0) CH3 OH CH2 Vin esine: C CHH, 3 NH2 H OH CH2 (VIII) \ / nnr- Ihin- • CH, CH, CH, H single bond Vinblastine: Vincristine: Vindesine: Vinorelbine: Simple link Analogs typically require the lateral group (shaded area) to have activity. These compounds are considered to act as inhibitors of the cell cycle by functioning as an anti-microtubule agent, and more specifically to inhibit polymerization. These compounds are shown to be useful in the treatment of proliferative disorders, including cancers of the NSC lung; small lung cells; of the breast; of the prostate; of the brain; of the head and neck; retinoblastoma; of the gallbladder or bladder; and of the penis; and soft tissue sarcoma. In another aspect, the cell cycle inhibitor is a camptothecin, or an analog or a derivative thereof. The camptothecins have the following general structure with formula (IX): In that structure, X is typically O, but may also be other groups, for example, NH in the case of 21-lactam derivatives. R1 is typically H or OH, but may be other groups, for example, a Cl-3 alkane with hydroxylated termination. R2 is typically H or an amine containing group such as (CH3) 2NHCH2, but may be other groups eg, N02, NH2, halogen (as disclosed in, for example, US Patent 5,552,156) or an alkane short that contains those groups. R3 is typically H or an alkyl short such as C2H5. R 4 is typically H but may be other groups, for example, a methylenedioxy group with R 1. Examples of camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20 (S) -camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. Examples of compounds possess the structures of formula (X) -.

(X) Ri R- R Camptothecin: H H H Xopotecan: OH (CH3) 2NHCH2 H C Caammpptto- tootteecciinnaa :: OH H C C2H5 Topotecan: analogs, NH for 21-lactam analogs X: O for most analogues, NH for 21-lactam analogues The camptothecins possess the five rings shown here. The ring identified as Y must be intact (the lactone form instead of carboxylate) for maximum activity and minimal toxicity. These compounds are useful as cell cycle inhibitors, where they can function as inhibitors of topoisomerase I and / or DNA fragmentation agents. They were useful in the treatment of proliferative disorders, including, for example, cancers of the lung NSC; small lung cell; and cervical. In another aspect, the cell cycle inhibitor is a podophyllotoxin, or a derivative or analogue thereof. Examples of compounds of that type are etoposide or teniposide, which possess the following structures of formula (XI): These compounds are considered to function as cell cycle inhibitors because they are inhibitors of topoisomerase II and / or DNA fragmentation agents. They proved useful as proliferative antiagent agents in, for example, lung cancers with small cells, of the prostate, and of the brain, and in retinoblastoma. Another example of a DNA topoisomerase inhibitor is lurtotecan dihydrochloride (HH-1, 4-dioxino [2,3-g] pyrano [3 ', 4': 6,7] indolizine [1,2-b] quinolin-9 , 12 (8H, 14H) - dione, 8-ethyl-2,3-dihydro-8-hydroxy-15 - [(4-methyl-1-piperazinyl) methyl] -, dihydrochloride, (S) -). In another aspect, the cell cycle inhibitor is an anthracycline. The anthracyclines have the following general structure of formula (XII), where the R groups can be a variety of organic groups: In accordance with US Pat. 5,594,158, suitable R groups are: R1 is CH3 or CH20H; R2 is daunosamine or H; R3 and R4 are, independently, one of OH, N02, NH2, F, Cl, Br, I, CN, H or groups derived therefrom; R5-7 are all H or R5 and R6 are H and R7 and R8 are alkyl or halogen, or vice versa: R7 and R8 are H and R5 and R6 are alkyl or halogen. In accordance with US Pat. 5,843,903, R2 can be a conjugated peptide. In accordance with US Pat. No. 4,215,062 and 4,296,105, R 5 can be OH or an alkyl group with ether linkage. Rl can also be linked to the anthracycline ring by means of a group other than C (O), such as an alkyl or branched alkyl group possessing the functional linking group C (0) at its end, such as - CH2CH ( CH2-X) C (0) -R1, where X is H or an alkyl group (see, for example, US Pat. 4,215,062). R 2 may alternatively be a group linked by the functional group = N-NHC (0) -Y, where Y is a group such as a phenyl or a substituted phenyl ring. Alternatively R3 may have the following structure of formula (XIII): where R9 is OH or in the plane of the ring or outside it, or is a second sugar functional group such as R3. RIO can be H or form a secondary amine with a group such as an aromatic group, a saturated or partially unsaturated 5- or 6-membered heterocyclic group possessing at least one nitrogen in the ring (see US Patent 5,843. 903). Alternatively, RIO can be derived from an amino acid, which has the structure -C (O) CH (NHRll) (R12), where Rll is H, or forms an alkylene with C3-4 member with R12. R 12 can be H, alkyl, aminoalkyl, amine, hydroxy, mercapto, phenyl, benzyl or methylthio (see US Patent 4,296,105). Examples of anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have structures with the formula (XIV): Doxorubicin: OCH3 CH2OH OH out of ring plane Epirubicin: OCH3 CH2OH OH ring ring orubicin) Doxorubicin OCH3 CH3 OH outside ring ring Epirubicin H CH3 OH in the ring plane number 41 of doxorubicin OH A = N-NHC (0) C Daunorubicin 3 'ß OH outside the plane of the ring CH3 Idarubicin OH outside the plane of ring B: Pirarubicin ^ 4 < H Cv Zorubicin NH2 Carubicin Other suitable anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A3, and plicamycin with the structures: Mitoxantrone Plicapiicin These compounds are considered to function as cell cycle inhibitors because they are inhibitors of topoisomerase and / or because they are DNA fragmenting agents. They were considered useful in the treatment of proliferative disorders, including small cell lung cancers; of the breast; endometrial; of the head and neck; retinoblastoma; of the liver; of the bile duct; of tiny cells; and of the bladder and vesicle; and soft tissue sarcoma. In another aspect, the cell cycle inhibitor is a platinum compound. In general, platinum complexes suitable may be of the Pt (II) or Pt (IV) type and possess that basic structure of formula (XV): where X and Y are anionic groups leaving groups such as sulfate, phosphate, carboxylate, and halogen; R1 and R2 are alkyl, amine, amino alkyl and any one can also be substituted, and they are basically inert or ponte groups. For Pt (II) complexes, Zl and Z2 are non-existent.

For Pt (IV), Zl and Z2 can be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate.

See, for example, US Pat. Nos. 4,588,831 and 4,250,189. Suitable platinum complexes may contain multiple Pt atoms. See, for example, US Pat.

Nos. 5,409,915 and 5,380,897. For example, bisplatin and triplatin complexes of the type: Examples of platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin that possesses the structures: Oxaliplastino Miboplastino These compounds are considered to function as inhibitors of the cell cycle by binding to DNA, that is, acting as alkylating agents of DNA. These compounds proved useful in the treatment of cell proliferative disorders, including, for example, cancers of the lung NSC; of the lung with small cells; of the breast; cervical; of the brain; of the head and neck; of the esophagus; retinoblastoma; of the liver; of the bile duct; of the bladder or vesicle; of the penis and of the vulva; and soft tissue sarcoma. In another aspect, the cell cycle inhibitor is a nitrosourea. The Nitrosoureas possess the following general formula (XVI), where typical R groups are shown below. I (XVI) Group R: Other suitable R groups include the cyclic alkane groups, alkanes, substituted halogens, sugars, aryl and heteroaryl groups, phosphonyl and sulfonyl. As disclosed in US Patent No. 4,367,239, R may suitably be CH2-C (X) (Y) (Z), where X and Y may be the same or different members of the following groups: phenyl, cyclohexyl, or a phenyl or cyclohexyl group substituted with groups such as halogen, lower alkyl (Cl-4), trifluor methyl, cyano, phenyl, cyclohexyl, lower alkyloxy (Cl-4). Z has one of the following structures: -alkylene-N-RlR2, where R1 and R2 may be the same or different members of the following groups: lower alkyl (Cl-4) and benzyl, or R1 and R2 together may form a heterocyclic group with 5 or 6 saturated members such as pyrrolidine, piperidine, morpholine, thiomorpholine, N-lower alkyl piperazine, wherein the heterocyclic may be optionally substituted with lower alkyl groups. As disclosed in U.S. Pat. No. 6,096,923, R and R 'of formula (XVI) may be the same or different, wherein each may be a substituted or unsubstituted hydrocarbon having between 1-10 carbons. Substitutions may include hydrocarbyl, halo, ester, amide, carboxylic acid, ether, thioether and alcohol groups. As disclosed in U.S. Pat. No. 4,472,379, R of formula (XVI) can be an amide bond and a pyranose structure (eg, methyl 2 '- (N- (N- (2-chloroethyl) -N-nitroso-carba oil) -glycyl ) amine-2 '-deoxi-aD- glucopyranoside). As disclosed in U.S. Pat. No. 4,150,146, R of formula (XVI) can be an alkyl group of 2 to 6 carbons and can be substituted with an ester, sulfonyl, or hydroxyl group. Ele can also be substituted with a carboxylic acid or a CONH2 group. Examples of nitrosoureas are BCNU (carmustine), methyl-CCNU (semustine), CCNU (lomustine), ranimustine, nimustine, chlorozotocin, fotemustine, and streptozocin, which possesses the following structures: These nitrosourea compounds are considered to function as cell cycle inhibitors by DNA binding, that is, they function as alkylating agents of the agents.

DNA alkylation. These cell cycle inhibitors have proved useful in the treatment of cell proliferative disorders such as, for example, very small cell cancers, of the small cell lung; melanoma; and the brain. In another aspect, the cell cycle inhibitor is a nitroimidazole, where the examples of nitroimidazoles are metronidazole, benzidazole, etanidazole, and misonidazole, which possess the structure of formula (XVII): (XVII) R1 R2 R3 Metronidazole OH CH3 N02 Benznidazole C (0) NHCH2-benzyl N02 H Metrodinazole CONHCH2CH2OH N02 H Benzinidazole Etanidazole Suitable nitroimidazole compounds are disclosed in, for example, US Pat. Nos. 4,371,540 and 4,462,992. In another aspect, the cell cycle inhibitor is an antagonist of folic acid, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexate, piritrexime, denopterin, tomudex, and pteropterin. Methotrexate analogs possess the following general structure of formula (XVIII): (XVIII) An identity of the group R group can be selected among organic groups, particularly those groups set forth in US Pat. Nos. 5,166,149 and 5,382,582. For example, R1 can be N, R2 can be N or C (CH3), R3 and R3 'can be H or alkyl, for example, CH3, R4 can be a single bond or NR, where R is H or an alkyl group . R5,6,8 can be H, OCH 3, or alternatively they can be halogens or hydro groups. R7 is a side group with general structure of formula (XIX): where n = 1 for methotrexate, n = 3 for pteropterin. The carboxyl groups in the side group can be esterified or in the form of salts such as a salt of Zn2 +. R9 and RIO may be NH2 or they may be alkyl substituted. Examples of folic acid antagonist compounds have the structures of formulas (XX) and (XXI) -.

Methotrexate NH2 NNHN (CH3) HHA (n = 1) H Edatrexate NH2 NNHN (CH2CH3) HHA (n = 1) H Trimetrexate NH2 NC (CH3) H NH H OCH3 OCH3 OCH Pteropterin NH2 NNHN (CH3) HHA (n = 3) H Denopterin OH NN CH3 N (CH3) HHA (n = 1) H Pinitrexime NH2 NC (CH3) H single OCH3 HH OCH3 H bond Simple link (XXI) These compounds are considered to function as cell cycle inhibitors serving as folic acid antimetabolites. They were shown to be useful in the treatment of cell proliferative disorders including, for example, soft tissue sarcoma, lung cancers by small cells, breast, brain, head and neck, gall bladder and bladder, and the penis. In another aspect, the cell cycle inhibitor is an analogue of cytidine, such co or cytarabine or derivatives or analogues thereof, including enocythabin, FMdC ((E (-2'-deoxy-2 '- (fluoromethylene) cytidine) ), gemcitabine, 5- azacytidine, ancitabine, and 6-azauridine Examples of compounds possessing the structure of formula (XXII): Citarabine H OH H CH Enocitabine C (0) (CH2) 8CH3 OH H CH Gemcitabine H F F CH Azacitidine H H OH N FMdC H CH, F H CH Ancitabine 6-Azauridine These compounds are considered to function as cell cycle inhibitors insofar as they act as pyrimidine antimetabolites. These compounds proved useful in the treatment of cell proliferative disorders including, for example, cancers pancreatic, breast, cervical, lung NSC, and biliary duct. In another aspect, the cell cycle inhibitor is an analogue of pyrimidine. In one aspect, the pyrimidine analogs possess the general structure of formula (XXIII): (XXIII) where the 2 ', 3' and 5 'positions in the sugar ring (R2, R3 and R4, respectively) can be H, hydroxyl, phosphoryl (see, for example, US Patent 4,086,417) or ester (see, for example, US Patent 3,894,000). The esters can be of the alkyl, cycloalkyl, aryl or heterocycle / aryl types. The carbon 2 'can be hydroxylated or in R2 or R2', the other group is H. Alternatively, the carbon 2 'can be substituted with halogens for example, fluorine or difluor cytidines such as Gemcitabine. Alternatively, the sugar may be substituted by another heterocyclic group such as a furyl group or an alkane, an alkyl ether or an amide linked alkane such as C (0) NH (CH2) 5CH3. The 2nd amine can be replaced by a aliphatic acyl (Rl) linked to an amide (see, for example, US Patent 3,991,045) or a urethane linkage (see, for example, US Patent 3,894,000). Ele can also be substituted to form a quaternary ammonium salt. R5 in the pyrimidine ring can be N or CR, when R is H, halogen-containing groups, or alkyl (see, for example, US Patent No. 4,086,417). R6 and R7 can each form an oxo group or R6 = -NH-R1 and R7 = H. R8 is H or R7 and R8 can together form a double bond or R8 can be X, where X is a structure with formula (XXIV ): Specific analogs of pyrimidine are disclosed in US Pat. No. 3,894,000 (see, for example, 2'-O-palmityl-ara-cytidine, 3'-O-benzoyl-ara-cytidine, and more than 10 other examples); US Patent No. 3,991,045 (see, for example, N 4-acyl-l-β-D-arabinofuranosylcytosine, and numerous derivatives of acyl groups as listed therein, such as palmitoyl). In another aspect, the cell cycle inhibitor is an analogue of fluoropyrimidine, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine. Examples of compounds have structures with formulas (XXV): R- (XXV) 5-Fluorouracil H H Carmofur C (?) NH (CH2) 5CH3 H Doxifluridine A, H Floxuridine A. H Emitefur CH2OCH2CH3 B Tegafur C H Other suitable analogues of fluoropyrimidine include 5- FudR (5-fluoro-deoxyuridine), or an analog or derivative thereof, including 5-iodo-deoxyuridine (5-IudR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5- FUTP), and fluor-deoxyuridine monophosphate (5-dFU P). The examples of compounds possess the structures of formula (XXVI): -Fluor -2'-deoxyuridine: R = F 5-Bromo-2'-deoxyuridy: R = Br 5 -Iodo-2'-deoxuridine: R = I These compounds are considered to function as cell cycle inhibitors serving as pyrimidine antimetabolites. These compounds proved useful in the treatment of cell proliferative disorders such as cancers of the breast, cervical, non-melanoma of the pelle, head and neck, esophagus, bile duct, pancreatic, tiny cells, penis, and of the vulva. In another aspect, the cell cycle inhibitor is an analogue of purine. The purine analogues possess the following general structure of formula (XXVII): (XXVII) where X is typically carbon; R1 is H, halogen, amine or a substituted phenyl; R2 is H, a primary, secondary or tertiary amine, a sulfur-containing group, typically -SH, an alkane, a cyclic alkane, a heterocyclic or a sugar; R3 is H, a sugar (typically a furanose or pyranose structure), a substituted sugar or an aryl or cyclic or heterocyclic alkane group. See, for example, US Pat. No. 5,602,140 for compounds of that type. In the case of pentostatin, X-R2 is -CH2CH (OH) -. In that case a second carbon atom is inserted into the ring between X and the adjacent nitrogen atom. The double bond X-N becomes a simple link. The US patent No. 5,446,139 describes suitable analogs of the purine of the type shown in the structure of formula (XXVIII): (XXVIII) where N means nitrogen and V, W, X, Z can be carbon or nitrogen with the following restrictions. Ring A can have 0 to 3 nitrogen atoms in its structure. If two nitrogens are present in ring A, one must be in position W. If only one is present, it must not be in position Q. V and Q must not be simultaneously nitrogen. Z and Q must not be simultaneously nitrogen. If Z is nitrogen, R3 is not present. In addition, Rl-3 are independently one of H, halogen, Cl-7 alkyl, Cl-7 alkenyl, hydroxyl, mercapto, Cl-7 alkylthio, Cl-7 alkoxy, C 2-7 alkenyloxy, aryl oxy, nitro, primary, secondary or tertiary amino group. R5-8 are H or up to two of the positions can independently contain one of OH, halogen, cyano, azido, substituted amino, R5 and R7 can form a bond to each other. Y is H, an alkylcarbonyl Cl-7, or a mono-di or tri-phosphate. Suitable examples of purine analogs include 6-mercaptopurine, tiguanosin, tiamiprin, cladribine, fludaribine, tubercidin, puromycin, pentoxifylline; wherein those compounds can optionally be phosphorylated. The examples of compounds have structures of formulas (XXIX) and (XXX): Tiamíprina Pentoxifylline Those compounds are considered to function as cell cycle inhibitors by serving as purine antimetabolites. In another aspect, the cell cycle inhibitor is a nitrogen mustard. Muites suitable nitrogen mustards are known and are suitably used as a cell cycle inhibitor in the present invention. The Suitable nitrogen mustards are also known as cyclophosphamides. A preferred nitrogen mustard possesses the structure of general formula (XXXI): where A is or -CH3 or other alkane, or chlorinated alkane, typically CH2CH (CH3) Cl, or a polycyclic group such as B, or a substituted phenyl such as C or a heterocyclic group such as D.

(B) Examples of suitable nitrogen mustards are disclosed in U.S. Pat. No. 3,808,297, where A is: Rl-2 are H or CH2CH2C1; R3 is H or oxygen-containing groups such as hydroperoxy; and R4 can be alkyl, aryl, heterocyclic. The cyclic functional group does not need to be intact. See, for example, US Pat. No. 5,472,956, 4,908,356, 4,841,085 that the following type of structure of formula (XXXII): (XXXII) where R1 is H or CH2CH2C1, and R2-6 are several substituent groups. Examples of nitrogen mustards include methylchloroethamine, and analogues or derivatives thereof, including methylchloroetheramide hydrochloride, novembichin, and manomustine (a halogenated sugar). The examples of compounds have the following structures: Novembichin CH2CH (CH3) CI Novembichina Mechloretanimine Oxide Nitrogen mustard may be cyclophosphamide, ifosfamide, perfosfamide, or torophosfamide, where these compounds possess the structures of formula (XXXIII): (XXXIII) R1 R2 R3 Cyclophosphamide H CH2CH2CI H Ifosfamide CH2CH2CI H H Perphosphamide CH2CH2Cl H OOH Torophosphamide CH2CH2CI CH2CH2Cl H Nitrogen mustard may be estramustine, or an analog or derivative thereof, including fenesterin, prednimustine, and estramustine P04. Thus, nitrogen mustard type cell cycle inhibitors suitable for the present invention possess the structures of formulas (XXXIV) and (XXXV): (XXXIV) R Estramustma OH Fenesterin C (CH3) (CH2) 3CH (CH3) 2 The nitrogen mustard may be chlorambucil, or an analogue or derivative thereof, including melflan and chlormaphazine. In this way, cell-cycle inhibitors of the nitrogen mustard type suitable for the present invention possess the structures of formula (XXXVI): (XXXVI) R? R. R3 Chlorambucil - CH2COOH H H Melphalan COOH NH2 H Clornafazine H Together form a benzene ring Nitrogen mustard can be mustard uracil, which has the structure of formula (XXXVII): (XXXVII) Nitrogen mustards are considered to function as cell cycle inhibitors for serving as alkylating agents for DNA. Nitrogen mustards have proved useful in the treatment of cell proliferative disorders including, for example, small cell lung, breast, cervical, head and neck, prostate, retinoblastoma, and tissue sarcoma cancers. soft. The cell cycle inhibitor of the present invention can be a hydroxyurea. The hydroxyureas possess the following general structure of formula (XXXVIII): (XXXVIII) Suitable hydroxyureas are disclosed in, for example, US Pat. No. 6,080,874, where Rl is the group represented by the structure of formula (XXXIX): (XXXIX) R2 is an alkyl group having 1-4 carbons and R3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methyl ether. Other suitable hydroxyureas are disclosed in, for example, US Pat. No. 5,665,768, where R 1 is a cycloalkenyl group, for example N- (3- (5- (4-fluorophenylthio) -furyl) -2-cyclopenten-1-yl) N-hydroxyurea; R2 is H or an alkyl group having 1 to 4 carbons and R3 is H; X is H or a cation. Other suitable hydroxyureas are disclosed in, for example, US Pat. No. 4,299,778, where Rl is a phenyl group substituted by one or more fluorine atoms; R2 is a cyclopropyl group; and R3 and X are H. Other suitable hydroxyureas are disclosed in, for example, US Pat. No. 5,066,658, where R2 and R3 together with the adjacent nitrogen form the one represented in the structure of formula (XL): where m is 1 or 2, n is 0-2 and Y is an alkyl group. In one aspect, the hydroxyurea possesses the structure with the formula (XLI): Hydroxyurea Hydroxyureas are considered to function as inhibitors of the cell cycle by serving in the inhibition of DNA synthesis. In another aspect, the cell cycle inhibitor is a mitomycin, such as mitomycin C, or an analogue or derivative thereof, such as porphyromycin. The examples of these compounds have structures of formula (XLII): R Mitomycin C H Porphyromycin CH3 (N-methyl Mitomycin) These compounds are considered to function as cell cycle inhibitors for serving as DNA alkylating agents. Mitomycins were found useful in the treatment of cell proliferative disorders such as, for example, cancers of the esophagus, liver, bladder or vesicle, and of the breast. In another aspect, the cell cycle inhibitor is an alkyl sulfonate, such as busulfan, or an analog or derivative thereof, such as treosulfan, improsulfan, piposulfan, and pipobroman. The examples of compounds have the following structures: Busulfan Simple link Improsulfan -CH2-NH-CH2- Piposulfan Pipobroman These compounds are considered to function as cell cycle inhibitors by serving as DNA alkylating agents. In another aspect, the cell cycle inhibitor is a benzamide. In also another aspect, the cell cycle inhibitor is a nicotinamid. These compounds have the basic structure of formula (XLIII): (LXIII) where X is u or S; A is commonly NH 2 or it can also be OH or an alkoxy group; B is N or C-R4, where R4 is H or a hydroxylated alkane with ether-type bonds such as OCH2CH20H, the alkane can be linear or branched and can contain one or more hydroxyl groups. Alternatively, B may be N-R5 in which case the double bond in the ring involving B is a single bond. R5 can be H, and an alkyl or aryl group (see, for example, US Patent No. 4,258,052); R2 is H, OR6, SR6 or NHR6, where R6 is an alkyl group; and R3 is H, a lower alkyl, a lower alkyl with ether bond such as -O-Me or -0-ethyl (see, for example, US Patent No. 5,215,738). Suitable benzamide compounds possess the structures of formula (XLIV): Benzamides X = O or S Y = H, OR, CH3, or acetoxy Z = H, OR, SR, or NHR R = alkyl group (XLIV) where additional compounds are disclosed in US Pat. No. 5,215,738, (which lists compounds). Suitable nicotinamide compounds possess the structures of formula (XLV): Nicotinamides X = O or S Z = H, OR, SR, NHR R = alkyl group where additional compounds are disclosed in U.S. Pat. No. 5,215,738, Uredepa CH3 H Carboquone In another aspect, the cell cycle inhibitor is a halogenated sugar, such as mitolactol, or an analogue or derivative thereof, including mitobronitol and manomustine. Examples of these compounds have the structures: Mitolactol Mitobronitol Manno ustine Manomustine In another aspect, the cell cycle inhibitor is a diazo compound, such as azaserin, or an analogue or derivative thereof, including 6-diazo-5-oxo-L-norleucine and 5-diazouracil ( also an analogue of pyrimidine). Examples of these compounds have the structures of formula (XLVI): Azaserine 0 single bond Azarezina Simple link 6-diazo- -oxo-L ~ single bond CH2 norleucine Simple link Other compounds that can serve as cell cycle inhibitors according to the present invention are pazliptin; ortmanin; metoclopramide; RSU; butionine sulfoxime; tumérica; curcumin; AG337, an inhibitor of thymidylate synthesis; levamisole; lentinana, a pslisacarídeo; razoxane, an analogue of EDTA; indomethacin; chlorpromazine; a and ß interferon; MnBOPP; gadolinium texaphrine; 4-amine-l, 8-naphthalimide; staurosporine derivative of CGP; and SR-2508. Thus, in one aspect, the cell cycle inhibitor is a DNA-allylating agent. In another aspect, the cell cycle inhibitor is an anti-microtubule agent. In another aspect, the cell cycle inhibitor is a topoisomerase inhibitor. In another aspect, the cell cycle inhibitor is a DNA fragmenting agent. In another aspect, the cell cycle inhibitor is an antimetabolite. In another aspect, the inhibitor of Cell cycle works by the inhibition of adenosine deaminase (for example, as an analogue of purine). In another aspect, the cell cycle inhibitor functions by the inhibition of purine ring synthesis and / or as an inhibitor of nucleotide interconversion (eg, as a purine analog such as mercaptopurine). In another aspect, the cell cycle inhibitor functions by inhibiting the reduction of the dihydrofolate and / or as a thymidine monophosphate block (e.g., methotrexate). In another aspect, the cell cycle inhibitor works causing DNA damage (eg, bleomycin). In another aspect, the cell cycle inhibitor functions as a DNA intercalating agent and / or in the inhibition of RNA synthesis (eg, doxorubicin, aclarubicin, or detorubicin (acetic acid, diethoxy-, 2- [4 - [(3-amine-2,3,6-trideoxy-alpha-L-lixo-hexopyranosyl) oxy] -1,2,3,4,6,11-hexahydro-2, 5, 12-trihydroxy-7- methoxy-6, 11-dioxo-2-naphthacenyl] -2-oxoethyl ester, (2S-cis) -)). In another aspect, the cell cycle inhibitor functions by inhibiting the synthesis of pyrimidine (e.g., N-phosphonoacetyl-L-aspartate). In another aspect, the cell cycle inhibitor functions by the inhibition of ribonucleotides (e.g., hydroxyurea). In another aspect, the cell cycle inhibitor works by inhibiting thymidine monophosphate (e.g., 5-fluorouracil). In another aspect, the cell cycle inhibitor works by inhibiting DNA synthesis (eg, cytarabine). In another aspect, the cell cycle inhibitor works by causing an adduction formation of the DNA (e.g., platinum compounds). In another aspect, the cell cycle inhibitor functions by the inhibition of protein synthesis (for example, L-asparginase). In another aspect, the cell cycle inhibitor works by inhibiting the microtubule function (eg, taxanes). In another aspect, the cell cycle inhibitor acts in one or more stages in the biological pathway shown in FIG. 1. Additional cell cycle inhibitors useful in the present invention, as well as a discussion of the mechanisms of action, can be found in Hardman J.G. , Limbird L.E. Molinoff R.B., Ruddon R. W., Gilman A.G. editors, Chemoutroapy of Neoplastic Diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics Ninth Edition, McGraw-Hill Health Professions Division, New York, 1996, pages 1225-1287. See also Patents USA No. 3,387,001; 3,808,297 3,894,000; 3,991,045; 4. 012,390 4,057,548; 4,086,417 4,144,237; 4,150,146; 4. 210,584 4,215,062; 4,250,189 4,258,052; 4,259,242; 4,296,105 4,299,778; 4,367,239; 4,374,414; 4,375,432; .472,379; 4,588,831; 4,639,456; 4,767,855; 4,828,831 .841,045 4,841,085 4,908,356 4,923,876 5,030,620,034,320 5,047,528 5,066,658 5,166,149 5,190,929 . 215,738 5,292,731 5,380,897 5,382,582 5,409,915 . 440,056 5,446,139 5,472,956 5,527,905 5,552,156 . 594,158 5,602,140 5,665,768 5,843,903 6,080,874 6. 096,923; and RE030561. In another configuration, the cell cycle inhibitor is camptothecin, mitoxantrone, etoposide, 5-fluor-uracil, doxorubicin, methotrexate, peloruside A, mitomycin C, or a CDK-2 inhibitor or an analogue or derivative of any member of the class of listed compounds. In another configuration, the cell cycle inhibitor is HTI-286, plicamycin; or mithramycin, or an analogue or derivative thereof. Other examples of cell cycle inhibitors also include, for example, 7-hexanoyltaxol (QP-2), cytochalasin A, lantrunculin D, actinomycin-D, Ro-31-7453 (3- (6-nitro-1-methyl-3 -indolyl) -4- (1-methyl-3-indolyl) pyrrole-2,5-dione), PNU-151807, brostalicin, C2-ceramide, cytarabine octofosphate (2 (1H) -pyrimidinone, 4-amine-1- (5-0- (hydroxy (octadecyloxy) phosphinyl) -β-D-arabinofuranosyl) -, monosodium salt), paclitaxel (5β, 20-epoxy-1,2 alpha, 4,7β, 10β, 13 alpha-hexahydroxitax-ll -in-9-one-4, 10-diacetate-2-benzoate-13- (alpha-phenyl-hipurate)), doxorubicin (5, 12-naphtacenedione, 10- ((3-amine-2,3,6-trideoxy-alpha-L-lixo-hexopyranosyl) oxy) -7,8,9, 10-tetrahydro-6, 8, ll -trihydroxy-8- (hydroxyacetyl) -1-methoxy-, (8S) -cis-), daunorubicin (5, 12-naphtacenedione, 8-acetyl-10- ((3-amine-2,3,6-trideoxy) alpha-L-lixo-hexopyranosyl) oxy) -7,8,9, 10-tetrahydro-6,8,1-trihydroxy-1-methoxy-, (8S-cis) -), gemcitabine hydrochloride (cytidine, 2'- deoxy-2 ', 2'-difluor-, monohydrochloride), nitacrine (1,3-propanediamine, N, N-dimethyl-N' - (1-nitro-9-acridinyl) -), carboplatin (platinum, diamine (1) , l-cyclobutanedicarboxylate (2-)), (SP-4-2) -), altretamine (1, 3, 5-triazine-2,4,6-triamine, N, N, N ', N', N '', N '' -hexamethyl-), teniposide (furo (3 ', 4': 6,7) naphtho (2,3-d) -1, 3-dioxol-6 (5aH) -one, 5,8, 8a, 9-tetrahydro-5- (4- hydroxy-3, 5-dimethoxyphenyl) -9- ((4,6-0- (2-thienylmethylene) -β-D-glucopyranosyl) oxy) -, (5R- (5alpha, 5aβ, 8aAlfa, 9β (R *) )) -), eptaplatin (platinum, ((4R, 5R) -2- (1-methylethyl) -1, 3-dioxolane-4, 5-dimethanamine-kapa N4, kapa N5) (propanedioate (2-) -kapa 01, kapa 03) -, (SP- 4-2) -), anrubicin hydrochloride (5, 12-naphtacenedione, 9-acetyl-9-amine-7- ((2-deoxy-β-D-erythro-pentopyranosyl) oxy) - 7, 8, 9, 10-tetrahydro-6,11-dihydroxy-, hydrochloride, (7S- cis) -), ifosfamide (2H-1,3, 2-oxazaphosphorine-2-amine, N, 3- bis (2-chloroethyl) tetrahydro-, 2-oxide), cladribine (adenosine, 2-chloro-2'-deoxy-), mitobronitol (D-mannitol, 1,6-dibromo-l, 6-dideoxy-), fludaribine phosphate (9H-purin-6) amine, 2-fluoro-9- (5-O-phosphono-β-D-arabinofuranosyl) -), enocythabin (docosanamide, N- (1-β-D-arabinofuranosyl-l, 2-dihydro-2-oxo-4) -pyrimidinyl) -), vindesine (vincaleucoblastin, 3- (aminocarbonyl) -04-deacetyl-3-de (methoxycarbonyl) -), idarubicin (5, 12-naphtacenedione, 9-acetyl-7- ((3-amine-2,3,6-trideoxy) alpha-L-lixo-hexopyranosyl) oxy) -7, 8, 9, 10-tetrahydro-6, 9, 11-trihydroxy-, (7S-cis) -), zinostatin (neocarzinostatin), vincristine (vincaleucoblastine, 22-oxo) -), tegafur (2,4 (1H, 3H) -pyrimidinedione, 5-fluoro-1- (tetrahydro-2-furanyl) -), razoxane (2,6-piperazinatedione, 4, '- (1-methyl-1) , 2- ethanediyl) bis-), methotrexate (L-glutamic acid, N- (4- (((2,4-diamino-6-pteridinyl) methyl) methylamino) benzoyl) -), raltitrexate (L-glutamic acid, N- ((5- (((1,4-dihydro-2-methyl-4-oxo-6-quinazolinyl) methyl) methylamino) -2-thienyl) carbonyl) -), oxaliplatin (platinum, (1,2- cyclohexanediamine-N, N ') (ethanedioate (2-) -0,0') -, (SP-4-2- (lR-trans)) -), doxifluridine (uridine, 5'-deoxy-5-fluoro- ), mitolactol (galactitol, 1,6-dibromo-l, 6-dideoxy-), pyrazubicin (5, 12-naphtacenedione, 10- ((3-amine-2,3,6-trideoxy-4-0- (t etrahydro-2H-pyran-2-yl) -alpha-L-lixo-hexopyranosyl) oxy) -7,8,9,10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl) -1-methoxy- , (8S- (8 alpha, 10 alpha (S *))) -), daxel ((2R, 3S) -N-carboxy-3-phenylisoserin \, N-tert-butyl ester, 13-ester with 5β, 20 -epóxi-l, 2 alpha, 4, 7ß, 10ß, 13 alfa- hexahydroxitax-ll-en-9-one 4-acetate 2-benzoate-), capecitabine (cytidine, 5-deoxy-5-fluoro-N- ((pentyloxy) carbonyl) -), cytarabine (2 (1H) -pyrimidone, 4-amine-1-ß-D-arabino furanosyl-), valrubicin (pentanoic acid, 2- (1, 2, 3, 4, 6, ll-hexahydro-2, 5, 12-trihydroxy-7-methoxy-6 , 11-dioxo-4- ((2,3, 6-trideoxy-3- ((trifluoroacetyl) amine) -alpha-L-lixo-hexopyranosyl) oxy) -2-naphthacenyl) -2-oxoethyl ester (2S-cis ) -), trofosfamide (3-2- (chloroethyl) -2- (bis (2-chloroethyl) amine) tetrahydro-2H-l, 3, 2-oxazaphosphorine 2-oxide), prednimustine (pregna-l, 4-diene) - 3,20-dione, 21- (4- (4- (bis (2-chloroethyl) amine) phenyl) -1-oxobutoxy) -11, 17-dihydroxy-, (llß) -), lomustine (urea, N - (2-Chloroethyl) -N'-cyclohexyl-N-nitroso-), epirubicin (5,12-naphtacenedione, 10- ((3-amine-2,3,6-trideoxy-alpha-L-arabino-hexopyranosyl) oxy) -7, 8,9, 10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-, (8S-cis) -), or an analogue or derivative thereof). 7. Inhibitors of the Cyclin-dependent Protein Kinase In a further configuration, the pharmacologically active compound is an inhibitor of the cyclin-dependent protein kinase (eg, R-roscovitine, CYC-101, CYC-103, CYC -400, MX-7065, alvocidib (4H-l ~ Benzopyran-4-one, 2- (2-chlorophenyl) -5,7-dihydroxy-8- (3-hydroxy-1-methyl-4-piperidinyl) -, cis- (-) -), SU-9516, AG-12275, PD-0166285, CGP-79807, fascaplysine, GW-8510 (benzenesulfonamide, 4- (((Z) - (6,7-dihydro-7-oxo-8H-pyrrole (2,3-g) benzothiazol-8-ylidene) methyl) amine ) -N- (3-hydroxy-2,2-dimethylpropyl) -), G-491619, Indirubin 3 'monoxim, GW8510, AZD-5438, ZK-CDK or an analogue or derivative thereof). 8. Receptor Kinase Inhibitors EGF (Epidermal Growth Factor) In another configuration, the pharmacologically active compound is an inhibitor of the EGF (epidermal growth factor) kinase (e.g., erlotiniba (4-quinazolinamine, N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -, monohydrochloride), erbstatin, BIBX-1382, gefitinib (4-quinazolinamine, N- (3-chloro-4-fluorophenyl) -7-methoxy-6 - (3- (4-morpholinyl) propoxy)), or an analogue or derivative thereof). 9. Elastase Inhibitors In another configuration, the pharmacologically active compound is an elastase inhibitor (e.g., ONO-6818, sivelestat sodium hydrate (glycine, N- (2- (((4- (2,2- dimethyl-1-oxopropoxy) phenyl) sulfonyl) amine) benzoyl) -), erdosteine (acetic acid, ((2-oxo-2- ((tetrahydro-2-oxo-3-thienyl) amine) ethyl) thio) -) , MDL-100948A, MDL-104238 (N- (4- (4-morpholinylcarbonyl) benzoyl) -L-valyl-N '- (3,3,4,4,4-pentafluor-1- (1-methylethyl) - 2-oxobutyl) -L-2-azetamide), MDL-27324 (L-prolinamide, N- ((5- (dimethylamino) -1- naphthalenyl) sulfonyl) -L-alanyl-L-alanyl-N- (3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl) -, (S) -), SR-26831 (thieno ( 3,2-c) pyridinium, 5- ((2-chlorophenyl) methyl) -2- (2,2-dimethyl-l-oxopropoxy) -4,5,6,7-tetrahydro-5-hydroxy-), Win -68794, Win-63110, SSR-69071 (2- (9 (2-piperidinoethoxy) -4-oxo-4H-pyrido (1,2-a) pyrimidin-2-yloxymethyl) -4- (1-methylethyl) - 6-methoxy-1,2-benzisothiazole-3 (2H) -one-1,1-dioxide), (N (Alpha) - (1-adamantylsulfonyl) N (epsilon) -succinyl-L-lysyl-L-prolyl- L-valine), Ro-31-3537 (N alpha- (1-adamantanesulfonyl) -N- (4-carboxybenzoyl) -L-lysyl-alanyl-L-valine), R-665, FCE-28204, ((6R , 7R) -2- (benzoyloxy) -7-methoxy-3-methyl-4-pivaloyl-3-cephem 1,1-dioxide), 1,2-benzisothiazol-3 (2H) -one, 2- (2, 4- dinitrophenyl) -, 1,1-dioxide, L-658758 (L-proline, 1- ((3- ((acetyloxy) methyl) -7-methoxy-8-oxo-5-thia-l-azabicyclo (4.2 .0) oct-2-en-2-yl) carbonyl) -, S, S-dioxide, (6R-cis) -), L-659286 (pyrrolidine, 1- ((7-methoxy-8-oxo-3 - (((1,2,5,6-tetrahydro-2-meti) l-5,6-dioxo-l, 2,4-triazin-3-yl) thio) methyl) -5-thia-l-azabicyclo (4.2.0) oct-2-en-2-yl) carbonyl) - , S, S-dioxide, (6R-cis) -), L-680833 (benzeneacetic acid, 4- ((3, 3-diethyl-1- (((1- (4-methylphenyl) butyl) amine) carbonyl) -4-oxo-2-azetidinyl) oxy) -, (S- (R *, S *)) -), FK-706 (L-prolinamide, N- [4- [[(carboxymethyl) amine] carbonyl] benzoyl ] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -, monosodium salt), Roche R-665, or an analogue or derivative thereof).

. Inhibitors of Factor Xa In another configuration, the pharmacologically active compound is a factor Xa inhibitor (eg, CY-222, fondaparinux sodium (alpha-D-glucopyranoside, methyl 0-2-deoxy-6-0-sulfo-2). - (sulfoamino) -alpha-D-glucopyranosyl- (1-4) -O-β-D-glucopyranuronosyl- (1-4) -0 ~ 2-deoxy-3,6-di-0-sulfo-2- ( sulfoamino) -alpha-D-glucopyranosyl- (1-4) -0-2-0-sulfo-alpha-L-idopyranuronosyl- (1-4) -2-deoxy-2- (sulfoamino) -, 6- (hydrogeno) sulfate)), sodium danaparoid, or an analogue or derivative thereof). 11. Farnesyltransferase Inhibitors In another configuration, or pharmacologically active compound is an inhibitor of farnesyltransferase (eg, dichlorobenzoprim (2,4-diamino-5- (4- (3,4-dichlorobenzylamino) -3-nitrophenyl) -6-ethylpyrimidine), B-581, B-956 (N- (8 (R) -amine-2 (S) -benzyl-5 (S) -isopropyl-9-sulfanyl-3 (Z), 6 (E ) -nonadienoyl) -L-methionine), OSI-754, perilyl alcohol (1-cyclohexene-1-methanol, 4- (1-methyletenyl) -, RPR-114334, lonafarnib (1-piperidinocarboxamide, 4- (2- ( 4- ((11R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-1-yl) -1-piperidinyl) -2- oxoethyl) -), Sch-48755, Sch-226374, (7, 8-dichloro-5H-dibenzo (b, e) (1,4) diazepin-11-yl) -pyridin-3-ylmethylamine, J - 104126, L-639749, L-731734 (pentanamide, 2- ((2- ((2-amine-3-mercaptopropyl) amine) -3-methylpentyl) amine) -3-methyl-N- (tetrahydro-2-oxo-3-furanyl) -, (3S- (3R * (2R * (2R * (S *), 3S *), 3R *))))), L-744832 (butanoic acid, 2) - ((2- ((2- ((2-amine-3-mercaptopropyl) amine) -3-methylpentyl) oxy) -l-oxo-3-phenylpropyl) amine) -4- (methylsulfonyl) -, 1-methylethyl ester, (2S- (1 (R * (R *)), 2R * (S *), 3R *)) -), L-745631 (1-piperazinopropanethiol, β-amine-2- (2-methoxyethyl) - 4- (1-naphthalenylcarbonyl) -, (ßR, 2S) -), N-acetyl-N-naphthylmethyl-2 (S) - ((1- (4-cyanobenzyl) -lH-imidazol-5-yl) acetyl) amine-3 (S) -methylpentamine, (2alpha) -2-hydroxy-24,25-dihydroxylonost-8-en-3-one, BMS-316810, UCF-1C (2,4-decadienamide, N- (5-) hydroxy-5- (7- ((2-hydroxy-5-oxo-l-cyclopenten-1-yl) amine-oxo-1,3,5-heptatrienyl) -2-oxo-7- oxabicyclo (4.1.0) hept-3-en-3-yl) -2, 4, 6-trimethyl-, (1S- (lalfa, 3 (2E, 4E, 6S *), 5 alpha, 5 (1E, 3E, 5E), 6 alpha ))) -), UCF-116-B, Arglabin (3H-oxirene [8, 8a] azulene [4, 5-b] furan-8 (4aH) -one, 5, 6, 6a, 7, 9a, 9b- hexahydro-l, 4a-dimethyl-7- methylene-, (3aR, 4aS, 6aS, 9aS, 9bR) -) of ARGLABIN Paracur e, Inc. (Virginia Bcada, VA, USA), or an analogue or derivative thereof). 12. Fibrinogen Antagonists In another configuration, the pharmacologically active compound is a fibrinogen antagonist (e.g., 2 (S) - ((p-toluenesulfonyl) amine) -3- (((5,6,7,8 , - tetrahydro-4-oxo-5- (2- (piperidin-4-yl) ethyl) -4H-pyrazolo- (1,5-a) (1,4) diazepin-2-yl) carbonyl) -amine) propionic, streptokinase (kinase (enzyme activated r), strepto-), urokinase (kinase (enzyme activated r), uro -), activated r of plasminogen, pamiteplase, monteplasa, heberquinasa, anistreplase, alteplase, pro-urokinase, picotamide (1,3-benzenedicarboxamide, 4-methoxy-N, N'-bis (3-pyridinylmethyl) -), or a analogue or derivative thereof). 13. Stimulants of Guanylate Cyclase In a further configuration, the pharmacologically active compound is a stimulant of guanylate cyclase (e.g., isosorbite-5-mononitrate (D-glucitol, 1,4: 3,6-dianidro-, 5-nitrate) ), or an analogue or derivative thereof). 14. Heat Shock Protein Antagonists 90 In another configuration, the pharmacologically active compound is an antagonist of heat shock protein 90 (eg, geldanamycin, NSC-33050 (17-allylaminogeldanamycin, 17-AAG), rifabutin (rifamycin XIV) , 1 ', 4-didehydro-l-deoxy-l, 4-dihydro-5' - (2-methylpropyl) -1-oxo-), 17-DMAG, or an analogue or derivative thereof). 15. Inhibitors of HMGCoA Reductase In a further configuration, the pharmacologically active compound is an inhibitor of HMGCoA reductase (eg, BCP-671, BB-476, fluvastatin (6-heptenoic acid, 7- (3- (4- fluorophenyl) -1- (1-methylethyl) -lH-indol-2-yl) -3,5-dihydroxy-, monosodium salt, (R *, S * - (E)) - (±) -), dalvastatin (2H-pyran-2-one, 6- (2- (2- (2- (4-fluoro-3-methylphenyl) -4,4,6,6,6-tetramethyl-1-cyclohexen-1-yl) ethenyl) tetrahydro) -4-hydroxy-, (4alpha, 6β (E)) - (+/-) -), glenvastatin (2H-pyran-2-one, 6- (2- (4- (4-fluorophenyl) -2 - (1-Methylethyl) -6-phenyl-3-pyridinyl) ethenyl) tetrahydro-4-hydroxy-, (4R- (4alpha, 6β (E))) -), S-2468, N- (1-oxododecyl) -Alpha, 10-dimethyl-8-aza-trans-decal-3β-ol, atorvastatin calcica (lH-Pyrrol-1-heptanoic acid, 2- (4-fluorophenyl) -β, delta-dihydroxy-5- (1- methylethyl) -3-phenyl-4- ((phenylamino) carbonyl) -, calcium salt (R- (R *, R *)) -), CP-83101 (6,8-nonadienoic acid, 3,5-dihydroxy) 9,9-diphenyl-, methyl ester, (R *, S * - (E)) - (+/-) -), pravastatin (1-naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro) -β, delta, 6-trihydroxy-2-methyl-8- (2-methyl-1-oxobutoxy) -, monosodium salt, (1S- (1 alpha (ßS *, deltaS *), 2 alpha, 6 alpha, 8β (R *), 8a alpha)) -), U-20685, pitavastatin (6-heptenoic acid, 7- (2-cyclopropyl-4- (4-fluorophenyl) -3-quinolinyl) -3,5-dihydroxy-, Salt Calcium (2: 1), (S- (R *, S * - (E))) -), N - ((1-methylpropyl) carbonyl) -8- (2- (tetrahydro-4-hydroxy-6-) oxo-2H-pyran-2-yl) ethyl) -perhydro-isoquinoline, dihydromevinoline (butanoic acid, 2-methyl-, 1,2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl) -8- (2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl ester (1 alpha (R *), 3 alpha, 4a alpha, 7β, 8 ( 2S *, 4S *), 8aß)) -), HBS-107, dihydromevinoline (butanoic acid, 2-methyl-, l, 2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl) -8- (2- (tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl ester (1 alpha (R *), 3 alpha, 4a alpha, 7β, 8β (2S *, 4S *), 8aß)) - ), L-669262 (butanoic acid, 2, 2-dimethyl-, 1, 2, 6, 7, 8, 8a-hexahydro-3, 7-dimethyl-6-oxo-8- (2- (tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl (1S- (lAlfa, 7β, 8β (2S *, 4S *), 8aß)) -), simvastatin (butanoic acid, 2, 2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8- (2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl) ) -1-naphthalenyl ester, (1S- (lalfa, 3alpha, 7β, 8β (2S *, 4S *), 8aß)) -), calcium rosuvastatin (6-heptenoic acid, 7- (4- (4-fluorophenyl)) -6- (1-methylethyl) -2- (methyl (methylsulfonyl) amine) -5-pyrimdinyl) -3,5-dihydroxycalcium salt (2: 1) (S- (R *, S * ~ (E) ))), meglutol (2-hydroxy-2-methyl-1,3-propanedicarboxylic acid), lovastatin (butanoic acid, 2-methyl-, 1,2, 3, 7, 8, 8a-hexahydro-3, 7- dimethyl-8- (2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl ester, (1S- (1 alpha. (R *), 3 alpha, 7β , 8ß (2S * , 4S *), 8aß)) -), or an analogue or derivative thereof). 16. Hydroorotate Dehydrogenase Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of the hydroorotate dehydrogenase (for example, leflunomide (4-isoxazolecarboxamide, 5-methyl-N- (4- (trifluoromethyl) phenyl) -), laflunimus ( 2-propenamide, 2- cyano-3-cyclopropyl-3-hydroxy-N- (3-methyl- (trifluoromethyl) phenyl) -, (Z) -), or atovaquone (1,4- naphthalenedione, 2- [4- (4-chlorophenyl) cydohexyl] -3-hydroxy-, trans-, or an analogue or derivative thereof). 17. Inhibitors of IKK2 In another configuration, the pharmacologically active compound is an inhibitor of IKK2 (e.g., MLN-120B, SPC-839, or an analog or derivative thereof). 18. IL-1, ICE and iRAK Antagonists In another configuration, the pharmacologically active compound is an IL-1, ICE or an IRAK antagonist (e.g., E-5090 (2-propenoic acid, 3- (5- ethyl-4-hydroxy-3-methoxy-1-naphthalenyl) -2-methyl-, (Z) -), CH-164, CH-172, CH-490, AMG-719, igurati od (N- (3- (formylamino) -4-oxo-6-phenoxy-4H-chromen-7-yl) methanesulfonamide), AV94-88, pralnacasana (6H-pyridazino (1,2-a) (1,2) diazepine-1-carboxamide, N- ((2R, 3S) -2-ethoxytetrahydro-5-oxo-3-furanyl) octahydro-9- ((1-isoquinolinylcarbonyl) aitiin) -6, 10-dioxo-, (1S, 9S) -), acid (2S-cis) -5- (benzyloxycarbonylamino-1, 2,4,5,6,7-hexahydro-4- (oxoazepino (3,2, 1-hi) indole-2-carbonyl) -amine) -4- oxobutanoic, AVE-9488, esonarimod (benzenebutanoic acid, alpha- ((acetylthio) methyl) -4-methyl-gamma-oxo-), pralnacasana (6H-pyridazino (1, 2-a) (1, 2) diazepine-1 -carboxamide, N- ((2R, 3S) -2-ethoxytetrahydro-5-oxo-3-furanyl) octahydro-9- ((1-isoquinolinylcarbonyl) amine) -6, 10-dioxo-, (1S, 9S ) -), tranexamic acid (cyclohexanecarboxylic acid, 4- (aminomethyl) -, trans-), Win-72052, romazarit (Ro-31-3948) (propanoic acid, 2- ((2- (4-chlorophenyl) -4-methyl-5-oxazolyl) methoxy) -2- methyl-), PD-163594, SDZ-224-015 (L-alaninamide N- ((phenylmethoxy) carbonyl) -L-valyl-N- ((1S) -3- ((2,6-dichlorobenzoyl) oxy) - 1- (2-ethoxy-2-oxoethyl) -2-oxopropyl) -), L-709049 (L-alaninamide, N-acetyl-L-tyrosyl-L-valyl-N- (2-carboxy-l-formilethyl) -, (S) -), TA-383 (1H-imidazole, 2- (4-chlorophenyl) -4,5-dihydro-4,5-diphenyl-, monohydrochloride, cis-), EI-1507-1 (6a , 12a-epoxybenz (a) anthracene-1, 12 (2H, 7H) -dione, 3,4-dihydro-3,7-dihydroxy-8-methoxy-3-methyl-), ethyl 4- (3, 4- dimethoxyphenyl) -6,7-dimethoxy-2- (1, 2, 4-triazol-1-ylmethyl) quinoline-3-carboxylate, EI-1941-1, TJ-114, anakinra (interleukin 1 receptor antagonist (isoform human x reduczide), N2-L-methionyl-), IX-207-887 (acetic acid, (10-methoxy-4H-benzo [4,5] cyclohepta [1,2- b] thien-4-ylidene) - ), K-832, or an analogue or derivative thereof). 19. IL-4 Fighters In another configuration, the pharmacologically active compound is an IL-4 combatant (e.g., glatiramiryl acetate (L-glutamic acid, polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt)), or an analogue or derivative thereof). 20. Immunomodulatory agents In another configuration, the pharmacologically active compound is an immunomodulatory agent (eg, biolimus, ABT-578, methylsulfamic acid 3- (2-methoxyphenoxy) -2- (((methylamino) sulfonyl) oxy) propyl ester, sirolimus (also known as Rapamycin or Rapamune (American Home Products, Inc., Madison, NJ, USA)), CCI-779 (rapamycin 42- (3-hydroxy-2- (hydroxymethyl) -2-methylpropanoate)), LF-15-0195, NPC15669 (L-leucine, N - (((2,7-dimethyl-9H-fluoren-9-yl) methoxy) carbonyl) -), NPC-15670 (L-leucine, N - (((4,5-dimethyl-9H-fluoren-9- il) methoxy) carbonyl) -), acid NPC-16570 (4- (2- (fluoren-9-yl) ethyloxycarbonyl) aminobenzoic acid), sufosfamide (ethanol, 2- ((3- (2-chloroethyl) tetrahydro-2H-1,2,3-oxazaphosphorin-2-yl) ) amine) -, methanesulfonate (ester), P-oxide), tresperimus (2- (N- (4- (3-aminopropylamino) butyl) carbamoyloxy) -N- (6-guanidinohexyl) acetamide), 4- (2- (fluoren-9-yl) ethoxycarbonylamino) -benzo-hydroxamic, iaquinimod, PBI-1411, azathioprine (6- ((l-Methyl-4-nitro-lH-imidazol-5-yl) thio) -lH-purine), PBI0032, beclomethasone, MDL-28842 (9H - purin-6-amine, 9- (5-deoxy-5-fluoro-β-D-threo-pent-4-enofuranosyl) -, (Z) -), FK-788, AVE-1726, ZK-90695, ZK-90695, Ro-54864, didemnin-B, Illinois (didemnin A, N- (1- (2-hydroxy-1-oxopropyl) -L-prolyl) -, (S) -), SDZ-62-826 (Ethanaminium, 2- ((hydroxy ((1- ((octadecyloxy) carbonyl) -3-piperidinyl) methoxy) phosphinyl) oxy) -N, N, N-trimethyl-, salt internal), argirin B ((4S, 7S, 13R, 22R) -13-Ethyl-4- (1H-indol-3-ylmethyl) -7- (4-methoxy-1H-indol-3-ylmethyl) 18, 22 -dimethyl-16-methyl-ene-24-thia-3,6,9,12,15,18,21,26-octaazabicyclo (21.2.1) -hexacosa-1 (25), 23 (26) -dieno- 2, 5, 8, 11,14,17,20-heptaona), everolimus (rapamycin, 42-0- (2-hydroxyethyl) -), SAR-943, L-687795, 6- ((4-chlorophenyl) sulfinil ) -2,3-dihydro-2- (4-methoxy-phenyl) -5-methyl-3-oxo-4-pyridazinecarbonitrile, 91Y78 (1H-i-idazo (4,5-c) pyridin-4-amine, 1 -β-D-ribofuranosyl-), auranofin (ouro, (1-thio-β-D-glucopyranose 2,3,4,6-tetraacetate-S) (triethylphosphine) -), 27-0-demethylrapamycin, tipredana (androsta -l, 4-dien-3-one, 17- (ethylthio) -9-fluoro-l-hydroxy-17- (methylthio) -, (llß, 17 alpha) -), AI-402, LY-178002 (4 -thiazolidinone, 5- ((3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl) methylene) -), SM-8849 (2-thiazolamine, 4- (1- (2-fluoro (1,1 '-biphenyl) -4-yl) ethyl) -N-methyl-), piceatanol, resveratrol, triamcinolone acetonide (pregna-l, 4-diene-3,20-dione, 9-fluoro-l, 21 -dihydroxy-16, 17- ((1-methylethylidene) bis (oxy)) -, (llß, 16 alpha) -), cyclosporine (cyclosporin A), tacrolimus (15, 19-epoxy-3H-pyrido (2, 1 - c) (1,4) oxaazacyclotomycin-1, 7,20,21 (4H, 23H) -tetron, 5,6,8,11,12,13,14,15,16,17,18,19,24 , 25,26,26a- hexadecahydro-5,19-dihydroxy-3- (2- (4-hydroxy-3-methoxycyclohexyl) -1-methyletenyl) -14,16-dimethoxy-4,12,12,18-tetramethyl -8- (2-propenyl) -, (3S- (3R * (E (1S *, 3S *, 4S *)), 4S *, 5R *, 8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, 19S *, 26aR *)) -), gusperimus (heptanamide, 7- ((aminoiminomethyl) amine) -N- (2- ((4- ((3-aminopropyl) amine) butyl) amine) -l-hydroxy-2-oxoethyl) - , (+/-) -), tixocortol pivalate (pregn-4-ene-3,20-dione, 21- ((2,2-dimethyl-1-oxopropyl) thio) -11, 17-dihydroxy-, (llß ) -), alefacept (1-92 LFA-3 (antigen) (human) fusion protein with immunoglobulin Gl (human joint-CH2-CH3 gamal-cadeia), dimer), halobetasol propionate (pregna-1,4-diene- 3,20-dione, 21-chloro-6, 9-difluoro-11-hydroxy-16-methyl-17- (1-oxopropoxy) -, (6Alpha, llß, 16ß) -), iloprost trometamol (pentanoic acid, - (hexahydro-5-hydroxy-4- (3-hydroxy-4-methyl-l-octen-6-ynyl) -2 (ÍH) -pentanylidene) -), beraprost acid (lH-cyclopenta (b) benzofuran-5 -butanoic, 2, 3,3a, 8b-tetrahydro-2-hydroxy-l- (3-hydroxy-4-methyl-l-octen-6-ynyl) -), rimexolone (androsta-l, 4-dien-3) -one, 11-hydroxy-16,17-dimethyl-17- (1-oxopropyl) - , (llß, 16Alpha, 17ß) -), dexamethasone (pregna-l, 4-diene-3,20-dione, 9-fluoro, 17,21-trihydroxy-16-methyl-, (11β, 16alpha) - ), sulindac (cis-5-fluoro-2-methyl-l- ((p-methylsulfinyl) benzylidene) indene-3-acetic acid), proglumetacin (lH-Indol-3-acetic acid, 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-, 2- (4- (3- ((4- (benzoylamino) -5- (dipropylamino) -1 , 5- dioxopentyl) oxy) propyl) -1-piperazinyl) ethyl ester, (+/-) -), alclometasone dipropionate (pregna- 1,4-diene-3, 20 -dione, 7- chloro-11-hydroxy-16-methyl-17, 21-bis (1-oxopropoxy) -, (7alpha, llß, 16alpha) -), pimecrolimus (15, 19-epoxy-3H-pyrido (2, 1-c) (1,4) oxaazacyclotyrosine-1, 7, 20, 21 (4H, 23H) -tetrone, 3- (2- (4-chloro-3-methoxycyclohexyl) -1-methyletenyl) -8-ethyl-5,6, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 26, 26a-hexadecahydro-5,19-dihydroxy-14, 16-dimethoxy-4, 10, 12, 18- tetramethyl-, (3S- (3R * (E (1S *, 3S *, 4R *)), 4S *, 5R *, 8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, 19S *, 26aR *)) -), hydrocortisone-17-butyrate (pregn-4-ene-3,20-dione, 11, 21-dihydroxy-17- (1-oxobutoxy) -, (llß) -), mitoxantrone ( 9, 10-anthracenedione, 1,4-dihydroxy-5,8-bis ((2- ((2-hydroxyethyl) amine) ethyl) amine) -), mizoribine (1H-imidazole-4-carboxamide, 5-hydroxy) l-ß-D-ribofuranosyl-), prednicarbate (pregna-l, 4-diene-3,20-dione, 17- ((ethoxycarbonyl) oxy) -l-hydroxy-21- (1-oxopropoxy) -, (llß ) -), iobenzarit (benzoic acid, 2- ((2-carboxyphenyl) amine) -4- chloro-), glucametacin (D-glucose, 2- (( (1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indol-3-yl) acetyl) amine) -2-deoxy-, fluocortolone monohydrate ((6 alpha) -fluoro-16alpha-methylpregna- l, 4-dien-llß, 21-diol-3,20-dione), fluocortin butyl acid (pregna-l, 4-dien-21-oic, 6-fluoro-l-hydroxy-16-methyl-3, 20 -dioxo-, butyl ester, (6alpha, llß, 16alpha) -), difluprednate (pregna-l, 4-diene-3,20-dione, 21- (acetyloxy) -6,9-difluoro-11-hydroxy-17 - (1- oxobutoxy) -, (6 alpha, llß) -), diflorasone diacetate (pregna-l, 4-diene-3,20-dione, 17,21-bis (acetyloxy) -6,9-difluoro-11-hydroxy-16-methyl-, (6Alpha, llß, 16ß) -), dexamethasone valerate (pregna-l, 4-diene-3, 20-dione, 9-fluoro-11, 21-dihydroxy-16-methyl-17- ((1-oxopentyl) oxy) -, (llß, 16Alfa) -), methylprednisolone, deprodone propionate (pregna-1,4-diene-3, 20-dione, ll-hydroxy-17- (1-oxopropoxy) -, (11.beta.) -), bucillamine (L-cysteine, N- ( 2-mercapto-2-methyl-1-oxopropyl) -), amcinonide (benzeneacetic acid, 2-amine-3-benzoyl-, monosodium salt, monohydrate), acemetacin (1H-indole-3-acetic acid, 1- (4 -chlorobenzoyl) -5-methoxy-2-methyl-, carboxymethyl ester), or an analog or derivative thereof). In addition, rapamycin analogs include tacrolimus and its derivatives (e.g., EP0184162B1 and U.S. Patent No. 6,258,823) everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772). Further representative examples of analogs and sirolimus derivatives can be found in PCTs with Publication No. WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, and WO 92/05179. Among the Patents Representative USA US Patents No. 6,342,507 are included; 5,985,890; 5,604,234; 5,597,715 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193 . 541,189 5,534,632; 5,527,907 5,484,799 5,457,194 . 457,182 5,362,735; 5,324,644 5,318,895 5,310,903 . 310,901 5,258,389; 5,252,732 5,247,076 5,225,403 . 221,625 5,210,030; 5,208,241; 5,200,411; 5,198,421 . 147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; and 5,091,389. The structures of sirolimus, everolimus, and tacrolimus are given below in Tabela 3: Table 3 Everolimus Tacrolimus Sirolimus Other analogues and derivatives of sirolimus include tacrolimus and its derivatives (for example, EP0184162B1 and US Patent No. 6,258,823) everolimus and its derivatives (e.g., U.S. Patent No. 5,665,772). Examples Additional representative analogs and derivatives of sirolimus include ABT-578 and others can be found in PCT Publication Nos. WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 9600282, WO 95/16691. , WO 9515328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, and WO 92/05179. Representative patents USA include US Pat. ND 6. 342,507 5,985,890; 5,604,234; 5,597,715 5,583,139 . 563,172 5,561,228; 5,561,137; 5,541,193 5,541,189 . 534,632,527,907; 5,484,799; 5,457,194 5,457,182 . 362,735 5,324,644; 5,318,895; 5,310,903 5,310,901 . 258,389 5,252,732; 5,247,076; 5,225,403 5,221,625 . 210,030; 5,208,241. 5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; and 5,091,389. In one aspect, the fibrosis inhibiting agent can be, for example, rapamycin (sirolimus), everolimus, biolimus, tresperimus, auranofin, 27-0-demethylpapamycin, tacrolimus, gusperimus, pimecrolimus, or ABT-578. 21. Inosine Monophosphate Dehydrogenase Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) (e.g., mycophenolic acid, mycophenolate mofetil (4-hexenoic acid, 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-, 2- (4-morpholinyl) ethyl ester, (E) -), ribavirin (1H-1,2,4-triazole-3-carboxamide, 1-β-D-ribofuranosyl-), thiazofurine (4-thiazolecarboxamide, 2-β-D-ribofuranosyl-) , viramidine, aminothiadiazole, thiophenurine, thiazofurine) or an analogue or derivative thereof. Representative additional examples are included in U.S. Pat. Nos. 5,536,747, 5,807,876, 5,932,600, 6,054,472, 6,128,582, 6,344,465, 6,395,763, 6,399,773, 6,420,403, 6,479,628, 6,498,178, 6,514,979, 6,518,291, 6,541,496, 6,596,747, 6,617,323, 6,624,184, Patent Deposit Publication No. 2002 / 0040022A1, 2002 / 0052513A1, 2002 / 0055483A1, 2002 / 0068346A1, 2002 / 0111378A1, 2002 / 0111495A1 , 2002 / 0123520A1, 2002 / 0143176A1, 2002 / 0147160A1, 2002 / 0161038A1, 2002 / 0173491A1, 2002 / 0183315A1, 2002 / 0193612A1, 2003 / 0027845A1, 2003 / 0068302A1, 2003 / 0105073A1, 2003 / 0130254A1, 2003 / 0143197A1, 2003 / 0144300A1, 2003 / 0166201A1, 2003 / 0181497A1, 2003 / 0186974A1, 2003 / 0186989A1, 2003 / 0195202A1, and PCT Publication No. WO 0024725A1, WO 00 / 25780A1, WO 00 / 26197A1, WO 00 / 51615A1, WO 00 / 56331A1 , WO 00/73288 A1, WO 01/00622 A1, WO 01/66706 A1, WO 01/79246 A2, WO 01/81340 A2, WO 01/85952 A2, WO 02/16382 A1, WO 02/18369 A2, WO 2051814 A1, WO 2057287 A2, WO2057425 A2, WO 2060875A1, WO 2060896A1, WO 2060898A1, WO 2068058A2, WO 3020298A1, WO 3037349A1, WO 3039548A1, WO3045901A2, WO3047512A2, WO3053958A1, WO3055447A2, WO3059269A2, WO3063573A2, WO3087071A1, WO90 / 01545A1, WO97 / 40028A1, WO97 / 41211A1, WO98 / 40381A1, and WO 99 / 55663A1). 22. Leukotriene Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of leukotriene (eg, ONO-4057 (benzenepropanoic acid, 2- (4-carboxybutoxy) -6- ((6- (4-methoxyphenyl) - 5-hexenyl) oxy) -, (E) -), ONO-LB-448, pirodomast 1,8-naphthyridin-2 (1H) -one, 4-hydroxy-1-phenyl-3- (1-pyrrolidinyl) - , Sch-40120 (benzo (b) (1, 8) naphthyridin-5 (7H) -one, 10- (3-chlorophenyl) -6, 8, 9, 10-tetrahydro-), L-656224 (4-benzofuranol , 7-chloro-2- ((4-methoxyphenyl) methyl) -3-methyl-5-propyl-), MAFP (methyl arachidonyl fluorophosphonate), ontazolast (2-benzoxazolamine, N- (2-cyclohexyl-l- (2 - pyridinyl) ethyl) -5-methyl-, (S) -), amelubant (carbamic acid, ((4- ((3- ((4- (1- (4-hydroxyphenyl) -1-methylethyl) phenoxy) methyl ) phenyl) methoxy) phenyl) iminomethyl) -ethyl ester), SB-201993 (benzoic acid, 3- ((((6- ((1E) -2-carboxietenyl) -5- ((8- (4-methoxyphenyl)) octyl) oxy) -2- pyridinyl) methyl) thio) methyl) -), LY-203647 (ethanone, 1- (2-hydroxy-3-p) ropil-4- (4- (2- (4- (lH-tetrazol-5-yl) butyl) -2H-tetrazol-5-yl) butoxy) phenyl) -), LY-210073, LY-223982 (benzenepropanoic acid) , 5- (3-carboxybenzoyl) -2- ((6- (4-methoxyphenyl) -5-hexenyl) oxy) -, (E) -), LY-293111 (acid benzoic, 2- (3- (3- ((5-ethyl-4'-fluoro-2-hydroxy (1,1'-biphenyl) -4-yl) oxy) propoxy) -2-propylphenoxy) -), SM -9064 (pyrrolidine, 1- (4,11-dihydroxy-13- (4-methoxyphenyl) -1-oxo-5,7,9-tridecatrienyl) -, (E, E, E) -), T-0757 (2, 6-octadienamide, N- (4-hydroxy-3,5-dimethylphenyl) -3,7-dimethyl-, (2E) -), or an analogue or derivative thereof). 23. Antagonists of MCP-1 In another configuration, the pharmacologically active compound is an antagonist of MCP-1 (for example, nitronaproxen (2-naphthalene acetic acid, 6-methoxy-alpha-methyl 4- (nitrooxy) butyl ester (alpha S) -), bindarit acid (2- (1-benzylindazol-3-ylmethoxy) -2-methylpropanoic acid), 1-alpha-25-dihydroxy vitamin D3, or an analog or derivative thereof). 24. MMP Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of the metalloproteinase (MMP) matrix (e.g., D-9120, doxycycline (2-naphthalenecarboxamide, 4- (dimethylamino) -1,4,4a, 5 , 5a, 6, 11, 12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1, 11-dioxo- (4S- (4 alpha, 4 alpha, 5 alpha, 5 alpha, 6 alpha, 12a alpha)) -), BB-2827, BB-1101 (2S-allyl-Nl-hydroxy-3R-isobutyl-N4- (1S-methylcarbamoyl-2-phenylethyl) -succinamide), BB-2983, solimastat ( N'- (2, 2-dimethyl-l (S) - (N- (2-pyridyl) carbamoyl) propyl) -N 4 -hydroxy-2 (R) -isobutyl-3 (S) - methoxysuccinamide), batimastat (butanadiamide, N4-hydroxy-Nl- (2- (methylamino) -2-oxo-l- (phenylmethyl) ethyl) -2- (2-methylpropyl) -3- ((2-thienylthio) methyl) -, (2R- (1 (S *), 2R *, 3S *)) -), CH-138, CH-5902, D-1927, D-5410, EF-13 (gamma-linolenic acid salt of lithium) , CMT-3 (2-naphthacenecarboxamide, 1,4,4a, 5, 5a, 6,11, 12a-octahydro-3, 10, 12, 12a-tetrahydroxy-1,11-dioxo-, (4aS, 5aR, 12aS ) -), marimastat (N- (2, 2-dimethyl-1 (S) - (N-methylcarbamoyl) propyl) -N, 3 (S) -dihydroxy-2 (R) -isobutylsuccinamide), TIMP'S, ONO-4817 , rebimastat (L ~ Valinamide, N- ((2S) -2-mercapto-1-oxo-4- (3,4,4-trimethyl-2, 5-dioxo-1-imidazolidinyl) butyl) -L-leucyl- N, 3-dimethyl-), PS-508, CH-715, nimesulide (methanesulfonamide, N- (4-nitro-2-phenoxyphenyl) -), hexahydro-2- (2 (R) - (1 (RS) - (hydroxycarbamoyl) -4-phenylbutyl) nonanoyl) -N- (2,2,6,6-emethyl-4-piperidinyl) -3 (S) -pyridazine carboxamide, Rs-113-080, Ro-1130830, cipemastat (1 -piperidinebutanamide, ß- (cyclopentylmethyl) -N-hydroxy-gamma-oxo-al fa- ((3,4,4-trimethyl-2, 5-dioxo-1-imidazolidinyl) methyl) -, (alpha R, ßR) -), 5- (4'-biphenyl) -5- (N-) acid (4- nitrophenyl) piperazinyl) barbituric acid, 6-methoxy-1,2,4,4-tetrahydro-norharman-l-carboxylic acid, Ro-31-4724 (L-alanine, N- (2- (2- (hydroxyamino ) -2-oxoethyl) -4-methyl-l-oxopentyl) -L-leucyl-, ethyl ester), prinomastat (3-thiomorpholinecarboxamide, N-hydroxy-2, 2-dimethyl-4- ((4- (4- pyridinyloxy) phenyl) sulfonyl) -, (3R) -), AG-3433 (acid- pyrrole-3-propranic acid, 1- (4'-cyano (1,1'-biphenyl) -4-yl) -b- ((((3S) -tetrahydro-4,4-dimethyl-2-oxo-3- furanyl) amine) carbonyl) -, phenylmethyl ester, (bS) -), PNU-142769 (2H-Isoindole-2-butanamide, 1,3-dihydro-N-hydroxy-alpha- ((3S) -3- (2 -methylpropyl) -2-oxo-l- (2-phenylethyl) -3-pyrrolidinyl) -1,3-dioxo-, (alpha R) -), (S) -1- (2- (((((4, 5-dihydro-5-thioxo-l, 3,4-thiadiazol-2-yl) amine) -carbonyl) amine) -l-oxo-3- (pentafluorophenyl) propyl) -4- (2-pyridinyl) iperazine, SU -5402 (lH-pyrrole-3-propanoic acid, 2- ((1,2-dihydro-2-oxo-3H-indol-3-ylidene) methyl) -4-methyl-), SC-77964, PNU-171829 , CGS-27023A, N-hydroxy-2 (R) - ((4-methoxybenzenesulfonyl) (4-picolyl) amine) -2- (2-tetrahydrofuranyl) -acetamide, L-758354 ((1,1'-biphenyl) -4-hexanoic acid, alpha-butyl-gamma- (((2,2-dimethyl-1- ((methylamino) carbonyl) propyl) amine) carbonyl) -4'-fluoro- , (alpha S- (alpha R *, range S * (R *))) -, GI-155704A, CPA-926, TMI-005, XL-784, or an analogue or derivative thereof). Additional representative examples are included in the US Patent No. 5,665,777; 5,985,911 6,288,261; 5,952,320 6,441,189 6,235,786 6,294,573 6,294,539; 6. 563,002 6,071,903 6,358,980 5,852,213 6,124,502; 6. 160,132 6,197,791 6,172,057 6,288,086 6,342,508; 6. 228,869 5,977,408 5,929,097 6,498,167 6,534,491; 6. 548,524 5,962,481 6,197,795 6,162,814 6,441,023; 6,444,704 6,462,073 6,162,821 6,444,639 6,262,080; .486.193; 6,329,550; 6,544,980; 6,352,976; 5,968,795,789,434; 5,932,763 6,500,847; 5,925,637 6,225,314,804,581 5,863,915 5,859,047; 5,861,428 5,886,043 .288,063 5,939,583 6,166,082; 5,874,473 5,886,022,932,577 5,854,277 5,886,024; 6,495,565 6,642,255,495,548 6,479,502 5,696,082; 5,700,838 6,444,639 .262,080 6,486,193 6,329,550; 6,544,980 6,352,976 . 968,795 5,789,434 5,932,763; 6,500,847 5,925,637 6. 225,314 5,804,581 5,863,915; 5,859,047 5,861,428 . 886,043 6,288,063 5,939,583; 6,166,082 5,874,473 . 886,022 5,932,577 5,854,277; 5,886,024 6,495,565 6. 642,255 6,495,548 6,479,502; 5,696,082 5,700,838 . 861,436 5,691,382 5,763,621; 5,866,717 5,902,791 . 962,529 6,017,889 6,022,873; 6,022,898 6,103,739 6. 127,427 6,258,851 6,310,084; 6,358,987 5,872,152 . 917,090 6,124,329 6,329,373; 6,344,457 5,698,706 . 872,146 5,853,623 6,624,144; 6,462,042 5,981,491 . 955,435 6,090,840 6,114,372; 6,566,384 5,994,293 6. 063,786 6,469,020 6,118,001; 6,187,924 6,310,088 5,994,312 6,180,611 6,110,896; 6,380,253 5,455,262 . 470,834 6,147,114 6,333,324; 6,489,324 6,362,183 6. 372,758 6,448,250 6,492,367; 6,380,258 6,583,299 . 239,078 5,892,112 5,773,438; 5,696,147 6,066,662 6. 600,057 5,990,158 5,731,293; 6,277,876 6,521,606 6,168,807 6,506,414 6,620,813; 5,684,152 6,451,791 .476.027; 6,013,649; 6,503,892; 6,420,427; 6,300,514 6. 403,644 6,177,466 6,569,899 5,594,006; 6,417,229 5,861,510 6,156,798; 6,387,931 6,350,907; 6,090,852 6,458,822 6,509,337; 6,147,061 6,114,568; 6,118,016 5,804,593 5,847,153; 5,859,061 6,194,451; 6,482,827 6,638,952 5,677,282; 6,365,630 6,130,254; 6,455,569 6,057,369 6,576,628; 6,110,924 6,472,396; 6,548,667 5,618,844 6,495,578; 6,627,411 5,514,716 5,256,657 5,773,428,060,772; 6,579,890 5,932,595 6,013,792 6,420,415 5,532,265; 5,691,381 5,639,746 5,672,598 5,830,915 6,630,516; 5,324,634 6,277,061 6,140,099 6,455,570 5,595,885; 6,093,398 6,379,667 5,641,636 5,698,404 6,448,058; 6,008,220 6,265,432 6,169,103 6,133,304 6,541,521; 6,624,196 6,307,089 6,239,288 5,756,545 6,020,366; 6,117,869 6,294,674 6,037,361 6,399,612 6,495,568; 6,624,177 5,948,780 6,620,835 6,284,513 5,977,141; 6,153,612 6,297,247 6,559,142 6,555,535 6,350,885; 5,627,206 5,665,764 5,958,972 6,420,408 6,492,422; 6,340,709 6,022,948 6,274,703 6,294,694 6,531,499; 6,465,508 6,437,177 6,376,665 5,268,384 5,183,900; 5,189,178 6,511,993 6,617,354 6,331,563 5,962,466; 5,861,427; 5,830,869; and 6,087,359. 25. Inhibitors of NF kapa B In another configuration, the pharmacologically active compound is an inhibitor of NF kapa B (NFKB) (e.g.

AVE-0545, Oxi-104 (benzamide, 4-amine-3-chloro-N- (2- (diethylamino) ethyl) -), dexlipote, R-flurbiprofen ((1,1 '-biphenyl) -4-acetic acid , 2-fluoro-alpha-methyl), SP100030 (2-chloro-N- (3,5-di (trifluoromethyl) phenyl) -4- (trifluoromethyl) irimidine-5-carboxamide), AVE-0545, Viatris, AVE- 0547, Bay 11-7082, Bay 11-7085, 15 deoxy-prostailandin J2, bortezomib (boronic acid, ((IR) -3-methyl-1- (((2S) -l-oxo-3-phenyl-2- ((pyrazinylcarbonyl) amine) propyl) amine) butyl) -, benzamide derivatives and nicotinamide which inhibit NF-kapa B, such as those described in US Patent Nos. 5,561,161 and 5,340,565 (OxiGene), PG490-88Na, or an analogue or derivative thereof). 26. NO fighters In another configuration, the pharmacologically active compound is a NO fighter (eg, NCX-4016 (benzoic acid, 2- (acetyloxy) -, 3- ((nitrooxy) methyl) phenyl ester, NCX-2216, L-arginine or an analogue or derivative thereof). 27. P38 MAP Kinase Inhibitors In a further configuration, the pharmacologically active compound is an inhibitor of the p38 MAP kinase (e.g., GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ - 67657, RWJ-68354, SCIO-469, SCIO-323, AMG-548, CMC-146, SD-31145, CC-8866, Ro-320-1195, PD-98059 (4H-l-benzopyran-4- ona, 2- (2-amine-3-methoxyphenyl) -), CGH-2466, doramapimod, SB-203580 (pyridine, 4- (5- (4-fluorophenyl) -2- (4- (methylsulfinyl) phenyl) - lH-imidazol-4-yl) -), SB-220025 ((5- (2-amine-4-pyrimidinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole), SB-281832, PD169316, SB202190, GSK-681323, EO-1606, GSK-681323, or an analogue or derivative thereof). Representative additional examples are included in U.S. Pat. No. 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361; 6,579,874; 6,630,485, U.S. Patent Deposit Publication. N ° 2001 / 0044538A1 2002 / 0013354A1 2002 / 0049220A1 2002 / 0103245A1 2002 / 0151491A1 2002 / 0156114A1 2003 / 0018051A1 2003 / 0073832A1 2003 / 0130257A1 2003 / 0130273A1 2003 / 0130319A1 2003 / 0139388A1 20030139462A1; 2003 / 0149031A1; 2003 / 0166647A1 2003 / 0181411A1; and PCT with Publication No. WO 00 / 63204A2 WO 01 / 21591A1; WO 01 / 35959A1; WO 01 / 74811A2; WO 02 / 18379A2 WO 2064594A2; WO 2083622A2; WO 2094842 A2; WO 2096426A1; WO 2101015A2; WO 2103000A2; WO 3008413A1; WO 3016248A2; WO 3020715A1; WO 3024899A2; WO 3031431A1; WO3040103A1; WO 3053940A1; WO 3053941A2; WO 3063799A2; WO 3079986A2; WO 3080024A2; WO 3082287A1; WO 97/44467A1; WO 99 / 01449A1; and WO 99 / 58523A1. 28. Phosphodiesterase inhibitors In another configuration, the pharmacologically active compound is a phosphodiesterase inhibitor (e.g., CDP-840 (pyridine, 4- ((2R) -2- (3- (cyclopentyloxy) -4-methoxyphenyl) -2-phenylethyl) -), CH-3697, CT-2820, D-22888 (imidazo (1, 5-a) pyrido (3, 2-e) pyrazin-6 (5H) -one, 9-ethyl-2-methoxy-7 methyl-5-propyl-), D-4418 (8-methoxyquinoline-5- (N- (2,5-dichloropyridin-3-yl)) carboxamide), 1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (2,6-dichloro-4-pyridyl) ethanone oxime, D-4396, ONO-6126, CDC-998, CDC-801, V-11294A (3- (3- (cyclopentyloxy) -4-methoxybenzyl) -6- (ethylamino) -8- isopropyl-3H-purine hydrochloride), S, S '-methylene-bis (2- (8-cyclopropyl-3-propyl-6- (4-pyridylmethylamino) -2-thio-3H-purine) ) tetrahydrochloride, rolipram (2-pyrrolidinone, 4- (3- (cyclopentyloxy) -4-methoxyphenyl) -), CP-293121, CP-353164 (5- (3-cyclopentyloxy-4-methoxyphenyl) pyridine-2-carboxamide) , oxagrelato (6-phthalazine carboxylic acid, 3,4-dihydro-l- (hydroxymethyl) -5, 7-dimethyl-4-oxo-, ethyl ester) , PD-168787, ibudilast (1-propanone, 2-methyl-1- (2- (1-methylethyl) pyrazolo (1,5-a) pyridin-3-yl) -), oxagrelate (6-phthalazine carboxylic acid, 3, 4-dihydro-l- (hydroxymethyl) -5,7-dimethyl-4-oxo-, ethyl ester), griseolic acid (alpha-L-talo-oct-4-enofuranuronic acid, 1- (6-amine- 9H-purin-9-yl) -3,6-anhydro-6-C-carboxy-l, 5-dideoxy-, KW-4490, KS-506, T-440, roflumilast (benzamide, 3- (cyclopropylmethoxy) -N- (3,5-dichloro-4-pyridinyl) -4- (difluoromethoxy) -), rolipram, milrinone, triflusinal (benzoic acid, 2- (acetyloxy) -4- (trifluoromethyl) -), anagrelide hydrochloride (imidazo (2, 1-b) quinazolin-2 (3H) -one, 6,7-dichloro-l, 5 -dihydro-, monohydrochloride), cilostazol (2 (ÍH) -quinolinone, 6- (4- (1-cyclohexyl-lH-tetrazol-5-yl) butoxy) -3,4-dihydro-), propentofylline (lH-purine) -2,6-dione, 3,7-dihydro-3-methyl-1- (5-oxohexyl) -7-propyl-), sildenafil citrate (piperazine, 1- (3- (4,7-dihydro- 1-Methyl-7-oxo-3-propyl-lH-pyrazolo (4,3-d) pyrimidin-5-yl) -4-ethoxyphenyl) sulfonyl) -4-methyl, 2-hydroxy-l, 2,3- propanotricarboxylate- (1: 1)), tadalafil (pyrazine (1 ', 2': 1, 6) pyrido (3,4-b) indole 1,4-dione, 6- (1,3-benzodioxol-5-yl) -2,3,6,7, 12, 12a-hexahydro-2-methyl-, (6R-trans)), vardenafil (piperazine, 1- (3- (1,4-dihydro-5-methyl (-4- oxo-7-propylimidazo (5, 1-f) (1,2,4) -triazin-2-yl) -4- ethoxyphenyl) sulfonyl) -4-ethyl-), milrinone ((3,4'-bipyridine) -5-carbonitrile, 1,6-dihydro-2-methyl-6-oxo-), enoximone (2H-imidazol-2-one, 1,3-dihydro) -4-methyl-5- (4- (methylthio) benzoyl) -), theophylline (lH-purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-), ibudilast (1-propanone, 2-methyl-1- (2- (1-methylethyl) pyrazolo (1, 5-a) pyridin-3-yl) -), aminophylline (1H-purine-2,6-dione, 3,7-dihydro-1) , 3-dimethyl-, compound with 1,2-ethanediamine (2: 1) -), acebrofylline (7H-purine-7-acetic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2, 6-dioxo-, compound with trans-4- (((2-amine-3,5-dibromophenyl) methyl) amine) cyclohexanol (1: 1)), plafibrid (propanamide, 2- (4-chlorophenoxy) -2-methyl-N- (((4-morpholinylmethyl) amine) carbonyl) -), ioprinone hydrochloride (3-pyridinecarbonitrile, 1,2-dihydro-5-imidazo (1, 2-a) pyridin-6-yl-6-methyl-2-oxo-, monohydrochloro-), phosphosal (benzoic acid, 2- (phosphonooxy) -), amrinone ((3,4'-bipyridin) -6 (1 H) -one, 5-amine-, or an analogue or derivative thereof). Other examples of phosphodiesterase inhibitors include denbufilin (lH-purine-2, 6-dione, 1,3-dibutyl-3,7-dihydro-7- (2-oxopropyl) -), propentofylline (lH-purine-2,6-dione, 3,7-dihydro-3-methyl-1) - (5-oxohexyl) -7-propyl-) and pelrinone (5-pyrimidinecarbonitrile, 1,4-dihydro-2-methyl-4-oxo-6- [(3-pyridinylmethyl) amine] -). Other examples of phosphodiesterase III inhibitors include enoximone (2H-imidazol-2-one, 1,3-dihydro-4-methyl-5- [4- (methylthio) benzoyl] -), and saterinone (3-pyridinecarbonitrile, 1,2-dihydro-5- [4- [2-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] propoxy] phenyl] -6-methyl-2-oxo-). Other examples of phosphodiesterase IV inhibitors include AWD-12-281, 3-auinolino carboxylic acid, 1-ethyl-6-fluoro-l, 4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo -), tadalafil (pyrazine (1 ', 2': 1, 6) pyrido (3,4-b) indole 1,4-dione, 6- (1, 3-benzodioxol-5-yl) -2,3, 6, 7, 12, 12a-hexahydro-2-methyl-, (6R-trans)), and filaminaste (ethanone, 1- [3- (cyclopentyloxy) -4-methoxyphenyl] -, 0- (aminocarbonyl) oxime, ( 1E) -) Another example of a phosphodiesterase V inhibitor is vardenafil (piperazine, 1- (3- (1,4-dihydro-5-methyl (4-oxo-7-propylimidazo (5, lf) (1,2, 4) -triazin-2-yl) -4-ethoxyphenyl) sulfonyl) -4-ethyl-). 29. Inhibitors of TGF beta In another configuration, the pharmacologically active compound is a TGF beta inhibitor (eg mannos-6-phosphate, LF-984, tamoxifen (ethanamine, 2- (4- (1,2-diphenyl) - l-butenyl) phenoxy) -N, N-dimethyl-, (Z) -), tranylate, or an analogue or derivative thereof). 30. Thromboxane A2 Antagonists In a further configuration, the pharmacologically active compound is an antagonist of thromboxane A2 (eg, CGS-22652 (3-pyridinoheptanoic acid,? - (4- (((4-chlorophenyl) sulfonyl) amine) butyl) -, (. + -.) -), ozagrel (acid 2-prspenoic, 3- (4- (lH-imidazol-1-ylmethyl) phenyl) -, (E) -), argatroban (2-piperidino carboxylic acid, 1- (5- ((aminoiminobrethyl) amine) -l- oxo-2- (((1,2,3,4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl) amine) pentyl) -4-methyl-), ramatroban (9H-carbazole-9-propanoic acid) - (((4- fluorophenyl) sulfonyl) amine) -1,2,3,4-tetrahydro-, (R) -), torasemide (3-pyridinesulfonamide, N- (((1-methylethyl) amine) carbonyl) - 4- ((3-methylphenyl) amine) -), gamma linoleic acid ((Z, Z, Z) -6, 9, 12-octadecatrienoic acid), seratrodast (benzeneheptanoic acid, zeta- (2, 4, 5-trimethyl) - 3, 6-dioxo-l, 4-cyclohexadien-1-yl) -, (+/-) -, or an analog or derivative thereof). 31. TNFa Antagonists and TACE Inhibitors In another configuration, the pharmacologically active compound is a TNFa antagonist or a TACE inhibitor. (e.g., E-5531 (2-deoxy-6-0- (2-deoxy-3-0- (3 (R) - (5 (Z) -dodecenoyloxy) -decyl) -6-0-methyl-2 - (3-oxotetradecanamido) -4- O-phosphono-β-D-glucopyranosyl) -3-0- (3 (R) -hydroxydecyl) -2- (3-oxotetradecanamido) -alpha-D-glucopyranose-1-O -phosphate), AZD-4717, glycophosphopeptical, UR-12715 (B = benzoic acid, 2-hydroxy-5- ((4- (3- (4- (2-methyl-1H-imidazole (4, 5-c) pyridin-1-yl) methyl) -1-piperidinyl) -3-oxo-l-phenyl-1-propenyl) phenyl) azo) (Z)), PMS-601, AM-87, xyloadenosine (9H-purin-6) -amine, 9-ß-D-xylofuranosyl-), RDP-58, RDP-59, BB2275, benzidamine, E-3330 (undecanoic acid, 2- ((4,5-dimethoxy-2-methyl-3, 6- dioxo-l, 4-cyclohexadien-1-yl) methylene) -, (E) -), N- (D, L-2- (hydroxyaminocarbonyl) methyl-4-methylpentanoyl) -L-3- (2'-naphthyl) ) alanyl-L-alanine, 2-aminoethyl amide, CP-564959, MLN-608, SPC-839, ENMD-0997, Sch-23863 ((2- (10,1-dihydro-5-ethoxy-5H-dibenzo ( a, d) cyclohepten-S-yl) -N, N-dimethyl-ethanamine), SH-636, PKF-241-466, PKF-242-484, TNF-484A, cilomylast (cis-4-) cyano-4- (3- (cyclopentyloxy) -4-methoxyphenyl) cyclohexane-1-carboxylic acid), GW-3333, GW-4459, BMS-561392, AM-87, chloricromene (acetic acid, ((8-chloro- 3- (2- (diethylamino) ethyl) -4-methyl-2-oxo-2H-l-benzopyran-7-yl) oxy) -, ethyl ester), thalidomide (lH-Isoindole-1,3 (2H) -dione, 2- ( 2, 6-dioxo-3-piperidinyl) -), vesnarinone (piperazine, 1- (3,4-dimethoxybenzoyl) -4- (1,2,3,4-tetrahydro-2-oxo-6-quinolinyl) -) , infliximab, lentinana, etanercept (fusion protein of receptor 1-235-tumor necrosis factor (human) with 236-467-immunoglobulin Gl (fragment gamal-cadeia Fe human)), diacerein (2-anthracene carboxylic acid, 4,5-bis (acetyloxy) -9, 10-dihydro-9, 10-dioxo-, or an analogue or derivative thereof). 32. Tyrosine Kinase Inhibitors In another configuration, the pharmacologically active compound is a tyrosine kinase inhibitor (e.g., SKI-606, ER-068224, SD-208, N- (6-benzothiazolyl) -4- ( 2- (1-piperazinyl) pyrid-5-yl) -2-pyrimidine-amine, celastrol (24,25,26-trinorolean-l (10), 3,5,7-tetraen-29-oic acid, 3- hydroxy-9,13-dimethyl-2-oxo-, (9 beta, 13alpha, 14β, 20 alpha) -), CP-127374 (geldanamycin, 17-demethoxy-17- (2-propenylamino) -), CP- 564959, PD-171026, CGP-52411 (1H-Isoindol-1,3 (2H) -dione, 4,5-bis (phenylamino) -), CGP-53716 (benzamide, N- (4-methyl-3- ((4- (3-pyridinyl) -2-pyrimidinyl) amine) phenyl) -), imatinib (4- ((methyl-1-piperazinyl) methyl) -N- (4-methyl-3- ((4- (3-pyridinyl) -2-pyrimidinyl) amine) -phenyl) benzamide methanesulfonate), NVP-AAK980-NX, KF-250706 (13-chloro, 5 (R), 6 (S) -epóxi-14, 16- dihydroxy-11- (hydroimino) -3 (R) -methyl-3, 4, 5, 6, 11, 12-hexahydro-lH-2-benzoxaciclotetradecin-l-one), 5- (3- (3-methoxy) 4- (2- ((E) -2-phenylethenyl) -4-oxazolylmethoxy) phenyl) propyl) -3- (2- ((E) -2-phenylethenyl) -4-oxazolylmethyl) -2, -oxazolidinedione, genistein , NV-06, or an analog or derivative thereof). 33. Vitronectin Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of vitronectin (eg, 0- (9,10-dimethoxy-1, 2,3,4,5,6-hexahydro-4-). ((1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazone) -8-benz (e) azul) -N- ((phenylmethoxy) carbonyl) -DL-homoserine 2, 3-dihydroxypropyl ester, (2S) -benzoylcarbonylamino-3- (2- ((4S) - (3- (4,5-dihydro-lH-imidazol-2-ylamino) -propyl) -2,5-dioxo-imidazolidin-1-yl) -acetylamino) -propionate, Sch-221153, S-836, SC-68448 (ß- ((2-2- (((3- ((aminoiminomethyl) amine) -phenyl) carbonyl) amine) acetyl) amine) -3,5- dichlorobenzenepropanoic acid), SD-7784, S-247, or an analogue or derivative thereof). 34. Inhibitors of Fibroblast Growth Factor In another configuration, the pharmacologically active compound is an inhibitor of fibroblast growth factor (e.g., CT-052923 (((2 H -benzo (d) 1, 3-dioxalan-5 -methyl) amine) (4- (6,7-dimethoxyguinazolin-4-) il) piperazinyl) methane-1-thione), or an analogue or derivative thereof). 35. Protein Kinase Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of the protein kinase (e.g., KP-02014 8, NPC15437 (hexanamide, 2,6-diamino-N- (( 1- (1-oxotridecyl) -2-piperidinyl) methyl) -), fasudyl (1H-1,4-diazepine, hexahydro-1- (5-isoquinolinylsulfonyl) -), midostaurin (benzamide, N- (2,3, 10, 11,12, 13-hexahydro-10-methoxy-9-methyl-l-oxo-9, 13-epoxy-lH, 9H-diindolo (1, 2,3-gh: 3 ', 2', 1 ' -lm) pyrrolo (3, 4-j) (1, 7) benzodiazonin-11-yl) -N-methyl-, (9Alfa, 10β, 11β, 13Alfa) -), fasudyl (1H-1,4-diazepine, hexahydro-1- (5-isoquinolinylsulfonyl) -, dexniguldipine (3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -, 3- (4,4-diphenyl- l-piperidinyl) propyl methyl ester, monohydrochloride, (R) -), LY-317615 (lH-pyrol-2,5-dione, 3- (l-methyl-lH-indol-3-yl) -4- [1 - [1- (2-pyridinylmethyl) -4-piperidinyl] -lH-indol-3-yl] -, monohydrochloride), periprosine (piperidinium, 4- [[h idroxy (octadecyloxy) phosphinyl] oxy] -1, 1-dimethyl-, internal salt), LY-333531 (9H, 18H-5, 21: 12, 17-dimethenobenzoate (e, k) pyrrole (3,4-h) (1,4, 13) oxadiazacyclohexadecin-18,20 (19H) -dione, 9- ((dimethylamino) methyl) -6, 7, 10, 11-tetrahydro-, (S) -), Kynac; SPC-100270 (1,3-octadecanodiol, 2-amine-, [S- (R *, R *)] -), Quinacite, or an analog or derivative thereof). 36. PDGF Receptor Kinase Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of the PDGF receptor kinase (e.g., RPR-127963E, or an analog or derivative thereof). 37. Inhibitors of the Endothelial Growth Factor Receptor Kinase In another configuration, the pharmacologically active compound is an inhibitor of the endothelial growth factor receptor kinase (e.g., CEP-7055, SU-0879 ((E) -3- (3,5-di-tert-butyl-4-hydroxyphenyl) -2- (aminothiocarbonyl) acrylonitrile), BIBF-1000, AG-013736 (CP-868596), AMG-706, AVE-0005, NM-3 (3- (2-methylcarboxymethyl) -6-methoxy-8-hydroxy-isocoumarin), Bay-43-9006, SU-011248, or an analog or derived from it). 38. Retinoic Acid Receptor Antagonists In another configuration, the pharmacologically active compound is a retinoic acid receptor antagonist (e.g., etarotene (Ro-15-1570) (naphtha, 6- (2- (4- (ethylsulfonyl ) phenyl) -1-methyletenyl) -1, 2, 3, 4-tetrahydro-1,1,4,4-tetramethyl-, (E) -), (2E, 4E) -3-methyl-5- (2 - ((E) -2- (2,6,6-trimethyl-l-cyclohexen-1-yl) ethenyl) -1-cyclohexen-1-yl) -2,4-pentadienoic acid, tonucleotinate (retinoic acid, 3) , 4-dihydro-2, 5, 7, 8-tetramethyl-2- (4, 8, 12- trimethyltridecyl) -2H-l-benzopyran-6-yl ester, (2R * (4R *, 8R *)) - (+) -), aliretinoin (retinoic acid, cis-9, trans-13-), bexarotene (benzoic acid, 4- (1- (5, 6, 7, 8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl) -), tonucleotinate (retinoic acid, 3,4-dihydro-2, 5, 7, 8-tetramethyl-2- (4 , 8, 12-trimethyltridecyl) -2H-l-benzopyran-6-yl ester, [2R * (4R *, 8R *)] - (+) -, or an analogue or derivative thereof). 39. Inhibitors of Growth Factor Receptor Kinase In a further configuration, the pharmacologically active compound is an inhibitor of platelet-derived growth factor receptor kinase (e.g., leflunomide (4-isoxazolocarboxamide, -methyl-N- (4- (trifluoromethyl) phenyl) -, or an analog or derivative thereof) 40. Fibrinogen Antagonists In another configuration, the pharmacologically active compound is a fibrinogen antagonist (eg, picotamide (1). , 3-benzenedicarboxamide, 4-methoxy-N, N'-bis (3-pyridinylmethyl) -, or an analog or derivative thereof) 41. Antifungal Agents In another configuration, the pharmacologically active compound is an antifungal agent ( example, miconazole, sulconazole, parthenolide, rosconitin, nystatin, isoconazole, fluconazole, ketoconazole, imidazole, itraconazole, terpinaphine, elonazole, bifonazole, clotrimazole, conazole, terconazole (piperazine, 1- (4- ((2- (2,4-dichlorophenyl) -2- (1H-1,2, 4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl) methoxy) phenyl) -4- (1-methylethyl) -, cis-), isoconazole (1- (2- (2-6-dichlorobenzyloxy ) -2- (2-, 4-dichlorophenyl) ethyl)), griseofulvin (spiro (benzofuran-2 (3H), 1 '- (2) cydohexane) -3,4'-dione, 7-chloro-2', 4,6-trimethoxy-6'-methyl-, (l'S-trans) -), bifonazole (lH-imidazole, 1- ((1,1'-biphenyl) -4-ylphenylmethyl) -), econazole nitrate (1- ( 2- ((4-chlorophenyl) methoxy) -2- (2,4-dichlorophenyl) ethyl) -lH-imidazole nitrate), croconazole (lH-imidazole, 1- (1- (2 - ((3-chlorophenyl) methoxy) ) phenyl) ethenyl) -), sertaconazole (1H- Imidazole, 1- (2- ((7-chlorobenzo (b) thien-3-yl) methoxy) -2- (2,4-dichlorophenyl) ethyl) -), omoconazole (lH-imidazole, 1- (2- (2- (4-chlorophenoxy) ethoxy) -2- (2,4-dichlorophenyl) -1-methyletenyl) -, (Z) -), flutrimazole (lH-imidazole, 1- ((2-fluorophenyl) (4- fluo rhephenyl) phenylmethyl) -), fluconazole (lH-1, 2,4-triazole-1-ethanol, alpha- (2, 4-difluorophenyl) -alpha- (1H-1, 2,4-triazol-1-ylmethyl) -), neticonazole (IH-Imidazole, 1- (2- (methylthio) -1- (2- (pentyloxy) phenyl) ethenyl) -, monohydrochloride, (E) -), butoconazole (lH-imidazole, 1- (4 - (-chlorophenyl) -2- ((2,6-dichlorophenyl) thio) butyl) -, (+/-) -), clotrimazole (1- ((2-chlorophenyl) diphenylmethyl) -IH-imidazole, or an analogue or derived from it). 42. Bisphosphonates In another configuration, the pharmacologically active compound is a bisphosphonate (for example, clodronate, alendronate, pamidronate, zoledronate, or an analog or derivative thereof). 43. Phospholipase Al Inhibitors In another configuration, the pharmacologically active compound is an inhibitor of phospholipase Al (for example, ioteprednol etabonate (androsta-l, 4-diene-17-carboxylic acid, 17- ((ethoxycarbonyl) oxy). ) -ll-hydroxy-3-oxo-, chloromethyl ester, (11β, 17 alpha) -, or an analogue or derivative thereof.) 44. Histamine H1 / H2 / H3 Receptor Antagonists In a further configuration, the pharmacologically compound active is a histamine H1, H2, or H3 receptor antagonist (eg, ranitidine (1,1-etheno diamine, N- (2- (((5- ((dimethylamino) methyl) -2-furanyl) methyl) thio) ethyl) -N'-methyl-2-nitro-), niperotidine (N- (2- ((5- ((dimethylamino) methyl) furfuryl) io) ethyl) -2-nitro-N'-piperonyl-1, 1 -enthia diamine), famotidine (propanimidamide, 3- (((2- ((aminoiminomethyl) amine) -4-thiazolyl) methyl) thio) -N- (aminosulfonyl) -), roxitadine acetate HCl (acetamide, 2- (acetyloxy) -N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) -, monohydroc loride), lafutidine (acetamide, 2 - ((2-furanylmethyl) sulfinyl) -N- (4- ((4- (1-piperidinylmethyl) -2- pyridinyl) oxy) -2-butenyl) -, (Z) -), nizatadine (1,1-ethenediamine, N- (2- (((2- ((dimethylamino) methyl) -4-thiazolyl) methyl) thio) ethyl) -N '-methyl-2-nitro-), ebrotidine (benzenesulfonamide, N- (((2- (((2- ((aminoiminomethyl) amine) -4-thiazole) methyl) thio) ethyl) amine) methylene) -4-bromo-), rupatadine (5H-benzo (5 , 6) cyclohepta (1, 2-b) pyridine, 8-chloro-6,11-dihydro-11- (1- ((5-methyl-3-pyridinyl) methyl) -4-piperidinylidene) -, trihydrochloride-) , fexofenadine HCl (benzeneacetic acid, 4- (l-hydroxy-4- (4 (hydroxydiphenylmethyl) -1-piperidinyl) butyl) -alpha, alpha-dimethyl-, hydrochloride, or an analogue or derivative thereof). 45. Macrolide Antibiotics In another configuration, the pharmacologically active compound is a macrolide antibiotic (e.g., dirithromycin (erythromycin, 9-deoxo-ll-deoxy-9, 11- (imino (2- (2-methoxyethoxy) ethylidene) oxy ) -, (9S (R)) -), fluritromycin ethylsuccinate (erythromycin, 8-fluoro-mono (ethyl butanedioate) (ester) -), erythromycin estinoprate (erythromycin, 2 '-propanoate, compound with N-acetyl-L-) cysteine (1: 1)), clarithromycin (erythromycin, 6-O-methyl-), azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin-A), telithromycin (3-de ((2, 6-dideoxy-3 ~ C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy) -11,12-dideoxy-6-0-methyl-3-oxo-12,11- (oxycarbonyl ( (4- (4- (3-pyridinyl) -lH-imidazole-1- il) butyl) imino)) -), roxithromycin (erythromycin, 9- (O- ((2-methoxyethoxy) methyl) oxime)), rokitamycin (leucomycin V, 4B-butanoate 3B-propanoate), RV-11 (erythromycin monopropionate mercaptosuccinate), midecamycin acetate (leucomycin V, 3B, 9-diacetate 3,4B-dipropanoate), midecamycin (leucomycin V, 3, 4B-dipropanoate), josamycin (leucomycin V, 3-acetate 4B- (3-methylbutanoate), or an analogue or derivative thereof). 46. GPIIb Illa Receptor Antagonists In another configuration, the pharmacologically active compound is an GPIIb Illa receptor antagonist (for example, tirofibana hydrochloride (L-tyrosine, N- (butylsulfonyl) -O- (4- (4-piperidinyl)). butyl) -, monohydrochloride-), eptifibatide (L-cysteinamide, N6- (aminoiminomethyl) -N2- (3-mercapto-1-oxopropyl) -L-lysylglycyl-L-alpha-aspartyl-L-tryptopyl-L-prolyl- , cyclic (l-> 6) -disulfide), xemilofiban hydrochloride, or an analogue or derivative thereof). 47. Endothelin Receptor Antagonists In another configuration, the pharmacologically active compound is an endothelin receptor antagonist (eg, bosentan (benzenesulfonamide, 4- (1,1-dimethylethyl) -N- (6- (2-hydroxyethoxy) - 5- (2-methoxyphenoxy) (2,2'-bipyrimidine) -4-yl) -, or an analogue or derivative thereof). 48. Fighters of Peroxisome Proliferator-Activated Receptor In another configuration, the pharmacologically active compound is a peroxisome proliferator-activated receptor fighter (e.g., gemfibrozil (pentanoic acid, 5- (2,5-dimethylphenoxy) -2, 2- dimethyl-), fenofibrate (propanoic acid, 2- (4- (4-chlorobenzoyl) phenoxy) -2-methyl-, 1-methylethyl ester), ciprofibrate (propanoic acid, 2- (4- (2,2-dichlorocyclopropyl) phenoxy) -2-methyl-), rosiglitazone maleate (2,4-thiazolidinedione, 5- ((4- (2- (methyl-2-pyridinylamino) ethoxy) phenyl) methyl) -, (Z) -2-butenedioate ( 1: 1)), pioglitazone hydrochloride (2,4-thiazolidinedione, 5- ((4- (2- (5-ethyl-2-pyridinyl) ethoxy) phenyl) methyl) -, monohydrochloride (+/-) -), Ethofilin Clofibrate (Propanoic acid, 2- (4-chlorophenoxy) -2-methyl-, 2- (1,2,3,6-tetrahydro-l, 3-dimethyl-2,6-dioxo-7H-purin-7- il) ethyl ester), etofibrate (3-pyridine carboxylic acid, 2- (2- (4-chlorophenoxy) -2-methyl-1-oxopropoxy) ethyl ester), clinofibrate (butanoic acid, 2,2 '- (cyclohexylidenebis (4, 1-phenyleneoxy)) bis (2-methyl-)), bezafibrate (propanoic acid, 2- (4- (2- ((4-chlorobenzoyl) amine) ethyl) phenoxy) -2-methyl-), binifibrate (3-pyridine carboxylic acid, 2- (2- (4-chlorophenoxy) -2-methyl-1-oxopropoxy) -1,3-propanediyl ester), or an analogue or derived from it).

In one aspect, the pharmacologically active compound is an alpha combatant of the peroxisome proliferator-activated receptor, such as GW-590735, GSK-677954, GSK501516, pioglitazone hydrochloride (2,4-thiazolidinedione, 5- [[4- [2 - (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl] -, monohydrochloride (+/-) - / or an analogue or derivative thereof). 49. Estrogen Receptor Agents In another configuration, the pharmacologically active compound is an estrogen receptor agent (eg, estradiol, 17-β-estradiol, or an analog or derivative thereof). 50. Somatostatin Analogs In another configuration, the pharmacologically active compound is an analogue of somatostatin (eg, angiopeptin, or an analog or derivative thereof). 51. Neurokinin 1 Antagonists In a further configuration, the pharmacologically active compound is an antagonist of neurokinin 1 (for example, GW-597599, lanepitante ((1, 4 '-bipiperidina) -1' -acetamida, N- ( 2- (Acetyl ((2-methoxyphenyl) methyl) amine) -1- (1 H -indol-3-ylmethyl) ethyl) - (R) -), nolpitantium chloride (1-azoniabicyclo [2.2.2] octane, 1 - [2- [3- (3,4-dichlorophenyl) -1 - [[3- (1-methyletoxy) phenyl] acetyl] -3-piperidinyl] ethyl] -4- phenyl-, chloride, (S) -) , or saredutant (benzamide, N- [4- [4- (acetylamino) -4-phenyl-1-piperidinyl] -2- (3,4- dichlorophenyl) butyl] -N-methyl-, (S) -), or vofopitant (3-piperidinamine, N - [[2-methoxy-5- [5- (trifluoromethyl) -1H-tetrazol-1-yl] phenyl] methyl] -2-phenyl-, (2S, 3S) -, or an analogue or derivative thereof). 52. Neurokinin 3 Antagonist In another configuration, the pharmacologically active compound is an antagonist of neurokinin 3 (for example, talnetant (4-quinolinocarboxamide, 3-hydroxy-2-phenyl-N- [(1S) -1- phenylpropyl] -, or an analogue or derivative thereof) 53. Neurokinin Antagonist In another configuration, the pharmacologically active compound is a neurokinin antagonist (eg, GSK-679769, GSK-823296, SR-489686 ( benzamide, N- [4- [4- (acetylamino) -4-phenyl-1-piperidinyl] -2- (3,4-dichlorophenyl) butyl] -N-methyl-, (S) -), SB-223412; SB-235375 (4-quinolinecarboxamide, 3-hydroxy-2-phenyl-N- [(1S) -1-phenylpropyl] -), UK-226471, or an analog or derivative thereof). 54. VLA-4 Antagonist In another configuration, the pharmacologically active compound is an antagonist of VLA-4 (eg, GSK683699, or an analog or derivative thereof). 55. Osteoclast Inhibitor In another configuration, the pharmacologically active compound is an osteoclast inhibitor (e.g., acid) Ibandronic acid (phosphonic acid, [l-hydroxy-3- (methylpentylamino) propylidene] bis-), alendronate sodium, or an analogue or derivative thereof). 56. ATP Hydrolyzing Inhibitor of Topoisomerase DNA In another configuration, the pharmacologically active compound is a hydrolyzing inhibitor of ATP of the DNA topoisomerase (e.g., enoxacin (1,8-naphthyridine-3-carboxylic acid, l-ethyl-6- fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -), levofloxacin (7H-Pyrido [1, 2,3-de] -1,4-benzoxazine-6-carboxylic acid, 9- fluoro-2, 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-, (S) -), ofloxacin acid (7H-pyrido [1, 2,3-de] -l, 4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-, (+/-) -), pefloxacin (3-quinolinecarboxylic acid, l-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-), pipemidic acid (pyrido acid [2, 3-d] ] pyrimidine-6-carboxylic acid, 8-ethyl-5,8-dihydro-5-0x0-2- (1-piperazinyl) -), pirarubicin (5,12-naphtacenedione, 10- [[3-amine-2, 3 , 6-trideoxy-4-0- (tetrahydro-2H-pyran-2-yl) -alpha-L-lixo-hexopyranosyl] oxy] - 7,8,9, 10-tetrahydrate o-6, 8, 11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-, [8S- [8 alpha, 10 alpha (S *)]] -), sparfloxacin (3-quinolinecarboxylic acid, 5-amine- l-cyclopropyl-7- (3,5-dimethyl-1-piperazinyl) -6,8-difluoro-l, 4-dihydro-4-oxo-, cis-), AVE-6971, cinoxacin (acid [1, 3 ] dioxolo [4, 5- g) cyclin-3-carboxylic acid, l-ethyl-l, 4-dihydro-4-oxo-), or an analogue or derivative thereof). 57, Angiotensin I Conversion Enzyme Inhibitor In another configuration, the pharmacologically active compound is an inhibitor of the angiotensin I converting enzyme (e.g., ramipril (cyclopenta [b] pyrrole-2-carboxylic acid, 1- [2- [ [1- (ethoxycarbonyl) -3-phenylpropyl] amine] -l-oxopropyl] octahydro-, [2S- [1 [R * (R *)], 2 alpha, 3aß, 6aß]] -), trandolapril (lH acid) -indole-2-carboxylic acid, 1- [2 - [(1-carboxy-3-phenylpropyl) amine] -1-oxopropyl] octahydro-, [2S- [1 [R * (R *)], 2 alpha, 3a alpha, 7aß]] -), fasidotril (L-alanine, N- [(2S) -3- (acetylthio) -2- (1,3-benzodioxol-5-ylmethyl) -1- oxopropyl] -, phenylmethyl ester) , cilazapril (6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid, 9 - [[1- (ethoxycarbonyl) -3-phenylpropyl] amine] octahydro-10-oxo-, [1S- [1 alpha, 9 alpha (R *)]] -), ramipril (cyclopenta [b] pyrrole-2-carboxylic acid, 1- [2- [[1- (ethoxycarbonyl) -3-phenylpropyl] amine] -1- oxopropyl] octahydro-, [2S- [1 [R * (R *)], 2 alpha, 3aß, 6aß]] -, or an an catalog or derivative thereof). 58, Angiotensin II Antagonist In another configuration, the pharmacologically active compound is an angiotensin II antagonist (eg, HR-720 (lH-imidazole-5-carboxylic acid, 2-butyl-4- (methylthio) - 1- [[2'- [[[(propylamino) carbonyl] amine] sulfonyl] [1,1'-biphenyl] -4-yl] methyl] -, dipotassium salt, or an analogue or derivative thereof). 59. Encephalinase inhibitor In another configuration, the pharmacologically active compound is an enkephalinase inhibitor (eg, Aventis 100240 (pyrido [2, 1-a] [2] benzazepine-4-carboxylic acid, 7- [[ 2- (acetylthio) -l-oxo-3-phenylpropyl] amine] -1,2, 3,4, 6, 7, 8,12b-octahydro-6-oxo-, [4S- [4 alpha, 7 alpha ( R *), 12bβ]] -), AVE-7688, or an analogue or derivative thereof). 60. Insulin Sensitizer of the Gamma Receptor Activated by Peroxisome Proliferator In another configuration, the pharmacologically active compound is a proliferator-activated proliferator-reactive insulin sensitizer of the peroxisome (eg, rosiglitazone maleate (2). , 4- thiazolidinedione, 5- ((4- (2- (methyl-2-pyridinyl) -no) ethoxy) phenyl) methyl) -, (Z) -2-butenedioate (1: 1), farglitazar (GI-262570, GW -2570, GW-3995, GW-5393, GW-9765), LY-929, LY-519818, LY-674, or LSN-862), or an analogue or derivative thereof). 61. Protein Kinase C Inhibitor In another configuration, the pharmacologically active compound is an inhibitor of protein kinase C, such as the mesylate of ruboxistaurin (9H, 18H-5,21: 12, 17-dimethenobenzoate (e, k) pyrrole (3,4-h) (1,4,13) oxadiazacyclohexadecin-18,20 (19H) -dione, 9 - ((dimethylamino) methyl) -6, 7, 10, 11-tetrahydro-, (S) -), safingol (1,3-octadecanediol, 2-amine-, [S- (R *, R *)] - ), or enzastaurin hydrochloride (lH-pyrola-2,5-dione, 3- (l-methyl-lH-indol-3-yl) -4- [1- [1- (2-pyridinylmethyl) -4-piperidinyl] -IH-indol-3-yl] -, monohydrochloride), or an analogue or derivative thereof. 62. ROCK Inhibitors (Rho-Associated Kinase) In another configuration, the pharmacologically active compound is a ROCK inhibitor (rho-associated kinase), such as Y-27632, HA-1077, H-1152 and 4-1- (aminoalkyl) - N- (4-pyridyl) cyclohexanecarboxamide or an analogue or derivative thereof. 63. Inhibitors of CXCR3 In another configuration, the pharmacologically active compound is an inhibitor of CXCR3 such as T-487, T0906487 or analog or derivative thereof. 64. Itk Inhibitors In another configuration, the pharmacologically active compound is an Itk inhibitor such as BMS-509744 or an analog or derivative thereof. 65. Cytosolic phospholipase A2-alpha inhibitors In a further configuration, the pharmacologically active compound is an inhibitor of cytosolic phospholipase A2-alpha such as efipladib (PLA-902) or an analog or derivative thereof. 66. PPAR Fighter In another configuration, the pharmacologically active compound is a PPAR combatant (e.g., Metabolex ((-) -benzeneacetic acid, 4-chloro-alpha- [3- (trifluoromethyl) -phenoxy] -, 2- (acetylamino) ethyl ester), balaglitazone (5- (4- (3-methyl-4- oxo-3,4-dihydro-quinazolin-2-yl-methoxy) -benzyl) -thiazolidine-2,4-dione), ciglitazone (2,4-thiazolidinedione, 5- [[4- [(1-methylcyclohexyl) methoxy] ] phenyl] methyl] -), DRF-10945, farglitazar, GSK-677954, GW-409544, GW-501516, GW-590735, GW-590735, K-III, KRP-101, LSN-862, LY-519818, LY-674, LY- 929, muraglitazar; BMS-298585 (Glycine, N- [(4-methoxyphenoxy) carbonyl] -N- [[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] -), netoglitazone; isaglitazone (2,4-thiazolidinedione, 5- [[6- [(2-fluorophenyl) methoxy] -2- naphthalenyl] methyl] -), Actos AD-4833; U-72107A (2,4-thiazolidinedione, 5- [[4- [2- (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl] -, monohydrochloride (+/-) -), JTT-501; PNU-182716 (3, 5-IS? Xazolidinadione, 4- [[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] -), Avandia (from SB Pharmco Puerto Rico, Inc. (Porto Rico); BRL- 48482; BRL-49653; BRL-49653c; Nyracta and Venvia (both from (SmithKline Beecham (United Kingdom)); tesaglitazar ((2S) -2-ethoxy-3- [4- [2- [4- [(methylsulfonyl) oxy] phenyl] ethoxy] phenyl] propanoic acid ), troglitazone (2,4-thiazolidinedione, 5- [[4- [(3,4-dihydro-6-hydroxy-2, 5,7, 8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] ethyl] -), and analogs and derivatives thereof). 67. immunosuppressants In another configuration, the pharmacologically active compound is an immunosuppressant (e.g., batebulast (cyclohexanecarboxylic acid, 4- [[(aminoiminomethyl) amine] methyl] -, 4- (1, 1- dimethylethyl) phenyl ester, trans -), cyclomunine, exalamide (benzamide, 2- (hexyloxy) -), LYN-001, CCI-779 (rapamycin 42- (3-hydroxy-2- (hydroxymethyl) -2-methylpropanoate)), 1726, 1726-D; AVE-1726, or an analogue or derivative thereof). 68. Erb inhibitor In another configuration, the pharmacologically active compound is an Erb inhibitor (eg, cinchrtinib dihydrochloride (N- [4- (3- (chloro-4-fluoro-phenylamino) -7- (3-morpholin-4-yl) -propoxy) -quinazolin-6-yl] -acrylamide dihydrochloride), CP-724714, or an analogue or derivative thereof) 69. Apoptosis Fighter In another configuration, the pharmacologically active compound is a combatant of apoptosis (e.g., ceflatonin (CGX-635) (from Chemgenex Therapeutics, Inc., Menlo Park, CA, USA), CHML, LBH-589, metoclopramide (benzamide) , 4-amine-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxy-), patupilone (4,17-dioxabicyclo (14.1.0) heptadecane-5, 9-dione, 7, 11- dihydroxy-8, 8, 10, 12, 16-pentamethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl, (1R, 3S, 7S, 10R, 11S, 12S, 16R)) , AN-9; pivanex (butanoic acid, (2, 2-dimethyl-1-oxopropoxy) methyl ester), SL-100; SL-102; SL-11093; SL-11098; SL-11099; SL-93; SL -98; SL-99, or an analogue or derivative thereof.) 70. Lipocortin Fighter In another configuration, the pharmacologically active compound is a fighter of lipocortin (e.g., CGP-13774 (9Alfa-chloro-6Alfa -fluoro-llβ, 17 alpha-dihydroxy-16Alpha-methyl-3-oxo-l, 4-androstadiene-17β-carboxylic acid-methyl ester-17-propionate), or analogue or derivative thereof o). 71. Antagonist of VCAM-1 In another configuration, the pharmacologically active compound is an antagonist of VCAM-1 (eg, DW-908e, or an analogue or derivative thereof). 72. Collagen Antagonist In another configuration, the pharmacologically active compound is a collagen antagonist (e.g., E-5050 (Benzenepropanamide, 4- (2,6-dimethylheptyl) -N- (2-hydroxyethyl) -β-methyl-), luphironyl (2,4-pyridinedicarboxamide, N, N'-bis (2-methoxyethyl) -), or an analogue or derivative thereof). 73. Alpha 2 Integrin Antagonist In another configuration, the pharmacologically active compound is an alpha 2 integrin antagonist (e.g., E-7820, or an analog or derivative thereof). 74. TNF Alpha Inhibitor In another configuration, the pharmacologically active compound is an inhibitor of TNF alpha (eg, ethyl pyruvate, Genz-29155, lentinana (Ajinomoto Co., Inc.

(Japan)), linomide (3-quinolinecarboxamide, 1,2-dihydro-4-hydroxy-N, 1-dimethyl-2-oxo-N-phenyl-, UR-1505, or an analogue or derivative thereof). 75. Nitric Oxide Inhibitor In another configuration, the pharmacologically active compound is a nitric oxide inhibitor (eg, guanidium ethyldisulfide, or an analogue or derivative thereof). 76. Cathepsin Inhibitor In another configuration, the pharmacologically active compound is a cathepsin inhibitor (e.g., SB-462795 or an analog or derivative thereof). 77. Distribution of Cells and Genes The compositions of the invention can also be used to distribute various types of living cells or genes to a desired administration site in order to form a new tissue. The term "genes" as used here is intended to encompass genetic material from natural sources, synthetic nucleic acids, DNA, antisense DNA and RNA. Thus, that aspect of the invention is a method for the distribution of living cells or genes, wherein the composition also includes the gene cells to be distributed, and steps (a) and (b) are in accordance with those described for the method of sealing the tissue. Step (c) would involve allowing the formation of a three-dimensional matrix and the distribution of cells or genes. When used to distribute cells, for example, the cells of the mesenchymal stem can be distributed to produce cells of the same type as the tissue in which they are distributed. The cells of the mesenchymal stem are not differentiated and therefore can be differentiated to form several types of new cells due to the presence of an active agent or the effects (chemical, physical, etc.) of the local tissue environment. Examples of mesenchymal stem cells include osteoblasts, chondrocytes, and fibroblasts. Osteoblasts can be distributed to the site of a bone defect to produce a new bone; the chondrocytes can be sent to the local of a cartilage defect to produce a new cartilage; fibroblasts can be distributed to produce collagen whenever new connective tissues are needed; neuroectodermal cells can be distributed to form a nerve tissue; the epithelial cells can be distributed to form new epithelial tissues, such as the liver, pancreas, etc. The cells or genes can be either allogeneic or xenogenetic in origin. For example, the compositions can be used to distribute cells or genes from other species that were genetically modified. Due to the fact that the composition of the invention is not easily degraded in vivo, the cells and genes imprisoned inside the three-dimensional matrix will be isolated from the patient's own cells, and as such, will not cause an immune response in the patient. patient. In order to turn on the cells or genes inside that matrix, the cells or genes are pre-mixed with the components in an initial environment. With exposure to the aqueous environment, a three-dimensional matrix is formed, thereby turning on the cells or genes inside the matrix. As discussed above for biologically active agents, when used to distribute cells or genes, the components may also contain biodegradable groups, or the composition may also contain compounds biodegradable, to assist in the controlled release of cells or genes in the desired distribution site. 78. Bioadhesives As used herein, the terms "bioadhesive," "biological adhesive," and "surgical adhesive" are used interchangeably to refer to biocompatible compositions capable of effecting permanent temporary fixation between the surfaces of two native tissues, or between the surface of a native tissue and / or the surface of a non-native tissue or the surface of a synthetic implant. In a general method for effecting the attachment of a first surface to a second surface, the composition of the invention is applied to the first surface, which is then brought into contact with a second surface to effect adhesion therebetween. Preferably, the composition is exposed to the aqueous environment to initiate the reaction between the reactive groups, then it is distributed to the first surface before the occurrence of a substantial reaction. The first surface is then brought into contact with the second surface, preferably immediately, to effect adhesion. In this way, a further configuration of the invention consists of a bioadhesion method between two surfaces, where steps (a) and (b) are in accordance with what is described for the tissue sealing method, and step (c) involves allowing the formation of a three-dimensional matrix and the adhesion of the surfaces. The two surfaces can be held together manually, or through other appropriate means, w the reaction is proceeding in the direction of its conclusion. The reaction is typically sufficiently complete for the occurrence of adhesion within about 5 to 60 minutes after exposure of the composition to the aqueous environment; however, the time required for the complete reaction depends on a number of factors, including the type and molecular weight of each component reagent, the degree of functionality, and the concentration of the components (ie, higher concentrations result in times of faster reaction). At least one between the first and the second surface is preferably a native surface fabric. As used herein, the term "native tissue" refers to a biological tissue that is native to the body of the patient being treated, and is intended to include biological tissues that were elevated or removed from a part of a patient's body for implantation in another part of the body of the same patient (such as bone autografts, skin autografts, etc.). For example, the compositions of the invention can be used to adhere a piece of skin from a patient's body to another part of the body, as in the case of a burn victim. The other surface may be a native tissue surface, a non-native tissue surface, or a surface of a synthetic implant. As used herein, the term "non-native tissue" refers to biological tissues that were removed from the body of a donor patient (which may or may not be of the species of the recipient patient) for implantation in the body of a recipient patient (e.g. , transplants of tissues and organs). For example, the compositions of the invention can be used to adhere the cornea of a donor to the eye of a recipient patient. As used herein, the term "synthetic implant" refers to any biocompatible material that serves the purpose of implantation in the body of a patient not encompassed by the definitions above for native tissues and non-native tissues. Synthetic implants include, for example, artificial blood vessels, coronary valves, artificial organs, bone prostheses, implantable lenses, vascular grafts, extensions and combinations of extensions and grafts, etc. 79. Ophthalmic Applications Due to their optical clarity, the compositions of the invention are particularly well suited for use in ophthalmic applications. See, for example, Margalit et al. (2000) "Bioadesives for Infraocular Use" Retina 20: 469-477. For example, a synthetic lens for vision correction may be affixed to the Bowman's layer of the cornea of a patient's eye using the methods of the present invention. In a manner similar to that which is described in US Pat. No. 5,565,519 issued to Rhee et al. , the compositions can be molded according to the desired lenticular shape, or during or after the formation of the three-dimensional matrix. The resulting collagen lens can then be attached to the Bowman layer of a de-epithelialized cornea of a patient's eye using the methods of the present invention. By applying the composition to the anterior surface of the cornea, then by contacting the anterior surface of the cornea with the posterior surface of the lens before a substantial reaction has occurred, the reactive groups (e.g., the electrophilic groups) The components are also going to be covalently connected to the collagen molecules, both in the cornea tissue and in the lens, to firmly hold the lens in the room. Alternatively, the composition may be applied first to the posterior surface of the lens, which is then brought into contact with the anterior surface of the cornea.

Thus, a further configuration of the invention consists of an ophthalmic repair method of the cornea, wherein steps (a) and (b) are those that were described for the tissue sealing method, and step (c) involves allowing the formation of a three-dimensional matrix and the adhesion of a lens to the cornea. The compositions of the present invention are also suitable for use in vitreous substitution. In addition, the compositions of the present invention can be used for the distribution of active agents. 80. Tissue Augmentation The compositions of the invention can also be used for the augmentation of soft or hard tissues within the body of a mammalian object. As such, they must be better than the collagen-based materials currently marketed for soft tissue augmentation, as they are less immunogenic and more persistent. Examples of soft tissue augmentation applications include increased sphincter (eg, urinary, anal, esophageal) and the treatment of wrinkles and scars. Examples of applications in hard tissue augmentation include repair and / or replacement of bears and / or cartilaginous tissues. In that way, a further configuration of the invention consists of a tissue augmentation method for a preselected room, where the steps (a) and (b) are in accordance with those described for the tissue sealing method, and step (c) involves allowing the formation of a three-dimensional matrix in the preselected location. The compositions are particularly suitable for use as replacement material for synovial fluid in osteoarthritic joints, serving to reduce joint pains and to improve joint function by restoring a soft hydrogel network in the joint. The compositions can also be used as replacement material for the nucleus pulposus of a damaged invertebrate disk. The nucleus pulposus of the damaged disc is removed first, and the composition is then injected or otherwise introduced into the center of the disc. The composition can either be exposed to an aqueous environment prior to the introduction into the disk or be left to inter-react in situ. In a general method for effecting tissue augmentation within the body of a mammalian object, the composition is injected simultaneously with exposure to the aqueous environment, to the location of a tissue in need of augmentation through a small gauge needle (e.g. caliber 25-32). Once inside the patient's body, the reactive groups in the components inter-react one with the other to form a three-dimensional matrix in situ. In addition, in some configurations of the invention, the reactive groups in the components can react with the body tissue to further improve tissue augmentation. For example, some of the electrophilic reactive groups can also react with primary amino groups on lysine residues of the collagen molecules within the patient's own tissue, providing a "biological fixation" of the composition to the host tissue. 81. Prevention of Adhesion Another use of the compositions of the invention is to coat tissues with the aim of preventing the formation of adhesions after surgeries or injuries to internal tissues or organs. Surgical adhesions consist of abnormal and fibrous bands of scar tissue that can be formed inside the body as a result of the healing process that follows any opening or minimally invasive surgical procedure including abdominal, gynecological, cardiothoracic, spinal, plastic, vascular, ENT surgeries. , ophthalmological, urological, neurological, or orthopedic. Surgical adhesions are typically connective tissue structures that form between adjacent wounded areas within the body. In a succinct way, the localized areas of injuries they trigger an inflammatory and healing response that culminates in the healing and formation of a scar tissue. If the scarring results in the formation of bands of fibrous tissue or in the adherence of adjacent anatomical structures (which should be separated), it is said that the formation of a surgical adhesion has occurred. The adhesions can vary from fragile structures, easily separable to dense and tenacious fibrous structures that can only be separated by means of surgical dissection. While many adhesions are benign, some can cause significant clinical problems and are the main causes of repeated surgical intervention. Once the interventions involve a certain degree of trauma to the operative tissues, virtually any procedure (no matter how well done it is performed) has the potential to result in the formation of a clinically meaningful adhesion. The adhesions can be triggered by surgical traumas such as cutting, manipulation, retraction or suture, as well as inflammation, infection (for example, by fungus or mycobacteria), bleeding or the presence of a foreign body. Surgical trauma can also result from tissue drying, ischemia, or thermal injury. Due to the diverse etiology of adhesions Surgical, there is the potential for independent training whether the surgery is done in a manner known as minimally invasive (for example, catheter-based therapies, laparoscopy) or according to a standard open technique involving one or more relatively large incisions. Although a potential complication of any surgery, surgical adhesions are particularly problematic in surgical Gl (causing bowel obstruction), in gynecologic surgery (causing pain and / or infertility), repairs of tendons (resulting in a shortening and flexion deformities), in joint capsule procedures (causing capsular contractures), and in nerve and muscle repair procedures (causing a decrease or loss of function). The placement of medical devices and implants also increases the risk of surgical adhesion occurring. In addition to the mechanisms above, an implanted device can trigger the response of a "foreign body" where the immune system recognizes the implant as foreign and triggers an inflammatory reaction that ultimately leads to the formation of scar tissue. A specific form of foreign body reaction in response to the placement of a medical device is the complete closure ("walling off" or "tissue barrier") of the implant in a capsule of scar tissue (encapsulated). Encapsulating devices that have been implanted and implants can complicate any procedure, but increasing the breast and reconstruction surgery, surgical joint replacement surgery for hernia repair, surgical artificial vascular graft placement extension and neurosurgical they are particularly susceptible to that complication. In each case, the implant is encapsulated by a capsule of fibrous connective tissue that compromises or impairs the functioning of the surgical implants. (for example, breast implant, artificial joint, surgical mesh, vascular graft, extension patch or dural). The adhesions in general begin to form within the first days after the surgery. In general, the formation of adhesion is an inflammatory reaction where factors are released, which increase vascular permeability and result in the influx of fibrinogen and fibrin deposition. That deposit forms a protein matrix that connects the limiting tissues. Fibroblasts accumulate, attach to the protein matrix, deposit collagen and induce angiogenesis. If these cascade effects can be prevented within 4 to 5 days after the surgery is performed, then the adhesion formation can be inhibited.

The compositions of the invention may be used to prevent adhesion formation in a variety of surgical procedures including spinal and neurosurgical procedures (eg, surgical re-open section of a broken lumbar disc or the root of a spinal nerve attached ( laminectomy), disectomies, - and excision of the micro-lumbar disc (microdiscectomy)); gynecological surgical procedures (e.g., hysterectomy, myomectomy, endometriosis, infertility, birth control (such as tubal ligament), sterilization reversal, pain, dysmenorrhea, dysfunctional uterine bleeding, ectopic pregnancy, ovarian tumors, and gynecologic malignancies); abdominal surgical procedures (for example, hernia repair (abdominal, ventral, inguinal, incisional), bowel obstructions, inflammatory bowel disease (ulcerative colitis, Crohn's disease), appendectomy, trauma (perforating lesions, trauma drilling), resection of tumors, infections (abscess, peritonitis), cholecystectomy, gastroplasty (bariatric surgery), esophagus and pyloric restrictions, colostomy, ileostomy diversion, anal-rectal fistulas, hemorrhoidectomies, splenectomy, resection of liver tumors, pancreatitis, perforation of the intestine, bleeding upper and lower Gl, and intestinal ischemia); cardiac surgical procedure (e.g., transplant surgery, vascular repair, coronary artery bypass graft (CABG), congenital heart defects, and valve replacements, assayed procedures and re-operations (particularly repeated CABG surgery)); orthopedic surgical procedures (for example, surgical procedures performed as a result of injury or trauma (for example, fractures (open and closed), torsions, joint displacements, crush injuries, ligament and muscle ruptures, tendon injuries, nerve injuries, congenital deformities and malformations, total or partial replacement of joints and cartilage lesions), and cosmetic or reconstructive surgical procedures (eg, breast augmentation, reconstruction of the breast after surgery for cancer treatment, procedures craniofacial, reconstructions after trauma, congenital craniofacial reconstruction and oculoplastic surgical procedures.) For certain applications, the compositions may include and / or release a therapeutic agent capable of reducing scarring (i.e., a fibrosis inhibiting agent) in a surgical setting , such a omo to prevent or inhibit the formation of postoperative adhesions. Within a Accordingly, the compositions for the prevention of surgical adhesions may include or be adapted to release an agent that inhibits one or more of the five general components of the fibrosis (or healing) process, including: inflammatory responses and inflammation, migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), formation of new blood vessels (angiogenesis), deposit of extracellular matrix (ECM), and remodeling (maturation and organization of fibrous tissue). By the inhibition of one or more components of fibrosis (or scarring), the super growth of scar tissue in a surgical site can be inhibited or reduced. Examples of fibrosis inhibiting agents that can be combined with the compositions present to prevent adhesion formation include the following cell cycle inhibitors (A) anthracyclines (eg, doxorubicin and mitoxantrone), (B) taxanes (eg, paclitaxel, Taxotere and docetaxel), and (C) podophtoxins (eg, etoposide); (D) immunomodulators (eg, sirolimus, everolimus, tacrolimus); (E) heat shock protein 90 antagonists (e.g., geldanamycin, 17-AAG, 17-DMAG); (F) HMGCoA reductase inhibitors (e.g., simvastatin); (G) inhibitors of inosine monophosphate dehydrogenase (for example, mycophenolic acid, l-alpha-25 dihydroxy vitamin D3); (H) inhibitors of NF kapa B (e.g., Bay 11-7082); (I) antifungal agents (e.g., sulconazole) and (J) p38 MAP kinase inhibitors (e.g., SB202190), as well as analogs and derivatives of the above-mentioned. The dose of drug administered from the present compositions for the prevention of surgical adhesion will depend on a variety of factors, including the type of formulation, the location of the treatment and the type of condition being treated; however, certain principles can be applied in the application of that art. The dose of the drug can be calculated as a function of the dosage per unit area (of the treatment site), the total dose of drug administered can be measured and the appropriate surface concentrations of the active component of the drug can be determined. The drugs should be used in concentrations that vary from several times more than up to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in the application of a single systematic dose. In certain aspects, the agent to prevent healing is released from the polymer composition in effective concentrations for a period of time that it can be measured from the moment of infiltration into the tissue adjacent to the device, and varies from about less than 1 day to about 180 days. In general, the release time can also be from close to less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. In one aspect, the drug is released in effective concentrations for a period ranging from 1-90 days. Examples of antifibrosing agents, used alone or in combination, should be administered in accordance with the following dosage directions. The total amount (dose) of agent to prevent healing in the composition can be in the range of about 0.01 μg - 10 μg, or 10 μg - 10 mg, or 10 mg - 250 mg, or 250 mg - 1000 mg, or 1000 mg - 2500 mg. The dose (amount) of agent to prevent healing per unit area of area to which the agent is applied may be in the range of about 0.01 μg / mm2 - 1 μg / ram2, or 1 μg / mm2 - 10 μg / mm2, or 10 μg / mm2 - 250 μg / mm2, 250 μg / mm2 - 1000 μg / mm2, or 1000 μg / mm2 - 2500 μg / mm2. Examples of dosage ranges for various anti-scarring agents that they can be used in combination with compositions for the treatment or prevention of surgical adhesions according to the invention. (A) Cell cycle inhibitors including doxorubicin and mitoxantrone. Doxorubicin and its analogs and derivatives: the total dose should not exceed 25 mg (range 0.1 μg to 25 mg); preferably, 1 μg to 5 mg. Dosage per unit area of 0.01 μg - 100 μg per mm2; preferred dosage of 0.1 μg / mm2 - 10 μg / mm2. Mitoxantrone and its analogs and derivatives: the total dose should not exceed 5 mg (range of 0.01 μg to 5 mg); preferably, 0.1 μg to 1 mg. The dosage per unit area of 0.01 μg - 20 μg per mm2; preferably, a dose of 0.05 μg / mm2 - 3 μg / mm2. (B) Cell cycle inhibitors including paclitaxel and its analogues and derivatives (eg, docetaxel): the total dose should not exceed 10 mg (range 0.1 μg to 10 mg), preferably 1 μg to 3 mg. Dosage per unit area of 0.1 μg - 10 μg per mm2; preferred dosage of 0.25 μg / mm 2 - 5 μg / mm 2. (C) Cell cycle inhibitors such as podophyllotoxins (eg, etoposide): the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 1 μg to 3 mg. Dosage per unit area of 0.1 μg - 10 μg per mm2; preferred dosage of 0.25 μg / mm2 - 5 μg / mm2. (D) Immunomodulators including sirolimus and everolimus. Sirolimus (ie rapamycin, Rapamune): the total dose must not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2; preferred dose of 0.5 μg / mm2 -10 μg / mm2. Everolimus and derivatives and analogues thereof: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg), preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferred dosage of 0.3 μg / mm2 - 10 μg / mm2. (E) Heat shock protein 90 antagonists (e.g., geldanamycin) and its analogues and derivatives: the total dose should not exceed 20 mg (range 0.1 μg to 20 mg), preferably 1 μg a 5 mg. Dosage per unit area of 0.1 μg - 10 μg per mm2; preferred dosage of 0.25 μg / mm2 - 5 μg / mm2. (F) Inhibitors of HMGCoA reductase (eg, simvastatin) and its analogues and derivatives: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg); preferably 10 μg to 300 mg. Dosage per unit area of 1.0 μg - 1000 μg per mm2; preferred dose of 2.5 μg / mm.2 - 500 μg / mm2. (G) Inosine monophosphate dehydrogenase inhibitors (eg, mycophenolic acid, l-alpha-25 dihydroxy vitamin D3) and their analogues and derivatives: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg); preferably 10 μg to 300 mg. Dosage per unit area of 1.0 μg - 1000 μg per mm2; preferred dose of 2.5 μg / mm2 - 500 μg / mm2. (H) Inhibitors of NF kapa B (eg, Bay 11-7082) and its analogues and derivatives: the total dose should not exceed 200 mg (range of 1.0 μg to 200 mg); preferably 1 μg to 50 mg. Dosage per unit area of 1.0 μg - 100 μg per mm2; preferred dose of 2.5 μg / mm2 -50 μg / mm2. (I) Antifungal agents (e.g., sulconazole) and analogs and derivatives thereof: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg); preferably 10 μg to 300 mg. Dosage per unit area of 1.0 μg - 1000 μg per mm2; preferred dosage of 2.5 μg / mm2 - 500 μg / mm2 and (J) 38 MAP kinase inhibitors (eg, SB202190) and their analogues and derivatives: the total dose should not exceed 2000 mg (range of 10.0 μg to 2000 mg), preferably 10 μg to 300 mg. Dosage per unit area of 1.0 μg - 1000 μg per mm2; preferred dose of 2.5 μg / mm2 - 500 μg / mm2. In a method for coating tissues to prevent adhesion formation after surgery, the composition is exposed to an aqueous environment and a thin layer of the composition is then applied to the tissues comprising, involving and / or adjacent to the surgical site before the occurrence of a substantial reaction. The application of the composition to the tissue location can be done by extrusion, scrubbing, spraying (as described above), or by any other means convenient. In that way, the invention also relates to a method for preventing adhesions between the tissues of a patient, wherein steps (a) and (b) are in accordance with what was described for the tissue sealing method, and step (c) involves allowing the formation of a three-dimensional matrix on the tissue, and thereby preventing adhesion of the tissue. After the application of the composition to the surgery site, the inter-reaction is allowed to continue in situ before the closure of the surgical incision. Once the reaction has reached its equilibrium, the tissues that are placed in contact with the coated tissues will not adhere. The surgery site can then be closed using conventional means such as sutures, and so on. In general, compositions that achieve complete interreaction within a relatively short period of time (ie, 5-15 minutes after exposure of the multifunctional compounds to the modified environment) are preferred for use in the prevention of surgical adhesions, since that the local surgery can be closed relatively soon after the conclusion of the surgical procedure. Certain surgical procedures may involve the placement of a medical device or an implant in the location of the surgery, in which case it may be desirable to apply the composition (with or without a therapeutic agent) to the surface of the implant, to the surface of the implant-tissue interface, and / or to the tissue in the vicinity of the implanted device for minimize the formation of postoperative surgical additions, unwanted scarring in the vicinity of the implant and encapsulation of the implant by a capsule of fibrous connective tissue. For the prevention of adhesions in spinal and neurosurgical procedures, the compositions themselves or loaded with a therapeutic agent (for example, a fibrosis inhibiting agent) can be applied to the surface of the tissue in the spinal or neurosurgical room or to the surface of a implanted device (eg, dural patches, spinal prostheses, artificial discs, canes, bone fixation devices (eg, anchor plates and bone screws), injectable fillers or volume forming agents for discs, spinal grafts, core implants spinal, intervertebral disc spacers, fusion structures, or implants placed in the brain, such as drains, shunts, drug-feeding pumps, or neuro-stimulation devices) and / or the tissue involving the implant before, during, or after the surgical procedure.

For the prevention of adhesions associated with gynecological procedures, the compositions themselves or loaded with a therapeutic agent (for example, a fibrosis inhibiting agent) can be applied during gynecological endoscopic or open surgical procedures to the surface tissue of the pelvic side wall, adnexa, uterus and any adjacent tissues affected during the surgical procedure or to the surface of an implanted device or to an implant (eg, genital-urinary tracts, bulking agents, sterilization devices (eg, valves, clips and staples) and tubal occlusion implants and tampons) and / or tissue that involves the implant before, during or after the surgical procedure. For the prevention of adhesions associated with abdominal surgical procedures, the compositions themselves or loaded with a therapeutic agent (for example, a fibrosis inhibiting agent) can be applied during open, endoscopic, or abdominal laparoscopic surgeries to the cavity surface tissue. peritoneal, visceral peritoneum, abdominal organs, abdominal wall and any adjacent tissue affected during the surgical procedure or to the surface of an implanted device or implant and / or tissue that involves the implant before, during, or after the surgical procedure. Representative examples of implants for use in abdominal procedures include, but are not limited to, hernia mesh, obesity restriction devices, implantable sensors, implantable pumps, peritoneal dialysis catheters, peritoneal drug delivery catheters, Gl tubes. (gastrointestinal) for drainage or feeding, porto-systematic detours, deviation for ascites, gastrostomy or percutaneous feeding tubes, endoscopic jejunostomy tubes, colostomy devices, drainage tubes, bile "T" tubes, hemostatic implants, inter-feeding devices , colonic and biliary extensions, low profile devices, gastric bandage implants, capsule endoscopes, anti-reflux devices and extensions of the esophagus. For the prevention of adhesions associated with cardiac surgical procedures, the compositions themselves or loaded with a therapeutic agent (for example, a fibrosis inhibiting agent) can be applied during open or endoscopic cardiac surgeries to the surface tissue of the pericardium (or infiltrated at the inside of the pericardial sac), heart, large vessels, pleura, lungs, pectoral wall and any adjacent tissues affected during the surgical procedure or to the surface of an implanted device or implant and / or to the tissue that involves the implant before, during, or after the surgical procedure. Representative examples of implants for use in cardiac procedures include, but are not limited to, heart valves (porcine, artificial), ventricular assist devices, heart pumps, artificial hearts, extensions, bypass grafts (artificial and endogenous), patches, terminals cardiac, defibrillators and pacemakers. For the prevention of adhesions associated with orthopedic surgical procedures, the compositions themselves or loaded with a therapeutic agent (for example, a fibrosis inhibiting agent) can be applied during open or arthroscopic orthopedic surgeries to the bone surface tissue, to the joint , muscle, tendon, ligaments, cartilage and any adjacent tissue that has been affected during the surgical procedure or to the surface of an implanted orthopedic device or implant and / or tissue that involves the implant before, during, or after of the surgical procedure. Representative examples of implants for use in orthopedic procedures include plaques, rods, screws, pins, threads, total and partial prostheses of joints (artificial hips, knees, shoulders, phalanx joints), reinforcement patches, tissue fillings, fillings of synthetic bones, bone cements, synthetic graft material, allograft material, autograft material, artificial discs, spinal structures and intermedullary stems. For the prevention of adhesions associated with cosmetic or reconstructive surgical procedures, the compositions themselves or loaded with a therapeutic agent (for example, a fibrosis inhibiting agent) can be applied during open or endoscopic cosmetic surgeries to the implant surface of the tissue soft before, during or after the implantation procedure or to the tissue surface of the implantation pocket immediately before or during implantation of the soft tissue implant. Representative examples of soft tissue implants for use in cosmetic, plastic and reconstructive surgical procedures include implants of the face, nose, breast, chin, buttocks, chest, lips and cheek. or to the surface of the soft tissue implant and / or to the tissue that involves the implant before, during or after the implantation of the soft tissue implant. 82. Implants and Coating Materials for Implants The compositions of the invention can also be formed as a solid implant, a term that is used herein to refer to any solid object that is projected for insertion and use within the body, and includes bone and cartilage implants (for example, artificial joints, retaining pins, cranial plates, and so on, made of metal, plastic and / or other material), implants breast (for example, silicone gel envelopes, foam molds, and so on), catheters and cannulae for long-term use (in addition to about three days) in the premises, organs and artificial vessels (for example, hearts , pancreas, kidneys, artificial blood vessels, and so on), devices for the distribution of drugs (including monolithic implants, pumps and controlled release devices, such as Alzet® mini-pumps (DURECT Corporation, Cupertino, California, USA) , steroid paddles for anabolic growth or contraception, and so on), sutures for dermal or internal use, periodontal membranes, ophthalmic barriers, corneal lenses, and so on. Another use of the compositions is as a coating material for an implant (for example, synthetic implants). 83. Medical Implants Combined with Fibrosing Agents In one aspect, medical implants may contain and / or are adapted to release an agent that induces or promotes adhesion between the implant and the tissue or a reaction fibrotic The clinical performance of numerous medical devices can be improved by anchoring the device in an effective manner in the neighboring tissue or to provide structural support or to facilitate healing and healing. The effective fixation of the device in the neighboring tissue, however, is not always obtained immediately. One reason for ineffective fixation is that implantable medical devices are generally composed of materials that are highly biocompatible and designed to reduce the response of the host tissue. These materials (eg, stainless steel, titanium based alloys, fluoropolymers and ceramics) typically do not provide a good substrate for the binding of host tissue and internal growth during the healing process. As a result of poor fixation between the device and the host tissue, the devices may have a tendency to migrate into the vessel or tissue where they are implanted. The extent to which a particular type of medical device can move or migrate after implantation depends on a variety of factors including the type and design of the device, the material (s) from (the) which (them) the device is formed, the mechanical attributes (for example, flexibility and ability to conform to the geometry of the neighborhood in the implantation site), the properties of the surface and the porosity of the device or the surface of the device. The tendency of a device to loosen after implantation also depends on the type of tissue and the geometry in the treatment room, where the ability of the tissue to conform around the device can generally help to hold the device in the implantation site. . The migration of the device can result in the failure of the device and, depending on the type and location of the device, can lead to leakage, vessel occlusion, and / or damage to neighboring tissue. The incorporation of a fibrosis inducing agent with the compositions of the invention can provide an effective, long-lasting and biocompatible method for anchoring implantable medical devices inside or on a biological tissue. In certain configurations, the medical implant, when placed inside a tissue, releases an agent that induces or promotes adhesion between the implant and the tissue or the fibrotic reaction. In other configurations, the medical implant contains or is made of a fibrosing agent, but does not release the fibrosing agent. In such configurations, the fibrosing agent contained in the medical implant induces or promotes fibrosis by the Direct contact of the agent with the tissue where the implant is placed. Alternatively, or in addition, the tissue cavity within which the device or implant is placed may be treated with a fibrosis inducing agent before, during or after the implantation procedure. This can be obtained, for example, through the topical application of the composition comprising a fibrosing agent or by spraying the composition into the anatomical space where the device can be placed or at the interface between the implant and the surface of the implant. tissue. Representative examples of medical implants of particular utility for use in combination with a fibrotic inducing agent include, but are not limited to, orthopedic implants (joints, ligaments and artificial tendons, screws, plates, and other implantable parts), dental implants, intravascular implants (particularly arterial and venous occlusion devices and implants, destructive vascular implants), male and female contraceptives or sterilization devices and implants, soft palate implants, embolization devices, surgical meshes (eg, mesh for hernia repair) , tissue scaffolds), fistula treatments, spinal implants (e.g., artificial intervertebral discs, extension grafts, spinal fusion devices, etc.). As medical implants are made in a variety of configurations and sizes, the exact dose administered may vary with the amount injected or with the size of the device, the surface area and the project; however, certain principles can be applied in the application of that art. The dose of the drug can be calculated as a function of the dosage per unit area (of the fraction of the device being coated), the total drug dose administered can be measured, and the appropriate concentrations of the active component on the surface can be measured. be determined It should be readily apparent to a person skilled in the art that any one of the fibrosis inducing agents described above or derivatives or analogs thereof may be used with the present compositions without deviating from the spirit and scope of the invention. Regardless of the method of application of the drug to the implant, examples of fibrosing agents, used separately or in combination, should be administered in accordance with the following dosage directions: Using talc as an example of a fibrosis inducing agent, the total amount of talc distributed to an implant or coated on the surface of an implant must not exceed 100 mg (range of 1 μg to 100 mg). In one configuration, the total amount of talc released from the implant should be in the range of 10 μg to 50 mg. The dosage per unit area of the device (ie, the dosage of talc as a function of the surface area of the portion of the device to which the drug is applied and / or incorporated) should be within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In another configuration, the talc should be applied to the surface of an implant according to a dosage of 0.05 μg / mm2 - 10 μg / mm2 of coated surface area. Using silk as an example of fibrosis-inducing agent, the total amount of silk distributed from an implant or coated on the surface of an implant should not exceed 100 mg (range of 1 μg to 100 mg). In one configuration, the total amount of silk released from the prosthesis should be in the range of 10 μg to 50 mg. The dosage per unit area of the device (i.e., the dosage of silk as a function of the surface area of the portion of the device to which the drug is applied and / or incorporated) should be within the range of 0.05 μg - 10 μg per mm2 of coated surface area.

In another configuration, the silk must be applied to an implant according to a dosage of 0.05 μg / mm2 - 10 μg / mm2 of coated surface area. Using chitosan as an example of fibrosis inducing agent, the total amount of chitosan distributed from an implant or coated on the surface of an implant, should not exceed 100 mg (range of 1 μg to 100 mg). In one configuration, the total amount of chitosan distributed from one implant should be in the range of 10 μg to 50 mg. The dosage per unit area of the device (ie, the dosage of chitosan as a function of the surface area of the portion of the device to which the drug is applied and / or incorporated) should be within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In another configuration, the chitosan must be applied to the surface of an implant according to a dosage of 0.05 μg / mm2 - 10 μg / mm2 of coated surface area. Using polylysine as an example of a fibrotic inducing agent, the total amount of polylysine distributed from an implant or coated on the surface of an implant should not exceed 100 mg (range of 1 μg to 100 mg). In one configuration, the total amount of polylysine released from an implant should be in the range of 10 μg to 50 mg. The dosage per unit area of the device (ie the dosage of polylysine as a function of the surface area of the portion of the device to which the drug is applied and / or incorporated) should be within the range of 0.05 μg - 10 μg per mm 2 of coated surface area. In a further configuration, the polylysine must be applied to an implant surface in a dosage of 0.05 μg / mm2 - 10 μg / mm2 of coated surface area. Using fibronectin as an example of fibrotic inducing agent, the total amount of fibronectin distributed from an implant or coated on the surface of an implant, should not exceed 100 mg (range of 1 μg to 100 mg). In one configuration, the total amount of fibronectin released from the prosthesis should be in the range of 10 μg to 50 mg. The dosage per unit area of the device (i.e., the dosage of fibronectin as a function of the surface area of the portion of the device to which the drug is applied and / or incorporated) should be within the range of 0.05 μg - 10 μg per mm2 of coated surface area. In a further configuration, the talc should be applied to an implant surface according to a dosage of 0.05 μg / mm2 - 10 μg / mm2 of coated surface area. Using bleomycin as an example of a fibrosis-inducing agent, the total amount of bleomycin distributed from an implant, or coated on the surface of a implant, must not exceed 100 mg (range of 0.01 μg to 100 mg). In one configuration, the total amount of bleomycin released from the implant should be in the range of 0.10 μg to 50 mg. The dosage per unit area of the device (ie, the dosage of bleomycin as a function of the surface area of the portion of the device to which the drug is applied and / or incorporated) should be within the range of 0.005 μg - 10 μg per mm2 of coated surface area. In another configuration, bleomycin should be applied to an implant surface according to a dosage of 0.005 μg / mm2 - 10 μg / mm2 of coated surface area. In one configuration, bleomycin is released from the surface of an implant such that fibrosis in the tissue is promoted for a period ranging from several hours to several months.

Using CTGF as an example of fibrotic inducing agent, the total amount of CTGF distributed from an implant or coated on the surface of an implant should not exceed 100 mg (range 0.01 μg to 100 mg). In one configuration, the total amount of CTGF released from the implant should be in the range of 0.10 μg to 50 mg. The dosage per unit area of the device (i.e., the dosage of CTGF as a function of the surface area of the portion of the device to which the drug is applied and / or incorporated) should be within the range from 0.005 μg - 10 μg per mm2 of coated surface area. In a further configuration, the CTGF must be applied to an implant surface according to a dosage of 0.005 μg / mm2 - 10 μg / mm2 of coated surface area. The fibrosing agent (eg, talc, silk, chitosan, polylysine, fibronectin, bleomycin, CTGF) can be released from the surface of the implant so that fibrosis in the tissue is promoted for a period ranging from several hours to several months. . For example, the fibrosing agent can be released in effective concentrations for a period ranging from 1 hour to 30 days. It should be immediately apparent that considering the discussions provided herein, analogues and derivatives of the fibrosing agent (for example, analogues and derivatives of talc, silk, chitosan, polylysine, fibronectin, bleomycin, CTGF, according to those previously described) with similar functional activity they can be used for the purposes of that invention; the dosing parameters above are then adjusted according to the relative potency of the analog or derivative as compared to the parent compound (for example, a compound twice as potent as the agent is administered according to half of the parameters above, a compound with half of the power of the agent is administered twice in relation to the parameters above, etc. ). As described above, the device may additionally comprise an inflammatory cytokine (eg, TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-α, IL-1, IL-1β, IL-8). , IL-6, and growth hormone) and / or a bone morphogenic protein (BMP) (eg, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or a analogue or derivative thereof). Morphogenic bone (s) protein (s) (eg, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7) or an analogue or derivative thereof the same) should be used in formulations in concentrations ranging from 0.001 μg / ml to about 20 mg / ml depending on the specific clinical application, the type of formulation (eg gel, liquid, solid). , semi-solid), the chemistry of the formulation, the duration required for the application, the type of interface of the medical device and the volume of the formulation and / or the coverage of the required surface area. Preferably, the bone morphogenic protein is released in effective concentrations for a period ranging from 1 - 180 days. The total dosage for a single application is typically such that it does not exceed 500 mg (range of 0.001 μg to 500 mg), preferably 1 μg to 250 mg. When used as a coating device, the dosage is given per unit area of 0.001 μg - 1000 μg per mm2; with a preferred dosage of 0.01 μg / mm2 -200 μg / mm2. The minimum concentration of 10-9 - 10-4 M bone morphogenic protein must be maintained on the surface of the device. Inflammatory cytokines should be used in formulations in concentrations ranging from 0.0001 μg / ml to about 20 mg / ml depending on the specific clinical application, the type of formulation (eg, gel, liquid, solid, semi-solid). solid), the chemistry of the formulation, the duration required for the application, the type of interface of the medical device and the volume of the formulation and / or coverage of the required surface area. Preferably, the inflammatory cytokine is released in effective concentrations for a period ranging from 1 - 180 days. A total dosage for a single application is typically such that it does not exceed 500 mg (range of 0.0001 μg to 100 mg); preferably 0.001 μg to 50 mg. When used as a coating device, the dosage is given per unit area of 0.0001 μg - 500 μg per mm2; with a preferred dosage of 0.001 μg / mm2 - 200 μg / mm2. The minimum concentration of 10-10 - 10-4 g / ml of inflammatory cytokine should be maintained on the surface of the device.

In addition to that, the device can by itself or additionally comprise an agent that stimulates cell proliferation. Examples include: dexamethasone, isotretinoin (13-cis retinoic acid), 17-ß-estradiol, estradiol, l-ct-25 dihydroxyvitamin D3, diethylstilbestrol, cyclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analogs and derivatives thereof same. The doses used are those concentrations that demonstrate to stimulate cell proliferation. The proliferating agents should be used in the formulations in concentrations ranging from 0.1 ng / ml to 25 mg / ml depending on the specific clinical application, the type of formulation, the chemistry of the formulation, the duration required for the formulation. application, the type of interface of the medical device and the volume of the formulation and / or coverage of the required surface area. Preferably, the proliferating agent is released in effective concentrations for a period ranging from 1 - 180 days. The total dosage for a single application is typically such that it does not exceed 500 mg (range from 0.0001 μg to 200 mg); preferably 0.001 μg to 100 mg. When used as a coating device, the dosage is given per unit area of 0.00001 μg - 500 μg per mm2; with a preferred dosage of 0.0001 μg / mm2 - 200 μg / mm2. The minimum concentration of 10-11 - 10-6 M of Proliferative agent must be maintained on the surface of the device. 84. Medical Implants Combined with a Fibrosis Inhibiting Agent In another aspect, medical implants may be coated with, or otherwise adapted to, release or incorporate an agent that inhibits the formation of a reactive healing tissue on or around the surface of the device or implant. Compositions that include a fibrosis inhibiting agent can be used in combination with a variety of medical implants to make them resistant to supergrowth in the implantation of inflammatory and fibrous scar tissue. The compositions and methods are described for coating by medical devices and implants with drug delivery compositions such that the pharmaceutical agent is distributed at therapeutic levels over a period of time sufficient to allow the occurrence of a normal cure. With implantation, overgrowth of scar tissue can occur around all or parts of the implant, which can lead to a reduction in the performance of those devices. In certain cases, an implanted device may be combined with a therapeutic agent (e.g., an antifibrotic agent) to minimize the formation of postoperative surgical adhesions, unwanted scarring in the vicinity of the implant and the encapsulation of the implant by a capsule of fibrous connective tissue. Examples of medical devices of particular utility for use in combination with a fibrosis inhibiting agent include, but are not restricted to, vascular extensions, gastrointestinal tracts, extensions of the trachea / bronchi, genital-urinary extensions, ENT extensions, infraocular lenses, implants for hypertrophic scars and keloids, vascular grafts, anastomotic connectors, barriers to surgical adhesion, glaucoma drainage devices, films or meshes, prosthetic coronary valves, tympanostomy tubes, penile implants, endotracheal and tracheotomy tubes, catheters for peritoneal dialysis, intracranial pressure monitors, vena cava filters, central venous catheters, ventricular assist devices (for example, LVAD's), spinal prostheses and gastrointestinal drainage tubes. In one aspect, the medical device can be an electrical device (e.g., a device that has electrical components that can be placed in contact with tissue in an animal host and can provide electrical excitation to netissues or muscle). Electrical devices can generate electrical impulses and can be used to treat many body dysfunctions and disorders by blocking, masking or stimulating electrical signals inside the body. Electrical medical devices of particular utility in the present invention include, but are not restricted to, devices used in the treatment of heart rhythm abnormalities, in the release of pain, in epilepsy, together with Parkinson's Disease, in disorders of movement, in obesity, in depression, in anxiety and in hearing loss. Other examples of electrical devices include neuro-stimulation and neuro-stimulation devices (eg, electrical devices for electrical excitation of the central, autonomic or peripheral nervous system), cardiac stimulation device such as heart rate management devices, defibrillators implantable cardiac (ICD - Implantable Cardiac Defibrillators) and other electrical devices for electrical excitation of cardiac muscle tissue (including the specialized cardiac muscle cells that make up the conductive pathways of the heart). Electrical devices also include electrical terminals that are used as a conductor to conduct electrical signals from the generator to the tissues. He Electrical terminal can be a wire or other material that transmits electrical impulses from a generator (for example, a pacemaker, a defibrillator, or another neuro-stimulator). The electrical terminals can be unipolar, in which case they are adapted to provide effective therapy with only one electrode. Multipolar terminals are also available, including bipolar, tripolar and quadrupole terminals. In another aspect, the medical device may be an implantable sensor (i.e., a medical device that is implanted in the body to detect the levels of a particular chemical in the blood or in tissues (eg, glucose, electrolytes, drugs , hormones) and / or changes in body chemistry, metabolites, functioning, pressure, flow, physical structure, electrical activity or another variable parameter). Representative examples of implantable sensors include, blood / tissue glucose monitors, electrolyte sensors, blood constituent sensors, temperature sensors, pH sensors, optical sensors, amperage sensors, pressure sensors, biosensors, sensors transponders, voltage sensors, activity sensors and magnetoresistive sensors.

In another aspect, the medical device can be a pump for drug delivery (i.e., a medical device that includes a pump that is configured to deliver a biologically active agent (eg, a drug) at a regulated dose). These devices are implanted within the body and can include an external transmitter for programming the controlled release of the drug, or alternatively, they can include an implantable sensor that delivers the trigger for the drug delivery pump to release the drug according to the demands physiological Drug distribution pumps can be used to distribute virtually any agent, but specific examples include insulin for the treatment of diabetes, pain relief drugs, chemotherapy for the treatment of cancer, antispasmodic agents for the treatment of muscle disorders and of movement, or antibiotics for the treatment of infections. Representative examples of pumps for the distribution of drugs for use in the practice of the invention include, without limitation, drug pumps with constant flow, programmable pumps for the distribution of drugs, intrathecal pumps, implantable pumps for the distribution of insulin, osmotic pumps. implantables, pumps and implants for distribution of eye drugs, dosing systems, peristaltic pumps (bearing), pumps with electric drive, elastomeric pumps, spring-loaded contraction pumps, gas-driven pumps (for example, induced by electrolytic cell or chemical reaction), hydraulic pumps, pumps piston-dependent and independent piston pumps, dosing chambers, infusion pumps, passive pumps, infusion pumps and fluid dosers by osmotic drive. In another aspect, the medical device may be a soft tissue implant. Soft tissue implants consist of medical devices that may include a volume replacement material for augmentation or reconstruction, to replace all or part of a living structure. Soft tissue implants are used for the reconstruction of tissue voids that were created surgically or by trauma, for the augmentation of tissues or organs, for tissue contouring, for the restoration of volume to aging tissues, and for the correction of soft tissue folds or wrinkles (wrinkles). Soft tissue implants can be used for tissue augmentation for cosmetic improvements (aesthetics) or in association with reconstructive surgery after a disease or a surgical resection. Representative examples of implants soft tissues include breast implants, chin implants, tummy belly implants, cheek implants and other facial implants, buttock implants and nasal implants. Soft tissue implants that release a therapeutic agent for reducing scarring at the implant-tissue interface can be used to improve appearance, increase longevity, reduce the need for correction surgeries or repeat procedures, decrease incidence of pain and other symptoms, and improve the clinical function of an implant. Correspondingly, the present invention contemplates soft tissue implants that are coated or otherwise incorporate an agent to prevent scarring or a composition that includes an agent to prevent scarring. In accordance with the present invention, any fibrosis inhibiting agent described above can be used in the practice of that configuration. Within a configuration of the invention, medical implants can be adapted to deliver an agent that inhibits one or more of the four general components of the fibrosis process. (or scarring), including: the formation of new blood vessels (angiogenesis), the migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), extracellular matrix deposition (ECM), and remodeling (maturation and organization of fibrous tissue). By the inhibition of one or more of the components of fibrosis (or scarring), the supergrowth of the granulation tissue can be inhibited or reduced. Several examples of agents for use with medical implants include the following: cell cycle inhibitors including (A) anthracyclines (eg, doxorubicins and mitoxantrone), (B) taxanes (eg, paclitaxel, Taxotere and docetaxel), and (C) podophyllotoxins (eg, etoposide); (D) immunomodulators (eg, sirolimus, everolimus, tacrolimus); (E) heat shock protein 90 antagonists (e.g., geldanamycin), - (F) HMGCoA reductase inhibitors (e.g., simvastatin); (G) inosine monophosphate dehydrogenase inhibitors (e.g., mycophenolic acid, l-alpha-25 dihydroxy vitamin D3); (H) NF kapa B inhibitors (e.g., Bay 11-7082); (I) antifungal agents (e.g., sulconazole), (J) p38 MAP kinase inhibitors (e.g., SB202190), and (K) angiogenesis inhibitor (e.g., halofuginone bromide), as well as analogues and derivatives of those mentioned above. Regardless of the method of application of the drug to the device, examples of anti-fibrosing agent, used by themselves or in combination, must be administered in accordance with the following dosage guidelines. The total amount (dose) of agent to prevent scarring in or on the device may be in the range of about 0.01 μg - 10 μg, or 10 μg - 10 mg, or 10 mg - 250 mg, or 250 mg - 1000 mg, or 1000 mg - 2500 mg. The dose (amount) of anti-scarring agent per unit surface area of the device to which the agent is applied may be in the range of about 0.01 μg / mm2 - 1 μg / mm2, or 1 μg / mm2 - 10 μg / mm2, or 10 μg / mm2 - 250 μg / mm2, 250 μg / mm.2 - 1000 μg / mm2, or 1000 μg / mm2 - 2500 μg / mm2. Medical implants are made in a variety of configurations and sizes, the exact doses administered will vary with device size, surface area and design; however, certain principles can be applied in the application of that art. The drug dose can be calculated as a function of the dosage per unit area (of the portion of the device being coated), the total drug dose administered and the appropriate surface concentrations of the active component of the drug can be determined. Drugs should be used in concentrations ranging from several times more to 10%, 5%, or even less than 1% of the concentration typically used in the application of a single dose Systemic chemotherapy. Preferably, the drug is released in effective concentrations for a period ranging from 1-90 days. Below are given examples of ranges of dosages for various healing prevention agents that can be used in conjunction with medical implants according to the invention. A) cell cycle inhibitors including doxorubicin and mitoxantrone. Doxorubicin and its analogs and derivatives: the total dose should not exceed 25 mg (range 0.1 μg to 25 mg); preferably 1 μg to 5 mg. Dosage per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg / mm2 - 10 μg / mm2. Mitoxantrone and its analogs and derivatives: the total dose should not exceed 5 mg (range of 0.01 μg to 5 mg), preferably 0.1 μg to 1 mg. Dosage per unit area or device of 0.01 μg - 20 μg per mm2; preferred dose of 0.05 μg / mm2 - 3 μg / mm2. B) cell cycle inhibitors including paclitaxel and its analogs and derivatives (eg, docetaxel): the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 1 μg to 3 mg. Dosage per unit area of the device from 0.1 μg - 10 μg per mm2; preferred dose of 0.25 μg / mm2 - 5 μg / mm2. (C) cell cycle inhibitors such as podophyllotoxins (eg, etoposide): the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); from Preference 1 μg to 3 mg. The dosage per unit area of the device from 0.1 μg - 10 μg per mm2; preferred dose of 0.25 μg / mm2 - 5 μg / mm2. (D) Immunomodulators including sirolimus and everolimus. Sirolimus (ie, rapamycin, Rapamune): the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. The dosage per unit area of 0.1 μg - 100 μg per mm2; preferred dose of 0.5 μg / mm2 - 10 μg / mm2. Everolimus and its derivatives and analogues: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. The dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferred dose of 0.3 μg / mm2 - 10 μg / mm2. (E) Heat shock protein 90 antagonists (e.g., geldanamycin) and its analogues and derivatives: the total dose should not exceed 20 mg (range 0.1 μg to 20 mg); preferably 1 μg to 5 mg. The dosage per unit area of the device from 0.1 μg - 10 μg per mm2; preferred dose of 0.25 μg / mm2 - 5 μg / mm2. (F) HMGCoA reductase inhibitors (eg, simvastatin) and its analogues and derivatives: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg); preferably 10 μg to 300 mg. Dosage per unit area of the device from 1.0 μg - 1000 μg per mm2; preferred dose of 2.5 μg / mm2 - 500 μg / mm2. (G) Inosine monophosphate dehydrogenase inhibitors (e.g., mycophenolic acid, l-alpha-25 dihydroxy vitamin D3) and its analogues and derivatives: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg); preferably 10 μg to 300 mg. Dosage per unit area of the device from 1.0 μg - 1000 μg per mm2; Preferential dose of 2.5 μg / mm2 - 500 μg / mm2. (H) inhibitors of NF kapa B (eg, Bay 11-7082) and its analogues and derivatives: the total dose should not exceed 200 mg (range of 1.0 μg to 200 mg); preferably 1 μg to 50 mg. The dosage per unit area of the device of 1.0 μg - 100 μg per mm2; preferred dose of 2.5 μg / mm2 - 50 μg / mm2. (I) Antifungal agents (eg, sulconazole) and their analogues and derivatives: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg); preferably 10 μg to 300 mg. The dosage per unit area of the device of 1.0 μg - 1000 μg per mm2; preferred dose of 2.5 μg / mm2 - 500 μg / mm2. (J) inhibitors of p38 MAP kinase (eg, SB202190) and its analogs and derivatives: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg); preferably 10 μg to 300 mg. Dosage per unit area of the device from 1.0 μg - 1000 μg per mm2; preferred dose of 2.5 μg / mm.2 - 500 μg / mm2. (K) Antiangiogenic agents (for example, halofuginone bromide) and its analogs and derivatives: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 1 μg to 3 mg.

Dosage per unit area of the device from 0.1 μg -10 μg per mm2; preferred dose of 0.25 μg / mm2 - 5 μg / mm2. In addition to those described above (eg, sirolimus, everolimus, and tacrolimus), several other examples of immunomodulators and dosage ranges suitable for use with medical implants include the following: (A) Biolimus and derivatives and analogs thereof: total dose should not exceed 10 mg (range from 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferably a dose of 0.3 μg / mm2 - 10 μg / mm2. (B) Tresperimus and its derivatives and analogues: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferably a dose of 0.3 μg / mm2 - 10 μg / mm2. (C) Auranofin and its derivatives and analogues: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferably a dose of 0.3 μg / mm2 - 10 μg / mm2. (D) 27-0- Demethylrapamycin and its derivatives and analogues: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area 0.1 μg - 100 μg per mm2 of surface area; preferably a dose of 0.3 μg / mm2 - 10 μg / mm.2. (E) Gusperimus and its derivatives and analogues: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferably a dose of 0.3 μg / mm2 - 10 μg / mm2. (F) Pimecrolimus and its derivatives and analogues: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferably a dose of 0.3 μg / mm2 - 10 μg / mm.2. E (G) ABT-578 and its analogues and derivatives: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg); preferably 10 μg to 1 mg. Dosage per unit area of 0.1 μg - 100 μg per mm2 of surface area; preferably a dose of 0.3 μg / mm2 - 10 μg / mm2. In a general method for coating a surface of a synthetic implant, the composition is exposed to an aqueous environment, and a thin layer of the composition is then applied to a surface of the implant prior to the occurrence of a substantial inter-reaction. In one configuration, with the aim of minimize the cellular and fibrous reaction with the coated implant, the components are selected so as to result in a matrix having a neutral charge. The application of the composition to the surface of the implant can be done by extrusion, scrubbing, spraying (as described above), or by any other convenient means. Following the application of the composition to the surface of the implant, the inter-reaction is allowed to continue until its conclusion and the three-dimensional matrix has been formed. Although that method can be used to coat the surface of any type of synthetic implant, it is particularly useful for implants where reduced thrombogenicity is an important consideration, such as in artificial blood vessels and heart valves, vascular grafts, vascular extensions and combinations of extension and grafting. The method can also be used to coat implantable surgical membranes (e.g., monofilament polypropylene) or meshes (e.g., for use in hernia repairs). Breast implants can also be coated using the method above with the goal of minimizing capsular contracture. The compositions of the invention can also be coated with a suitable fibrous material, which can be Then wrap a bone to provide structural integrity to the bone. The term "suitable fibrous material" as used herein refers to a fibrous material that is substantially insoluble in water, is non-immunogenic, biocompatible and immiscible with the compositions of the invention capable of crosslinking. The fibrous material may comprise any one of a variety of materials possessing those characteristics and may be combined with the compositions capable of cross-linking herein for the purpose of forming and / or providing structural integrity to various implants or devices used in connection with uses. doctors and pharmacists. The compositions of the present invention can also be used to coat lenses, which are made from naturally occurring polymers or from synthetic polymers. 85. Treatment of Aneurysm The compositions can be extruded or molded in the form of a thread or a spiral, then dehydrated. The resulting dehydrated thread or coil can be distributed through a catheter to the site of a poor vascular formation, such as an aneurysm, for purposes of vascular occlusion and, finally, to repair the malformation. The dehydrated thread or spiral can be distributed in size compact and will rehydrate within the blood vessel, swelling in size several times compared to its dehydrated state, while maintaining its original shape. In that way, a further configuration of the invention consists of a method for treating an aneurysm, wherein steps (a) and (b) are in accordance with what was described for the tissue sealing method, and step (c) involves allowing the formation of a three-dimensional matrix with the desired shape, being distributed to the place of interest and allowing the matrix to rehydrate in situ. 86. Other Uses As discussed in US Pat. No. 5,752,974 issued to Rhee et al. , the compositions can be used to block or fill several lumens and voids in the body of a mammalian object. The compositions can also be used as a sealant bio-agent to seal fissures or grooves within a tissue or structure (such as a vessel), or junctions between adjacent tissues or structures, to prevent the leakage of blood or other biological fluid. . The compositions can also be used to seal or close a fistula, where a healing promoting agent or sclerosing agent, e.g., silk, can be included in the composition to promote tissue closure.

The compositions can also be used as a great device for filling spaces for the displacement of organs in a body cavity during surgical or radiation procedures, for example, to protect the intestines during a planned radiation course for the pelvis. The compositions can also be coated on the inner surface of a physiological lumen, such as a blood vessel or a fallopian tube, thereby serving as a sealing agent to prevent restenosis of the lumen after medical treatment, such as, for example, balloon catheterization removes deposits of arterial plaque from the interior surface of a blood vessel, or removal of scar tissue or endometrial tissue from inside a fallopian tube. A thin layer of the composition is preferably applied to the inner surface of the vessel (eg, via a catheter) immediately after exposure to the aqueous environment. Once the compositions of the invention are not immediately degradable in vivo, the potential for restenosis due to degradation of the coating is minimized. The use of a three-dimensional matrix that has a neutral liquid charge further minimizes the potential for restenosis. Experimental The following examples are set forth to provide those with ordinary skill in the art a complete disclosure and description of how to make and use the compounds of the invention, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts were made to ensure accuracy in relation to numbers (for example, quantities, temperature, etc.) but some errors and deviations must be taken into account. Unless stated otherwise, the parts are parts by weight, the temperature is in ° C and the pressure is the atmospheric pressure or is close to it.

Example 1 Gelation of NHS-PEG Tetra Functional, 10,000 molecular weight (NHS-PEG) with Tetra-Sulfidril PEG, 10,000 molecular weight (HS-PEG) A homogeneous mixture of pentaerythritol tetrakis [1- (1'-oxo-5 -succimidylpentanoate) -2-poly (oxyethylene) ether ("NHS-PEG," 10,000 molecular weight, Aldrich Chemical Co., (Milwaukee, WI, USA)) with (pentaerythritol tetrakis [mercaptoethyl poly (oxyethylene) ether ("HS-PEG," Aldrich Chemical (Milwaukee, WI, USA)) was obtained by mixing approximately equal amounts of the two powders in weight. A solution at 40% (w / v) of that PEG powder was then prepared by dissolving the powder in dilute HCl. The solution obtained (pH = 2.1) was then co-sprayed with an equal volume of a buffer at 300 mM sodium phosphate / sodium carbonate (pH 9.6). The gelation occurred almost immediately (< 3 sec) and the gel obtained its properties of a firm and gummed solid in less than one minute.

Example 2 Cross Link Formation Network of an NHS-PEG Tetra Functional and an MC containing 10% w / v amino groups of NHS-PEG tetra functional was mixed with a methylated collagen ("MC") containing amino groups and having a concentration of 22 mg / ml and pH 3-4 to form a solution homogeneous stable acid. That solution spontaneously formed a three-dimensional matrix when it was mixed with 0.3 M phosphate / carbonate solution at pH 9.6. That basic solution activated the amines of the MC that then reacted with the SG groups to form the amide bonds. The gelling occurred in seconds to form a strong biomaterial that adhered well to the tissue and did not swell after 24 hours of immersion in saline.

Example 3 Separated Hydrogels in Phases of TA-PEG 912 with 3-SH The hydrogels separated in phases containing 40% p of water were prepared from tri-functional acrylate-PEG ("TA-PEG 912," 912 g / mol , Aldrich Chemicals, Milwaukee, WI, USA)) and TP70 3-mercaptopropionate ("3-SH," 711 g / mol, Perstorp Polyols, Perstorp, Sweden). TA-PEG 912 (0.64 g) was mixed with 3-SH (0.50 g), according to a molar ratio of 1: 1 with respect to the functional groups. A dilute acid solution (0.60 g) was added to the mixture using a vortex mixer, which formed a latex. A basic aqueous buffer (0.16 g) (pH 9.6) was then added, which caused the mixture to solidify within a few seconds through the formation of thiol ether linkages. The hydrogel formed became quite firm in one minute or less.

EXAMPLE 4 Pre-Mixed Geling Formulation (Premix) I A 1 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a polyethylene glycol succinimidyl glutarate tetra functional mixture PEG-SG4 (50 mg) (Sunbio, Ine) and PEG-SH4 (polyethylene glycol thiol tetra functional) (50 mg) (Sunbio, Inc.) (known as "premix"). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 1 ml cap (syringe 3) was filled with 0.25 ml of 0.12 M buffer of monobasic sodium phosphate and 0.2 M sodium carbonate (pH 9.7). The solids content of the syringe 1 and the acid solution of the syringe 2 were mixed through a mixing connector by repeatedly transferring the contents of one syringe to the other. After the conclusion of the mixture, all the mixture was pushed into one of the seringas. The syringe containing the mixture was then fixed to an inlet of an applicator (Micromedics air assisted spray applicator (Model SA-6105)). The syringe 3 containing the solution with pH 9.7 was fixed on the other entrance of the applicator. The formulation was applied to the surface of a fabric as specified by the manufacturer of the applicator.

EXAMPLE 5 Mycophenolic Acid in Premix A 1 ml syringe (syringe 1) equipped with a locking mixer was filled with a mixture of PEG-SH4 (50 mg), PEG-SG4 (50 mg), and MPA (100 mg) , filtered < 100 miera). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1).

A 1 ml syringe with lid (syringe 3) was filled with 0.35 ml of 0.24 M sodium phosphate monobasic buffer solution and 0.4 M sodium carbonate (pH 10.0). The components were mixed and applied to a tissue surface using the procedure described in Example 4.

Example 6 Mycophenolic Acid and Mpa Disodium Salt (Na2MPA) in Premix A 1 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a mixture of PEG-SG4 (50 mg) and PEG-SH4 (50 mg). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 1 ml cap (syringe 3) was filled with 0.25 ml of 0.12 M buffer of monobasic sodium phosphate and 0.2 M sodium carbonate (pH 9.7). A 1 ml syringe (syringe 4) equipped with a lockable mixer connector was filled with MPA (5 mg) and Na2MPA (95 mg), both filtered to < 100 miera. The contents of syringe 4 and syringe 2 were mixed through a mixing connector by repeatedly transferring the contents of one syringe to the other. That solution was then used to reconstitute the solids in the syringe 1. After complete mixing, the entire formulation was placed inside one of the the seringas that was then fixed to an entrance of an applicator (air assisted spray applicator of the Micromedics (Model SA-6105)). Syringe 3 containing the solution at pH 9.7 was attached to the other entrance of the applicator. The formulation was applied to the surface of a fabric as specified by the manufacturer of the applicator.

EXAMPLE 7 Chlorpromazine in Premix A 1 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a mixture of PEG-SG4 (50 mg), PEG-SH4 (50 mg), and CPZ (5 or 10 mg). mg). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 1 ml cap (syringe 3) was filled with 0.25 ml of 0.12 M buffer of monobasic sodium phosphate and 0.2 M sodium carbonate (pH 9.7). The components were mixed and applied to the surface of a fabric using the procedure described in Example 4.

EXAMPLE 8 Microspheres Loaded with Paclitaxel in Premix A 1 ml syringe (syringe 1) equipped with a lockable mixing connector was filled with a mixture of PEG-SG4 (50 mg), PEG-SH4 (50 mg), and microspheres of MePEG5000-PDLLA (65:35) loaded with 10% PTX prepared in spray-dryer (0.5 or 2 mg) (prepared using the procedure that is described in Example 11). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 1 ml cap (syringe 3) was filled with 0.25 ml of 0.12 M buffer of monobasic sodium phosphate and 0.2 M sodium carbonate (pH 9.7). The components were mixed and applied to the surface of a fabric using the procedure described in Example 4.

EXAMPLE 9 Microspheres Loaded with CPZ in Premix A 1 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a mixture of PEG-SG4 (50 mg), PEG-SH4 (50 mg), and microspheres of MePEG5000-PDLLA (65:35) loaded with 10% CPZ prepared in spray dryer (50 or 100 mg) (prepared using the procedure described in Example 11). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 1 ml cap (syringe 3) was filled with 0.25 ml of 0.12 M buffer of monobasic sodium phosphate and 0.2 M sodium carbonate (pH 9.7). The components were mixed and applied to the surface of a fabric using the procedure described in Example 4.

Example 10 Microspheres loaded with MPA in Premix A 1 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a mixture of PEG-SG4 (50 mg), PEG-SH4 (50 g), and microspheres of MePEG5000-PDLLA 65:35 loaded with 10% MPA prepared in spray dryer (25 or 75 mg) (prepared using the procedure described in Example 11). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 1 ml lid (syringe 3) was filled with 0.35 ml of 0.24 M sodium monobasic phosphate buffer and 0.4 M sodium carbonate (pH 10.0). The components were mixed and applied to the surface of a fabric using the procedure described in Example 4.

EXAMPLE 11 Preparation of Spray-loaded Micro Spheres Dryer 3.6 grams of methoxy polyethylene glycol 5000-block - (poly (DL-lactide)) (mass ratio of 65:35 MePEG: PDLLA) were dissolved in 200 ml of methylene chloride. 400 mg of a drug (mycophenolic acid (MPA), chlorpromazine (CPZ) or paclitaxel (PTX)) were added and the resulting solution was dried in a spray dryer (Buchi spray model B191). Inlet temperature 50 ° C, outlet temperature < 39 ° C, 100% vacuum cleaner, 700 1 / hr flow. The collected microspheres were dried under vacuum at room temperature throughout the night to produce uniform and spherical particles with size ranges of less than 10 miera. (typically about 0.5 to 2 miera).

Example 12 Microspheres loaded with MPA (< 10 miera) by the W / O / W Emulsion Process 100 ml of freshly prepared 10% polyvinyl alcohol (PVA) solution and 10 ml of saturated 3% acetic acid solution with MPA were added to a 600 ml beaker. The acidified PVA solution was stirred at 2000 rpm for 30 minutes. Meanwhile, a solution of 400 mg MPA and 800 mg MePEG5000-PDLLA (65:35) in 20 ml dichloromethane was prepared. The polymer / dichloromethane solution was added dropwise to the PVA solution while stirring at 2000 rpm with a Fisher Dyna-Mix agitator. After the conclusion of the addition, the solution was left under agitation for more 45 minutes. The microsphere solution was transferred to Several polypropylene disposable graduated conical centrifuge tubes were washed with pH 3 saturated acetic acid solution with MPA and centrifuged at 2600 rpm for 10 minutes. The aqueous layer was decanted and the washing, centrifugation and decantation steps were repeated 3 times. The combined washed microspheres were dried by freezing under vacuum to remove any excess water.

Example 13 Microspheres Containing MPA (50-100 miera) by the Emulsion Process W / O / W Microspheres containing an average size of about 50-100 miera were prepared using a 1% PVA solution and 500 rpm stirring using the same procedure as described in Example 12.

EXAMPLE 14 Microspheres Containing CPZ and Ptx by the Emulsion Process W / O / W Microspheres containing Paclitaxel (PTX) and chlorpromazine (CPZ) were prepared using the procedure described in Example 12 except that the PVA solution and the Wash solution does not need to be acidified and saturated with the drug. Microspheres loaded with PTX and CPZ were incorporated into premix as described in Example 17.

Example 15 Micelles Containing Paclitaxel MePEG2000 (41 g) and MePEG2000-PDLLA (60:40) (410 g) were combined in a vessel and heated to 75 ° C under agitation. After the polymers had been completely melted and mixed, the temperature was reduced to 55 ° C. Meanwhile, a PTX solution in tetrahydrofuran (46 g / 200 ml) was prepared and poured into the polymer solution under constant stirring. The agitation continued for another hour. The micelles containing PTX were dried at 50 ° C under vacuum to remove the solvent and ground in a cloth with a 2 mm opening after cooling.

EXAMPLE 16 Incorporation of Micelles Loaded with Ptx into Premix A 1 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a mixture of PEG-SG4 (50 mg) and PEG-SH4 (50 mg). A 2 ml serum vial was filled with 1.5 ml of 6.3 mM HCl solution (pH 2.1). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 0.12 M sodium monobasic phosphate buffer and 0.2 M sodium carbonate (pH 9.7). A 2 ml serum vial was filled with micelles loaded with 10% PTX (2 mg or 8 mg) (prepared as in Example 15) and reconstituted with 1 ml of the solution at pH 2.1. 0.25 ml of the micelle solution was removed with a 1 ml syringe seringa; the syringe was attached to syringe 1 containing the solids PEG-SG4 and PEG-SH4; and the components were mixed through the mixing connector by repeatedly transferring the contents of one syringe to the other. After complete mixing, the entire mixture was placed inside one of the seringas, which was then fastened to an inlet of an applicator (MICROMEDICS air assisted spray applicator (Model SA-6105)). The syringe 3 containing the solution with pH 9.7 was attached to the other entrance of the applicator. The formulation was applied to the surface of a fabric as specified by the manufacturer of the applicator.

Example 17 Microspheres loaded with MPA in Premix A 1 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a mixture of PEG-SG4 (50 mg), PEG-SH4 (50 mg), and microspheres of MePEG5000-PDLLA (65:35) loaded with 10% PTX (0.5 or 2 mg) (prepared using the procedure described in Examples 12 and 13). A 1 ml syringe with lid (syringe 2) was filled with 0.25 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 1 ml cap (syringe 3) was filled with 0.25 ml of 0.12 M buffer of monobasic sodium phosphate and 0.2 M sodium carbonate (pH 9.7). The components were mixed and applied to the surface of a fabric using the procedure described in Example 4.

EXAMPLE 18 Geling Formulation (Premix) ii A 3 ml syringe (syringe 1) equipped with a lockable mixer connector was filled with a mixture of PEG-SG4 (200mg) and PEG-SH4 (200mg). A syringe with a 3 ml cap (syringe 2) was filled with 1.0 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 3 ml cap (syringe 3) was filled with 1 ml of 0.12 M sodium monobasic phosphate buffer and 0.2 M sodium carbonate (pH 9.7). The components were mixed and applied to the surface of a fabric using the procedure described in Example 4.

Example 19 Premix Loaded with MPA A 3 ml syringe (syringe 1) equipped with a locking mixer was filled with a mixture of PEG-SG4 (200mg), PEG-SH4 (200mg), and MPA (200mg or 400mg). A syringe with a 3 ml cap (syringe 2) was filled with 1 ml of 6.3 mM HCl solution (pH 2.1). A syringe with a 3 ml cap (syringe 3) was filled with 1.5 ml of 0.24 M sodium monobasic phosphate buffer and 0.4 M sodium carbonate (pH 10). The components were mixed and applied to the surface of a fabric using the procedure described in Example 4.

Example 20 Model of Surgical adhesions to Evaluate Agents Fibrosis Inhibitors in Mice The cecal lateral wall model of mice is used to evaluate the antifibrotic capacity of formulations in vivo. Sprague Dawley mice are anesthetized with halothane. Using aseptic precautions, the abdomen is opened via an incision in the central line. The caecum is exposed and raised to the outside of the abdominal cavity. The dorsal and ventral aspects of the caecum are successively scraped a total of 45 times on the 1.5 cm end using a scalpel blade # 10. The angle of the sheet and the pressure are controlled to produce a punctuated bleed at the same time avoiding a severe damage to the tissue. The left side of the abdomen is retracted and twisted to expose a section of the peritoneal wall that is close to the caecum. The superficial layer of muscle (transverses abdominis) is cut along an area of 1 X 2 cm2, leaving behind torn fibers of the second layer of muscle (internal oblique muscle). Scraped surfaces are pressed with cotton until bleeding stops. The scraped caecum is then positioned over the wound in the lateral wall and secured by two sutures. The formulation is applied on both the sides of the scraped cecum and on the scraped peritoneal lateral wall. Two new sutures are placed to hold the blind intestine to the wound lateral wall, using a total of 4 sutures and the incision of the abdomen is closed in two layers. After 7 days, the animals are evaluated post mortem with the extension and gravity of the adhesions being graded both quantitatively and qualitatively.

Example 21 Model of Surgical Adhesions to Evaluate Agents Rabbit Fibrosis Inhibitors The rabbit uterine horn model is used to evaluate the antifibrotic ability of formulations in vivo. Mature Females of White Rabbits from New Zealand (NZW - New Zealand White) are placed under general anesthesia. Using aseptic precautions, the abdomen is opened in two layers in the central line to expose the uterus. Both uterine tubes are lifted out of the abdominal cavity and evaluated for their size in the French Catheter Scale. The horns classified between # 8 and # 14 on the French Scale (2, 5 - 4.5 mm in diameter) are considered suitable for that model. Both uterine tubes and the opposite peritoneal wall are scraped with a scalpel blade # 10 at a 45 ° angle over an area of 2.5 cm in length and 0.4 cm in width until punctuated bleeding is observed. Scraped surfaces are pressed with cotton until bleeding stops. The individual tubes are then placed opposite the peritoneal wall and are fastened by two sutures that are placed 2 mm beyond the edges of the scraped area. The formulation is applied and the abdomen is closed in three layers. After 14 days, the animals are evaluated post mortem with the extension and gravity of the adhesions being graded both quantitatively and qualitatively.

Example 22 Model of Spinal Surgical Adhesions to Evaluate Fibrosis Inhibitory Agents in Rabbits There is often an extensive formation of scars and adhesions after lumbar spinal surgeries involving the vertebrae. The dense and thick fibrous tissue that adheres to the spine and adjacent muscles should be removed by surgery. Unfortunately, fibrous adhesions usually reform after secondary surgery. The adhesions are formed by the proliferation and migration of fibroblasts from the neighboring tissue at the surgery site. Those cells are responsible for the healing response after tissue injury. Once they have migrated to the wound, they release proteins such as collagen to repair the ferid tissue. Super proliferation and secretion by these cells induce local obstruction, compression and contraction of neighboring tissues with the side effects that accompany it. The model of spinal adhesion by laminectomy in mice described here is used to investigate the prevention of spinal adhesion by the slow local release of antifibrotic drugs. Five to six animals are included in each experimental group to allow a meaningful statistical analysis. Formulations with various concentrations of antifibrotic drugs are tested in comparison with control animals to evaluate the inhibition to the formation of adhesions. Rabbits are anesthetized with an IM injection of ketamine / zylazine. An endotracheal tube is inserted for the maintenance of halothane anesthesia. The animal is placed prostrate on the operating table above a heated blanket and the skin on the lower half of the coasts is scraped and prepared for a sterile surgery. A longitudinal incision in the central line of the skin is made from L-1 to L-5 and down in the lumbosacral fascia. The fascia is cut to expose the extremities of the spinal processes. The paraspinous muscles are dissected and retracted from the spinous process and lamina of L-4. A laminectomy is performed in L-4 by the removal of the spinal process through careful bilateral excision of the laminae, thereby creating a small defect of laminectomy of 5 x 10 mm. Hemostasis is obtained with Gelfoam. The test formulations are applied to the wound site and it is closed in layers with Vicryl suture. The animals are placed in an incubator until the recovery from anesthesia and then they are returned to their cage. Two weeks after surgery, the animals are anesthetized using procedures similar to those described above. The animals are euthanized with Eutanil. After the incision in the skin, the location of the laminectomy is analyzed by dissection and the amount of adhesion is graded using graduation systems published in the scientific literature for that type of wound.

Example 23 Surgical Tendon Adhesions Model to Evaluate Rabbit Fibrosis Inhibitory Agents This model is used to investigate whether adhesion of tendons can be prevented by the slow local release of drugs that recognize fibrosis. The polymer formulations are loaded with drugs and implanted around the injured tendons in rabbits. In animals without fibrosis - inhibitory formulations, adhesions develop within 3 weeks with a flexor tendon wound if the immobilization of the tendon is maintained during that period. An advantage of rabbits is that the anatomy of their tendons and the cellular behavior during the healing of the tendons are similar to those of man, except for the cure rate, which is much faster in rabbits. The rabbits are anesthetized and the skin on the right hind limb is scraped and prepared for sterile surgery. Sterile surgery is performed with the help ofa surgical microscope. A longitudinal incision in the center line of the skin is made on the volvar aspect of the proximal phalanx on fingers 2 and 4. The synovial lining of the tendons is carefully exposed and cut transversely to assess the distance of the flexor digitorum profundus to the bifurcation of the superficial flexor of the fingers. The tendon wound is made by gently lifting the flexor digitorum profundus with a curved forceps and the transverse incision through half of its substance. The formulation containing the test drug formulation is applied around the tendons in the coating of one of the two fingers selected at random. The other finger is left untreated and is used as a control. The coating is then repaired with 6-0 nylon suture. A 6-0 nylon immobilization suture is inserted through the transverse metacarpal ligament within the tension / coating complex to immobilize the tendon and lining with a single unit to promote adhesion formation. The wound is closed with interrupted 4-0 sutures. A bandage is applied around the hind paw to increase the immobilization of the fingers and ensure comfort and care of the animals. The animals are recovered and returned to their cages.

Three weeks after surgery, the animals are anesthetized. After cutting the skin, the plane of the tissue around the synovial lining is subjected to a dissection and the tendon-coating complex is collected in block and transferred into formaldehyde buffered with 10% phosphate for histopathological analysis. The animals are then euthanized. After the paraffin coating, cross sections in series with 5 mm thickness are cut every 2 mm through the lining and tendon complex. The sections are stained with spots of H &E and Movat to evaluate adhesion growth. Each photo is digitalized using a computer connected to a digital microscope camera (Nikon Micropublisher cooled camera). The morphometric analysis is then performed using image analysis software (ImagePro). The thickness and area of the adhesion defined as the substance that strangles the synovial space are measured and compared between the animals treated with the formulation and control.

It should be understood that while the invention was described in conjunction with specific preferred configurations thereof, the foregoing description, as well as the examples that are presented above, are intended to illustrate and Do not limit the scope of the invention. Other aspects, advantages and modifications will be apparent to those with skills in the art with which the invention is related.

Claims (62)

NOVELTY OF THE INVENTION Having described the present is considered as a novelty, and therefore, it is claimed as property contained in the following: CLAIMS

1. A dry powder composition composed of- a first component with a nucleus substituted with nucleophilic groups, where m > 2; and a second component with a core substituted with n electrophilic groups, where n = 2 and m + n > 4; where the nucleophilic and electrophilic groups are non-reactive in a moist medium, but are reactive when exposed to an aqueous medium such that the components interreact in the aqueous medium to form a three-dimensional composition.

The composition of claim 1, wherein the nucleophilic and electrophilic groups undergo a nucleophilic substitution reaction, a nucleophilic addition reaction, or both.

3. The composition of claim 1, wherein the nucleophilic groups are selected from -NH2, -NHR1, -N (R1) 2, -SH, -OH, -COOH, -C6H4-OH, -H, -PH2, - PHR1, -P (R1) 2, -NH-NH2, -C0-NH-NH2, and -C5H4N, where R1 is a hydrocarbyl group, and each R1 can be the same or different.

4. The composition of claim 1, wherein the electrophilic groups are selected from -C0-C1, - (CO) -O- (CO) -R (where R is an alkyl group), -CH = CH-CH = 0 and -CH = CH-C (CH3) = 0, halo, -N = C = 0 , -N = C = S, -S02CH = CH2, -0 (CO) -C = CH2, -0 (CO) -C (CH3) = CH2, -SS- (C5H4N), -0 (C0) -C (CH2CH3) = CH2, -CH = CH-C = NH, -COOH, - (CO) ON (C0CH2) 2, -CHO, - (CO) 0-N (COCH2) 2-S (0) 20H, and -N (COCH) 2.

The composition of claim 1, wherein the nucleophilic groups are amino groups and the electrophilic groups are amine-reactive groups.

The composition of claim 5, wherein the amine-reactive groups contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine.

The composition of claim 5, wherein the amine-reactive groups are selected from esters of carboxylic acids, acid chloride groups, anhydrides, ketones, aldehydes, halo, isocyanate, thioisocyanate, epoxides, activated hydroxyl groups, olefins, carboxyl, succinimidyl ester, sulfosuccinimidyl ester, maleimido, epoxy, and ethenesulfonyl.

8. The composition of claim 1, wherein the nucleophilic groups are sulfhydryl groups and the electrophilic groups are sulfhydryl-reactive groups.

The composition of claim 8, wherein the sulfhydryl reactive groups are selected so as to form a thioester, imido thioester, thioether, or bisulphide bond by reacting with the sulfhydryl groups.

The composition of claim 9, wherein the sulfhydryl reactive groups form a bisulfide bond and have the structure -SS-Ar, where Ar is a substituted or unsubstituted heteroatom moiety containing nitrogen or a non-heterocyclic aromatic group substituted with a half that removes electrons.

The composition of claim 9, wherein the sulfhydryl reactive groups form a thioether bond and are selected from maleimido, substituted maleimido, haloalkyl, epoxy, imino, aziridino, olefins, and β-unsaturated aldehydes and ketones.

The composition of claim 8, wherein the sulfhydryl reactive groups are selected from mixed anhydrides; ester-phosphorus derivatives; ester-derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N- hydroxyglutarimide esters; 1-hydroxybenzotriazole esters; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates.

The composition of claim 1, wherein the number of nucleophilic groups in the mixture is approximately equal to the number of electrophilic groups in the mixture.

The composition of claim 13, wherein the ratio of moles of nucleophilic groups to moles of electrophilic groups is about 2: 1 to 1: 2.

15. The composition of claim 14, where the ratio is 1: 1.

16. The composition of claim 1, wherein the core is selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C2-14 hydrocarbyls, and C2-14 hydrocarbyls containing heteroatoms.

The composition of claim 16, wherein the core is a synthetic or natural hydrophilic polymer.

The composition of claim 17, wherein the hydrophilic polymer is a linear, branched, dendrimer, hyperbranched, or star polymer.

19. The composition d of claim 17, wherein the hydrophilic polymer is selected from polyalkylene oxides.; polyols; diols and polyols substituted by poly (oxyalkylene), polyoxyethylated sorbitol; glucose polyoxyethylated; poly (acid acrylics) and analogs and copolymers thereof; polymaleic acids; polyacrylamides; poly (olefinic alcohols); poly (N-vinyl lactams); polyoxazolines; polyvinylamines; and copolymers thereof.

The composition of claim 19, wherein the hydrophilic polymer is a polyalkylene oxide or polyols selected from copolymers of polyethylene glycol and poly (ethylene oxide) -poly (propylene oxide).

The composition of claim 19, wherein the hydrophilic polymer is a polyol selected from glycerol, polyglycerol and propylene glycol.

22. The composition of claim 19, wherein the hydrophilic polymer is a polyol substituted by poly (oxyalkylene) selected from mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and trimethylene glycol mono- and diols. polyoxyethylated.

The composition of claim 19, wherein the hydrophilic polymer is a poly (acrylic acid), analog or copolymer thereof selected from poly (acrylic acid), poly (methacrylic acid), poly (hydroxyethyl methacrylate), poly (hydroxyethyl acrylate) , poly (methylalkylsulfoxide acrylates), and poly (methylalkylsulfoxide methacrylates).

24. The composition of claim 19, wherein the hydrophilic polymer is a polyacrylamide selected from polyacrylamide, poly (methacrylamide), poly (dimethylacrylamide), poly (N-isopropylacrylamide), and copolymers thereof.

The composition of claim 19, wherein the hydrophilic polymer is a poly (olefinic alcohol) selected from poly (vinyl alcohols) and copolymers thereof.

26. The composition of claim 19, wherein the hydrophilic polymer is a poly (N-vinyl lactam) selected from poly (vinyl pyrrolidones), poly (vinyl caprolactams), and copolymers thereof.

The composition of claim 19, wherein the hydrophilic polymer is a polyoxazoline selected from poly (ethyloxazoline) and poly (ethyloxazoline).

The composition of claim 17, wherein the hydrophilic polymer is selected from proteins, carboxylated polysaccharides, aminated polysaccharides, and activated polysaccharides.

29. The composition of claim 28, wherein the hydrophilic polymer is selected from collagen and glycosaminoglycans.

30. The composition of claim 16, wherein the core is a hydrophobic polymer selected from polylactic acid and polyglycolic acid.

31. The composition of claim 16, wherein the core is an amphiphilic polymer.

The composition of claim 16, wherein the core is a C2-14 hydroscarbyl selected from alkanes, diols, polyols, and polyacids.

The composition of claim 16, wherein the core is a C 2-14 hydrocarbyl containing heteroatom selected from di- and poly-electrophiles.

The composition of claim 1, wherein the first component has the structure of formula (I) [X (Ll) p] mR and wherein the second component has the structure of formula (II) (II) [Y- (L2 ) q] nR ', where m and n are integers from 2-12 and m + n > 4; R and R 'are independently selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C214 hydrocarbyls, and C2-14 hydrocarbyls containing heteroatoms; X is a nucleophilic group; And it's an electrophilic group; Ll and L2 are linking groups; and p and q are integers from 0-1.

35. The composition of claim 1, wherein the components inter-react to form covalent bonds, non-covalent bonds, or both.

36. The composition of claim 35, wherein the non-covalent bonds are ionic bonds, hydrogen bonds, or the association of hydrophobic molecular segments.

37. The composition of claim 36, wherein all molecular segments are the same.

38. The composition of claim 1, further comprising a biologically active agent.

39. The composition of claim 38, wherein the biologically active agent is mixed with the first and second components to form a mixture.

40. The composition of claim 38, wherein the biologically active agent is chemically coupled to the first component or the second component.

41. A method of forming a three-dimensional matrix, comprising the steps of: (a) providing the dry powder composition of claim 1; and (b) reactivating the nucleophilic and electrophilic groups, exposing the composition to an aqueous environment to effect inter-reaction; where said exposure comprises: (i) dissolving the composition in a first buffer solution, having a pH in the range of about 1.0 to 5.5 to form a homogeneous solution, and (II) adding a second buffer solution, having a pH within the near range from 6.0 to 11.0 to the homogeneous solution; and (c) allowing a three-dimensional composition to be formed.

42. The method of claim 41, wherein the composition is formed without the input of any external energy.

43. The method of claim 41, wherein the composition is formed by polymerization.

44. The method of claim 41, wherein the pH of the first buffer solution is selected to retard the reactivity of the nucleophilic groups on the first component, rendering the nucleophilic groups relatively non-nucleophilic.

45. The method of claim 44, wherein the second buffer solution neutralizes the effect of the first buffer solution, so that the nucleophilic groups of the first component recover their nucleophilic character and inter-react with the electrophilic groups of the second component.

46. The method of claim 41, wherein the composition, first buffer solution and second buffer solution are separately housed in a multi-compartment syringe system having multiple cylinders, a mixing head, and an exit orifice; step (b) (i) comprises the addition of the first buffer solution to the cylinder that hosts the composition to dissolve the composition and form a homogeneous solution, and extrude the homogeneous solution into the mixing head; step (b) (ii) comprises simultaneously extruding the second buffer solution into the mixing head; and step (c) further comprises extruding the resulting composition through the hole on a surface.

47. A kit for use in medical applications, comprising: (a) the dry powder composition of the claim 1; (b) a first buffer solution, having a pH within the range of about 1.0 to 5.5; and (c) a second buffer solution, having a pH within the range of about 6.0 to 11.0, where each component is packed separately and mixed immediately before use.

48. The kit of claim 47, wherein before use, each component is in a separate sterile package.

49. The kit of claim 47, further comprising a delivery device.

50. The kit of claim 49, wherein the delivery device is a multi-component atomizing device.

51. The kit of claim 50, wherein the multi-component atomizing device is a multi-compartment syringe system with multiple cylinders, a mixing head, and an exit orifice.

52. The kit of claim 51, wherein the dry powder composition, the first buffer solution and the second buffer solution are separately housed in the multi-compartment syringe system.

53. The kit of claim 52, wherein the delivery device is a pressurized delivery device.

54. The kit of claim 53, wherein the pressurized delivery device comprises: a variety of fluid component inlets, each adapted to communicate with a source of different fluid components, - at least one carrier fluid inlet adapted to communicate with a pressurized carrier fluid; a diffusing surface located downstream of the variety of fluid component inlets and at least one carrier fluid inlet; and an outlet extending across the surface of the diffuser, where the diffuser surface is adapted to receive fluid components therein and has an effective way to direct and maintain each fluid component received in a different flow path toward the outlet to mix and distribute through itself by the pressurized carrier fluid from at least one carrier fluid inlet.

55. The kit of claim 54, where the pressurized carrier fluid is pressurized air.

56. The kit of claim 55, wherein the fluid components are the first buffer solution and the second buffer solution.

57. The kit of claim 47, wherein the kit further comprises a biologically active agent and the medical application involves the administration of a biologically active agent.

58. The kit of claim 57, wherein the biologically active agent is packed with the dry powder composition.

59. The kit of claim 58, further comprising a pharmaceutically acceptable carrier packaged with the biologically active agent and the dry powder composition.

60. The kit of claim 59, wherein the biologically active agent is packaged as a solution with the first buffer.

61. The kit of claim 59, wherein the biologically active agent is packed as a solution with the second buffer.

62. The kit of claim 59, further comprising a pharmaceutically acceptable carrier as a fourth component.