Novel lipid-based small molecule integrin receptor ligand agonist adjuvant carrier compositions, integrin agonist adjuvant pharmaceutical compositions derived therefrom, and methods for making and using them

Abstract

The pharmaceutical composition comprises a drug-carrier system having a low water-soluble small molecule drug, such as one or more small molecule integrin agonist adjuvants, in a substantially non-aqueous carrier composition comprising at least one phospholipid, at least one neutral lipid, and at least one pharmaceutically acceptable solubilizer. The drug-carrier system, when mixed with an aqueous phase, typically forms a non-gelled and substantially opaque liquid dispersion. This composition is suitable for administration to a subject in need thereof by a suitable route, such as orally.

Description

Technical Field

[0001] Related Applications This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 348,852, filed on 06 / 03 / 2022 (June 3, 2022) and U.S. Provisional Patent Application No. 63 / 337,960, filed on 05 / 03 / 2022 (May 3, 2022). U.S. patent applications and patents are incorporated by reference in their entirety in the last paragraph: U.S. Patent Application No. 14 / 621,112, filed on 2 / 12 / 2015; U.S. Patent Application No. 14 / 754,931, filed on 6 / 30 / 2015; U.S. Patent Application No. 16 / 516,978, filed on 7 / 19 / 2019; U.S. Patent Application No. 17 / 471,922, filed on 9 / 10 / 2021; U.S. Patent Application Publication No. 20150250883; U.S. Patent Application Publication No. 20160000755; U.S. Patent Application Publication No. 20160000755; U.S. Patent Application Publication No. 20200054600; and U.S. Patent No. 10342866, issued on 7 / 9 / 2019; U.S. Patent No. 10,709,781, issued on 7 / 13 / 2020; U.S. Patent No. 10,716,849, issued on 7 / 20 / 2020; U.S. Patent No. 10,709,780, issued on 7 / 13 / 2020; U.S. Patent No. 11,311,619, issued on 4 / 26 / 2022.

[0002] Embodiments of the present invention relate to carrier compositions for poorly water-soluble pharmaceutical agents, poorly water-soluble pharmaceutical agent compositions derived therefrom, and methods for making and using them. More particularly, embodiments of the present invention relate to carrier compositions for poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents, poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agent compositions derived therefrom, and methods for making and using them, wherein the integrin agonist adjuvant carrier composition comprises one or more zwitterionic surfactants, one or more nonionic surfactants, one or more neutral lipids, and one or more polar organic co-solvents or solubilizers.

Background Art

[0003] An integrin agonist is an agent capable of increasing integrin activation and promoting the interaction between cells having integrin and cells having integrin-related ligands. Such interactions have been found to be important in a wide variety of pharmaceutical applications. Although numerous pharmaceutical carriers are known in the art, there remains a need in the art for carrier compositions for increasing the oral bioavailability of integrin agonists for use in enhancing vaccine efficacy, antigen presentation efficacy, immune response efficacy, and other therapies involving integrin activation. SUMMARY OF THE INVENTION

[0004] Embodiments of the present disclosure provide carrier compositions for administering poorly water-soluble pharmaceutical agents in the form of a lipid-based delivery system composed of one or more zwitterionic surfactants, such as one or more phospholipids, one or more neutral lipids, and one or more co-solvents or solubilizing agents. Using this lipid-based delivery system, it is possible to encapsulate or fill soft or hard gel capsules, and when mixed with an aqueous phase, an oral poorly water-soluble pharmaceutical agent solution can be formulated that typically forms a non-gel-like and substantially opaque liquid dispersion or emulsion. In certain embodiments, the one or more neutral lipids include neutral lipids or phospholipids containing fatty acid groups having more than 14 carbon atoms (i.e., >C 14 fatty acids), which is thought to enhance the distribution of the composition into the lymphatic circulation and reduce the extent of gastrointestinal mucosa and hepatic CYP450 enzymes. By doing so, this lipid-based drug delivery system will increase the solubility and oral bioavailability of poorly soluble integrin agonists having a LogP value greater than 5 (i.e., LogP > 5). Embodiments of the present disclosure provide integrin agonist carrier compositions comprising one or more zwitterionic surfactants, one or more neutral lipids, and one or more organic solvents.

[0005] Embodiments of the present disclosure provide an integrin agonist carrier composition and an integrin agonist pharmaceutical composition comprising an effective amount of one or more integrin agonists capable of enhancing the cell-cell interaction between cells having surface integrins and cells having surface-associated ligands. In certain embodiments, surface integrins targeted by such agonists include, but are not limited to, α4β1, α4β7, α5β1, αLβ2, and / or αVβ3, which promote interaction with ligands including, but not limited to, VCAM-1, fibronectin, MAdCAM-1, ICAM-1, ICAM-2, and / or vitronectin. In certain embodiments, the integrin agonist is a small molecule integrin agonist having a molecular weight of about 300 g / mol to about 2000 g / mol, about 300 g / mol to 1500 g / mol, or about 300 g / mol to 1000 g / mol. In other embodiments, the integrin agonist comprises a linker comprising at least one protonatable group, at least one aromatic or non-aromatic cyclic group, at least one aromatic or non-aromatic heterocyclic group, at least one hydrocarbylene group (i.e., -C n H 2n - group, n = 1 to about 10), at least one alkylene oxide group (i.e., -C n H 2n OC m H 2m -, n and m = 1 to about 10), or any combination of such linkers. In other embodiments, the end groups include aryl, aromatic, or non-aromatic heterocyclic alkyl groups, alkyl-substituted aromatic or non-aromatic heteroaryl groups, or any combination thereof.

[0006] The present disclosure will be better understood by reference to the following detailed description, taken in conjunction with the accompanying exemplary drawings, in which like elements are numbered the same.

Modes for Carrying Out the Invention

[0007] Definitions Used in the Present Invention In addition to having their customary and ordinary meanings, the following definitions apply throughout this specification and the claims, where the context permits. The term "integrin agonist pharmaceutical composition" refers to one or more integrin agonists contained in the integrin agonist carrier compositions of the present disclosure for administration as a drug to a mammal. The term "cell-based therapy" refers to a pharmaceutical composition comprising one or more cell types, one or more integrin agonists, or other chemical substances or agents for administration as a drug to a mammal.

[0008] The term "therapeutically effective amount" refers to the amount of an agent being administered that will at least to some extent reduce one or more of the symptoms of the disorder being treated. For example, it refers to the amount of a compound that is effective to prevent, alleviate, or ameliorate the symptoms of a disease, or to extend the survival of a subject being treated. With respect to a disease or disorder, the term "treatment" refers to preventing, inhibiting, arresting, reversing, or providing relief from the symptoms or side effects of the disease or disorder, and / or extending the survival of the subject being treated. The term "alkyl" as used herein, alone or in combination, refers to a C 1 ~C 12 straight-chain or branched-chain substituted or unsubstituted saturated chain radical derived from a saturated hydrocarbon by removing one hydrogen atom. Representative examples of alkyl groups include, among others, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.

[0009] The term "alkenyl" as used herein, alone or in combination, refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, and decenyl. The term "alkynyl", alone or in combination, refers to a substituted or unsubstituted linear or substituted or unsubstituted branched alkynyl radical containing 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, and decynyl. The term "lower", when used to modify "alkyl", "alkenyl", "alkynyl", or "alkoxy", refers to a C 1 ~C 6 unit. For example, lower alkyl means C 1 ~C 6 alkyl. The term "cycloalkyl", as used herein, alone or in combination, refers to a substituted or unsubstituted aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl. The cycloalkyl group may be unsubstituted or substituted with 1, 2, or 3 substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide. This term is intended to encompass cycloalkenyl groups and cycloalkynyl groups. "Cycloalkyl" includes cis- or trans-forms. Further, the substituents may be located at either the endo- or exo-position in a bridged bicyclic system.

[0010] The term "cycloalkenyl", as used herein, alone or in combination, refers to a cyclic carbocyclic ring containing 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, and cyclopentadienyl. The term "cycloalkylalkyl", as used herein, refers to a cycloalkyl group appended to a lower alkyl radical, including but not limited to cyclohexylmethyl. The term "halo" or "halogen", as used herein, refers to I, Br, Cl, or F. The term "haloalkyl", as used herein, refers to a lower alkyl radical to which at least one halogen substituent is appended, for example, but not limited to, chloromethyl, fluoroethyl, trifluoromethyl, and pentafluoroethyl.

[0011] The term "alkoxy", alone or in combination, refers to an alkyl ether radical, and the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. The term "alkenoxy", alone or in combination, refers to a radical of the formula alkenyl-O-, provided that this radical is not an enol ether, and the term "alkenyl" is as defined above. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, and E- and Z-3-methyl-2-propenoxy.

[0012] The term "alkynoxy", alone or in combination, refers to a radical of the formula alkynyl-O-, provided that this radical is not an -ynol ether. Examples of suitable alkynoxy radicals include, but are not limited to, propargyloxy, and 2-butynyloxy. The term "carboxyl", as used herein, refers to -CO 2 H. The term "thioalkoxy" refers to a thioether radical of the formula alkyl-S-, where "alkyl" is as defined above. The term "carboxaldehyde", as used herein, refers to -C(O)R, where R is hydrogen in the formula. The term "carboxamide", as used herein, refers to -C(O)NR 2 where R is hydrogen, alkyl, or any other suitable substituent in the formula.

[0013] The term "alkoxyalkoxy", as used herein, refers to R b O-R c O-, where R b is lower alkyl as defined above, and R c is alkylene, and alkylene is -(CH 2 ) n’ - and n' is an integer from 1 to 6. Representative examples of the alkoxyalkoxy group include, among others, methoxymethoxy, ethoxymethoxy, and t-butoxymethoxy. The term "alkylamino", as used herein, refers to R d NH-, where R d is a lower alkyl group, for example, among others, ethylamino, butylamino.

[0014] The term "alkenylamino", alone or in combination, refers to the radical of the formula alkenylNH- or (alkenyl) 2 N-, and the term "alkenyl" is defined above, provided that this radical is not an enamine. Examples of such alkenylamino radicals include the allylamino radical. The term "alkynylamino", alone or in combination, refers to the radical of the formula alkynylNH- or (alkynyl) 2 N-, and the term "alkynyl" is defined above, provided that this radical is not an amine. Examples of such alkynylamino radicals include the propargylamino radical. The term "dialkylamino", as used herein, refers to R e R f N-, where R eand R f is independently selected from lower alkyl, such as, among others, diethylamino and methylpropylamino. The term "amino", as used herein, refers to H 2 N-. The term "alkoxycarbonyl", as used herein, refers to an alkoxyl group as previously defined, attached to the parent molecular moiety via a carbonyl group. Examples of alkoxycarbonyl include, among others, methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl.

[0015] As used herein, the term "aryl" or "aromatic", alone or in combination, refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms, such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrazolo[1,5-c]triazinyl. The terms "arylalkyl" and "alkylaryl" use the term "alkyl" as defined above. The ring may be substituted. The aromatic ring may include other aromatic rings or non-aromatic rings and may be a fused ring system forming a polycyclic ring, and as used herein, is also included in the term "aromatic".

[0016] The term "aralkyl", alone or in combination, refers to an aryl-substituted alkyl radical, and the terms "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolylmethyl, furylmethyl, imidazolylmethyl, indolylmethyl, and thienylpropyl.

[0017] The term "aralkenyl", alone or in combination, refers to an aryl-substituted alkenyl radical, and the terms "aryl" and "alkenyl" are as defined above. The term "arylamino", alone or in combination, refers to a radical of the formula aryl-NRg-, where "aryl" is as defined above. Rg can be selected, among others, from the group consisting of H, lower alkyl, aryl, and aralkyl. Examples of arylamino radicals include, but are not limited to, phenylamino (anilide), naphthylamino, and 2-, 3-, and 4-pyridylamino.

[0018] The term "biaryl", alone or in combination, refers to a radical of the formula aryl-aryl, and the term "aryl" is as defined above. The term "thioaryl", alone or in combination, refers to a radical of the formula aryl-S--, and the term "aryl" is as defined above. An example of a thioaryl radical is the thiophenyl radical. The term "aroyl", alone or in combination, refers to a radical of the formula aryl-CO--, and the term "aryl" is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, and pyridylcarbonyl. The term "heterocyclyl", alone or in combination, refers to a non-aromatic 3- to 10-membered ring containing at least one ring N, O, or S atom. The heterocyclic ring may optionally be aryl-fused. Also, the heterocyclic ring may optionally be substituted with at least one substituent independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, alkoxycarbonyl, carboxyalkyl, oxo, arylsulfonyl, and aralkylaminocarbonyl.

[0019] As used herein, the term "alkylheterocyclyl" refers to an alkyl group, as previously defined, attached to the parent molecular moiety via a heterocyclyl group. As used herein, the term "heterocyclylalkyl" refers to a heterocyclyl group, as previously defined, attached to the parent molecular moiety via an alkyl group. As used herein, the term "aminal" refers to a hemiacetal of structure RCH(NH 2 )(OH). The terms "electron withdrawing" or "electron donating" refer to the ability of a substituent to withdraw or donate electrons compared to the ability of hydrogen when hydrogen occupies the same position in the molecule. Such terms are well understood by those skilled in the art and have the meaning described on pages 16 - 18 of ADVANCED ORGANIC CHEMISTRY by J. March, 1985. This reference is hereby incorporated by reference into this specification. Electron withdrawing groups include, among others, halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxamide, aryl, quaternary ammonium, trifluoromethyl, and aryl lower alkanoyl. Electron donating groups include, among others, hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide groups. Those skilled in the art will understand that a substituent may have electron donating or electron withdrawing characteristics under different chemical conditions. Further, in the present invention, any combination of substituents selected from the groups specified above is contemplated.

[0020] The most preferred electron-donating substituents or electron-withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salt, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The use of the above terms is intended to include both substituted and unsubstituted moieties. Substitution may be by one or more groups such as alcohol, ether, ester, amide, sulfone, sulfide, hydroxyl, nitro, cyano, carboxy, amine, heteroatom, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl, and aralkylaminocarbonyl, or any of the substituents of the preceding paragraph, or any of those substituents attached either directly or via a suitable linker. The linker is typically a short chain of 1 to 3 atoms including any combination of -C-, -C(O)-, -NH-, -S-, -S(O)-, -O-, -C(O)O-, or -S(O)O-. The ring may be substituted.

[0021] The term "mammal" includes humans and other animals. The term "heteroatom" as used herein includes nitrogen, sulfur, and oxygen. The term "alpha" as used herein refers to the position immediately adjacent to the position described. The term "LogP" means the ratio of the concentration of a substance in two immiscible phases that are in equilibrium with each other. Typically, not only n-octanol, but also organic solvents such as n-hexane, toluene, chlorobenzene, dichloromethane, methyl tert-butyl ether, isopropyl acetate, benzyl alcohol, cyclohexanol, or n-butanol can be used as well. As used herein, the term "inactive ingredient", which refers to a harmless drug that can be used as an inactive ingredient in the preparation of other drugs, such as coloring agents, emulsifiers, excipients, flavoring agents, lubricants, preservatives, solvents, etc., shall be exempt from the application of section 502(f)(1) of the Federal Law (21 CFR 201.117).

[0022] The term "gelatin" means an aggregate of peptides and proteins produced by partial hydrolysis of collagen extracted from the skin, bones, and connective tissues of animals such as domestic cattle, chickens, pigs, and fish. During the hydrolysis process, some of the bonds between or within the component proteins are cleaved. Its chemical composition is very similar to that of its parent collagen in many respects. Photo-grade and pharmaceutical-grade gelatin are made from bovine bones and pig skins. Gelatin is classified as a hydrogel. The term "excipient" or "adjuvant", as used herein, refers to any substance other than the active drug or product that is included in the drug delivery system for any one of the following purposes: to assist in the processing of the drug delivery system during manufacture, to protect, assist, or enhance stability, bioavailability, or patient acceptability, to assist in product identification, or to enhance any other attribute of the overall safety and effectiveness of the drug delivery system during storage or use (40 CFR 63.1251).

[0023] As used herein, the term "effector cell" means a cell that is activated by a cognate tumor antigen and is involved in the elimination of cancer cells. Effector cell types include, but are not limited to: 1) tumor-infiltrating lymphocytes (TILs), which are lymphocytes isolated from a tumor and expanded ex vivo, having cell surface markers including, but not limited to, CD8 or CD4; 2) T cell clones reactive to one or more tumor antigens, having cell surface markers including, but not limited to, CD8 or CD4; 3) genetically engineered T cells having a tumor-specific T cell receptor or a tumor-specific chimeric antigen receptor, having cell surface markers including, but not limited to, CD8 or CD4; and 4) natural killer cells reactive to specific or multiple tumor antigens.

[0024] As used herein, the term "adoptive T cell" means an effector cell derived from naive T cells or activated T cells capable of effector function. As used herein, the term "solid tumor" means an abnormal mass of tissue that usually does not contain cysts or liquid regions. Solid tumors can be benign (non-cancerous) or malignant (cancerous). Solid tumors are named according to the type of cells present in the solid tumor. Examples of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas. As used herein, the term "small molecule agonist" is synonymous with a stabilizer of cognate ligand-receptor interactions, rather than a conventional ligand.

[0025] As used herein, the term "linker" means a moiety that connects two parts of a molecular system. In the present disclosure, the linker is a molecular moiety that is likely to be at the end groups of a small molecule integrin agonist, for example, end group 1 - linker - end group 2. In the integrin agonist of formula (I), the linker is defined by -M 3 -M 4 -M 5 -M 6 - and end group 1 is R 1 -M 1 -N(R 2 )-M2 - as defined by, and the terminal group 2 is -R 3 - as defined by. In the integrin agonist of formula (II), the linker is -R a -Z-R b - as defined by, and the terminal group 1 is Q 1 - as defined by, and the terminal group 2 is -Q 2 - as defined by. The terms "at least one", "one or more", or "one or a plurality" mean one or two or more, and these three terms can be used interchangeably herein. For example, at least one device, one or more devices, or one or a plurality of devices mean one device, two devices, or a number of devices up to a finite number such as the numerical value 20, but higher and lower values can be used.

[0026] The term "one or a plurality" means one item or a plurality of items. The term "about" means that a given value of a quantity is within ±10% of the recited value. In other embodiments, the value is within ±5% of the recited value. In other embodiments, the value is within ±2.5% of the recited value. In other embodiments, the value is within ±1% of the recited value. The term "substantially" or "essentially" means that a given value of a quantity is within ±5% of the recited value. In other embodiments, the value is within ±2.5% of the recited value. In other embodiments, the value is within ±2% of the recited value. In other embodiments, the value is within ±1% of the recited value. In other embodiments, the value is within ±0.5% of the recited value. In other embodiments, the value is within ±0.1% of the recited value. The terms "substantially free of" or "essentially free of" mean that a given amount value is ≦ 5%. In other embodiments, the value is ≦ 2.5%. In other embodiments, the value is ≦ 2%. In other embodiments, the value is ≦ 1%. In other embodiments, the value is ≦ 0.5%. In other embodiments, the value is ≦ 0.1%. All ranges include both end values and sub-ranges thereof. All single values include all lower values. For example, the term "about 25" includes all values greater than 0 and up to 25.

[0027] Abbreviations used in the present invention The following abbreviations are used in this specification: Ac is acetyl, AcOH is acetic acid, 6-Ahx-OH is 6-aminohexanoic acid, Bn is benzyl, Boc is tert-butyloxycarbonyl, nBu is n-butyl, nBuLi is n-butyllithium, 1.6 M in hexanes (unless otherwise specified), CBz is benzyloxycarbonyl, CDI is N,N′-carbonyldiimidazole, COMU is (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, Dab is 2,4-diaminobutyryl, DBU is 1,8-diazabicyclo[5.4.0] is undeca-7-ene, DCE is 1,2-dichloroethane, DCHA is dicyclohexylamine, DCM is dichloromethane (methylene chloride), dioxane is 1,4-dioxane, DIPEA is N,N-diisopropylethylamine, DMED is N,N'-dimethylethylenediamine, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, Et is ethyl, EtOH is ethanol, Fmoc is 9H-fluoren-9-ylmethyloxycarbonyl, Glu is glutamic acid, Gly is glycine, HBTU is O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HMDS is hexamethyldisilazane, iPr is isopropyl, KHMDS is potassium bis(trimethylsilyl)amide, Lys is lysine, LHMDS is lithium bis(trimethylsilyl)amide, Me is methyl, MeOH is methanol, Nle is norleucine, NMM is 4-methylmorpholine, NSMC is N-succinimidyl-N-methylcarbamate, OAc is acetate, Orn is ornithine, pTsOH is para-toluenesulfonic acid, Ph is phenyl, RT is room temperature, tBu is tert-butyl, TEA is triethylamine, Tfa is trifluoroacetyl, THF is tetrahydrofuran, Tol is toluene, Tyr is tyrosine, and Z is benzyloxycarbonyl.

[0028] Detailed Description of the Invention The inventors have found that an integrin agonist carrier composition can be formulated to improve the bioavailability of an integrin agonist. An integrin agonist pharmaceutical composition for administration to an animal or a human can be formulated using the integrin agonist carrier composition. In addition, the inventors have found a method for producing and using the integrin agonist carrier composition and the integrin agonist pharmaceutical composition. The integrin agonist carrier composition includes one or more zwitterionic surfactants, one or more neutral lipids, and one or more polar organic solvents.

[0029] The inventors have found that integrin agonists that enhance integrin-mediated cell-cell adhesion can be beneficial in various therapies, particularly those therapies in which integrin-mediated binding of cells having certain integrins and cells having integrin-related ligands is known or suspected to be involved. Integrins targeted by integrin agonists include, but are not limited to, α4βl (very late antigen-4 (VLA-4)), α4β7, α5β1, αLβ2 (lymphocyte function-associated antigen 1 (LFA-1)), and / or αVβ3, and corresponding ligands include, but are not limited to, VCAM-1, fibronectin, MAdCAM-1, ICAM-1, ICAM-2, and / or vitronectin.

[0030] This specification discloses small molecule poorly water-soluble pharmaceutical integrin agonist adjuvant agents and immunogenic compositions thereof, as well as methods for using them to induce an immune response in a subject. The small molecule poorly water-soluble pharmaceutical integrin agonist adjuvant agents include compounds that facilitate the interaction of integrin α4β1, α4β7, α5β1, and / or αLβ2 with their cognate ligands. The integrin adjuvant agents described above can be used to enhance and potentiate the immunological effects of active agents including vaccine antigens derived from various pathogens, toxins, and / or tumors. The practical and preferred route of administration of such integrin agonist adjuvant agents is via the oral route in the form of capsules, tablets, solutions, or suspensions.

[0031] Ethane-1,2-diylbis(oxy)bis(ethane-2,1-diyl)bis(bis(thiophen-2-ylmethyl)carbamate (C1) is a representative small molecule poorly water-soluble pharmaceutical integrin agonist adjuvant agent having desirable pharmacological properties. However, C1 is subject to limitations due to its water solubility and oral bioavailability. To improve oral absorption, lipid-based carrier compositions have been formulated and methods have been developed for producing oral dosage forms that achieve optimal pharmacokinetic exposure. Poorly water-soluble pharmaceutical integrin agonist adjuvant agents, for example, those classified as "practically insoluble" or "insoluble" according to the United States Pharmacopeia (USP) 24 (2000), page 10, i.e., those having a solubility of less than about 1 part per 10,000 parts of water (less than about 100 μg / ml), are extremely difficult to formulate for oral delivery. Among other problems, the bioavailability of such drugs tends to be very low when administered via the oral route. The oral bioavailability is further worsened by the fact that such molecules have a molecular weight >500, have no ionizable groups, and are metabolized by the gastrointestinal mucosa and hepatic CYP450 enzymes.

[0032] C1 is a small molecule integrin agonist adjuvant agent with low water solubility, disclosed and used in US Patent Nos. 9,512,109; 10,071,980; 10,035,784; 10,287,264; 10,342,866; 10,709,780; 10,709,781; 10,716,849; and 11,311,619, as well as foreign corresponding patents. The relevant properties of 7HP349 are shown in Table 1. [Table 1]

[0033] Another specific exemplary small molecule drug with low water solubility is the compound 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7-dioxa-2-azanonan-9-yl bis(2-thienylmethyl)carbamate or 1,13-bis(2-thienyl)-2,12-bis(2-thienylmethyl)-3,11-dioxo-4,7,10-trioxa-2,12-diazatridecane (7HP577), an integrin agonist adjuvant disclosed in US Patent Nos. 9,512,109; 10,071,980; 10,035,784; 10,287,264; 10,342,866; 10,709,780; 10,709,781; 10,716,849; and 11,311,619, and foreign corresponding patents. This neutral compound has a molecular weight of 576.78 g / mol and a LogP value of 6.58.

[0034] U.S. Patent Application Publication No. 20070104780 to Lipari et al. discloses that a pharmaceutical composition comprises a poorly water-soluble small molecule drug, such as N-4-(3-amino-1H-indazol-4-yl)phenyl-N'-(2-fluoro-5-methylphenyl)urea (ABT-869) and (+)-1-(5-tert-butyl-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102), dissolved in a substantially non-aqueous carrier comprising at least one phospholipid and a pharmaceutically acceptable solubilizer. The drug-carrier system forms a typically non-gelled and substantially opaque liquid dispersion when mixed with an aqueous phase. This composition is suitable for administration to a subject in need thereof by a suitable route, such as orally.

[0035] Caliph et al., J. Pharm. Sci., Vol. 98, p. 1073, 2000 discloses that the use of a carrier comprising a neutral lipid containing a fatty acid side chain having more than 10 carbon atoms (i.e., >C 10 fatty acid), optimally a neutral lipid containing a fatty acid side chain having at least 18 carbon atoms (i.e., >C 18 fatty acid), can improve the lymphatic absorption and oral bioavailability of insoluble compounds such as halofantrine, and Ali Khan et al., Int J Nanomedicine, 2013; 8:2733-2744 discloses that such lipid-based formulations can reduce first-pass metabolism losses. In the pharmaceutical art, there is still a need for novel liquid formulations of poorly water-soluble small molecule drugs, such as 7HP349 and 7HP577, that are suitable for oral administration. More particularly, there is a need for a formulation having at least one of the following features, advantages, or benefits, without limitation: a concentration of an integrin agonist such as 7HP349 and 7HP577 that is acceptably high (e.g., at least about 5 mass / mass%); and a bioavailability when administered orally that is acceptable (e.g., at least about 5%).

[0036] Lipid-based carrier composition range The lipid-based carrier composition of the present disclosure comprises one or more zwitterionic surfactants, one or more neutral lipids, and one or more polar organic co-solvents or solubilizing agents. In certain embodiments, the one or more zwitterionic surfactants comprise one or more phospholipids. Tables 2 and 3 summarize the ranges of the three main components of the lipid-based carrier composition. [Table 2] [Table 3]

[0037] In addition, the lipid-based carrier composition may contain up to 10% by weight of other adjuvants and / or excipients, and the other percentages by weight are adjusted so that the composition is 100% by weight. In other embodiments, other components are included at up to 5% by weight. In other embodiments, other components are included at up to 2.5% by weight. In other embodiments, other components are included at up to 1% by weight.

[0038] Lipid-based carrier pharmaceutical composition ranges The lipid-based pharmaceutical composition of the present disclosure comprises one or more zwitterionic surfactants, one or more neutral lipids, one or more polar organic co-solvents or solubilizing agents, and one or more small molecule poorly water-soluble pharmaceutical integrin agonist adjuvant agents. In certain embodiments, the one or more zwitterionic surfactants comprise one or more phospholipids. Table 4 below summarizes the ranges of the four main components of the lipid-based carrier composition. [Table 4] In addition, the lipid-based pharmaceutical composition may contain up to 10% by weight of other adjuvants and / or excipients, and the other percentages by weight are adjusted so that the composition is 100% by weight. In other embodiments, other components are included at up to 5% by weight. In other embodiments, other components are included at up to 2.5% by weight. In other embodiments, other components are included at up to 1% by weight.

[0039] Dosage and Effective Amount In certain embodiments, the effective dosage amount of a poorly water-soluble pharmaceutical agent, such as an integrin agonist of the present disclosure, in a lipid-based delivery system is from about 1 milligram (mg) to about 500 mg or any sub-range, for example, from about 1 mg to about 250 mg, from about 1 mg to about 200 mg, from about 1 mg to about 150 mg, from about 1 mg to about 100 mg, from about 1 mg to about 75 mg, from about 1 mg to about 50 mg, from about 1 mg to about 25 mg, from about 5 mg to about 150 mg, from about 5 mg to about 100 nM, from about 5 mg to about 75 mg, from about 5 mg to about 50 mg, from about 5 mg to about 25 mg, or any other sub-range thereof.

[0040] In certain embodiments, the therapeutically effective amount of a poorly water-soluble pharmaceutical agent, such as an integrin agonist of the present disclosure, at the site of application is from about 1 femtomolar concentration (fM) to about 300 micromolar concentration (μM) or any sub-range, for example, from about 1 fM to about 200 μM, from about 1 fM to about 100 μM, from about 1 fM to about 50 μM, from about 1 fM to about 25 μM, from about 1 fM to about 20 μM, from about 1 fM to about 15 μM, from about 1 fM to about 5 μM, from about 1 fM to about 1 μM, from about 1 fM to about 100 nanomolar concentration (nM), from about 1 fM to about 75 nM, from about 1 fM to about 50 nM, from about 1 fM to about 25 nM, or any other sub-range thereof.

[0041] In certain embodiments, the plasma concentration of a poorly water-soluble pharmaceutical agent, such as an integrin agonist of the present disclosure, in nanograms per milliliter (ng / mL) is from about 1 ng / mL to about 25 ng / mL or any sub-range, for example, from about 1 ng / mL to about 20 ng / mL, from about 1 ng / mL to about 15 ng / mL, from about 1 ng / mL to about 5 ng / mL, from about 1 ng / mL to about 1 ng / mL, from about 1 ng / mL to about 100 ng / mL, from about 1 ng / mL to about 75 ng / mL, from about 1 ng / mL to about 50 ng / mL, from about 1 ng / kg to about 25 ng / mL, or any other sub-range thereof.

[0042] Poorly Water-Soluble Pharmaceutical Agent The lipid-based carrier compositions of the present disclosure can be used to deliver any poorly water-soluble pharmaceutical agent or mixture thereof to an animal or a human. In certain embodiments, the poorly water-soluble pharmaceutical agent comprises a poorly water-soluble integrin-activating pharmaceutical agent or mixtures thereof. Such agents are characterized by having a LogP value greater than 5.0 (>5.0), 5.25 or greater (≧5.25), 5.5 or greater (≧5.5), 5.75 or greater (≧5.75), or 6.0 or greater (≧6.0).

[0043] Basic types of integrin-activating pharmaceutical agents In certain embodiments, the integrin-activating pharmaceutical agent is provided by a compound of formula (I). R 1 -M 1 -N(R 2 )-M 2 -M 3 -M 4 -M 5 -M 6 -R 3 (I) In the formula, the first class of compounds of formula (I) is defined as follows: R 1 is selected from the group consisting of aryl and aralkyl, R 2 is alkyl, aryl, or aralkyl, M 1 is CH 2 and M 2 is CO, M 3 is O, S, or NR 6 and R 6 when present, is hydrogen or lower alkyl, M 4 is absent or CH 2 and M 5 is (CR 11 R 12 ) and R 11 is hydrogen, R 12is hydrogen, NR 21 CONR 22 R 23 、NR 21 COR 24 、NR 21 SO 2 R 24 、NR 21 COOR 24 、OCOR 24 、OR 24 、O(CH 2 CH 2 O) S R 24 、COOR 24 、selected from the group consisting of alkyl, and hydroxyalkyl, s is an integer from 1 to 6, R 21 and R 22 when present, are independently selected from the group consisting of hydrogen or lower alkyl, R 23 when present, is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl, and alkoxycarbonylalkyl, provided that M 3 is NR 6 and when M 4 is absent, R 23 is not 1-(1,3-benzodioxol-5-yl)-3-ethoxy-3-oxopropyl, R 24 when present, is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, and mixtures thereof, M 6 is (CH 2 ) q and q is an integer from 0 to 6, R 3 is hydrogen, CONR 13 R 14 、NR 15 COOR 16 、NR 15 COR 16 、NR 15 CONR13 R 14 、 NR 15 SO2R 16 、 OCOR 16 、 COOR 16 、 OR 16 、 SR 16 、 is selected from the group consisting of heterocyclyl, hydroxyl, hydroxyalkyl, guanadino, alkyl, and aryl, R 13 and R 15 are, when present, independently hydrogen or lower alkyl, R 14 and R 16 are, when present, independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl, R 1 、 R 2 、 R 3 、 R 12 、 R 14 、 R 16 、 R 23 、 and R 24 are, when present, independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azide, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO 2 (alkyl), -NHSO 2 (aryl), -NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), -OCO(dialkylamino), and mixtures thereof, or In the formula, the second class of the compounds of formula (I) is defined as follows: R 1 is aryl or aralkyl, R 2 is alkyl or aralkyl, M 1 is CH 2 and M 2 is CO M 3 is absent or is O or CH 2 and M 4 is absent or is CH 2 and M 5 is absent or is O or (CR 11 R 12 ) R 11 is hydrogen, R 12 is hydrogen, NR 21 CONR 22 R 23 NR 21 COR 24 NR 21 SO2R 24 and NR 21 COOR 24 selected from the group consisting of, R 21 and R 22 each of which, when present, is independently selected from the group consisting of hydrogen and lower alkyl, R 23 and R 24 each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, M 6 is (CH 2 ) q is (CH 2 ) q -CH=CH-(CH 2 ) r is (CH 2 ) q-arylene-(CH 2 ) r 、and (CH 2 CH 2 O) q selected from the group consisting of, where q and r are each independently an integer from 0 to 6, R 3 is CONR 13 R 14 where R 13 and R 14 each, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, R 1 、R 2 、R 13 、R 14 、R 23 、and R 24 each, when present, is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azide, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO 2 (alkyl), -NHSO 2 (aryl), -NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), -OCO(dialkylamino), and mixtures thereof, or wherein a third class of compounds of formula (I) is defined as follows: R 1 is aryl or aralkyl, R2 is alkyl or aralkyl, M 1 is CH 2 and M 2 is SO 2 or CO, M 3 is absent or CH 2 and M 4 is absent or CH 2 and M 5 is absent or (CR 11 R 12 ) R 11 when present, is hydrogen, R 12 when present, is selected from the group consisting of hydrogen, alkyl, NR 21 CONR 22 R 23 NR 21 COR 24 NR 21 SO2R 24 and NR 21 COOR 24 and R 21 and R 22 each of which, when present, is independently selected from the group consisting of hydrogen, lower alkyl, and aralkyl, R 23 and R 24 each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, M 6 is (CH 2 ) q or NR 34 (CH 2 ) q and q is an integer from 0 to 6, R 34 when present, is alkyl, aralkyl, COR 35 and SO 2 R35 selected from the group consisting of R 35 when present, is selected from the group consisting of alkyl, aryl, and aralkyl, R 3 is CONR 13 R 14 、SO 2 NR 13 R 14 、NR 15 COOR 16 、NR 15 COR 16 、NR 15 CONR 13 R 14 、and NR 15 SO 2 R 16 selected from the group consisting of R 13 and R 14 each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, R 15 and R 16 each of which, when present, is independently selected from the group consisting of hydrogen, lower alkyl, and aralkyl, R 1 、R 2 、R 13 、R 14 、R 15 、R 16 、R 23 、R 24 、R 34 、and R 35is, when present, unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azide, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO 2 (alkyl), -NHSO 2 (aryl), -NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), and -OCO(dialkylamino), and is either unsubstituted or substituted with one or more substituents selected from the group consisting of: provided that when M 2 is CO, M 6 is NR 34 (CH 2 ) q and q is not 0, or wherein a fourth class of compounds of formula (I) is defined as follows: R 1 is alkyl, aryl, or aralkyl, R 2 is selected from the group consisting of aralkyl and alkyl, provided that when R 1 is alkyl, R 2 is aralkyl, M 1 is CO or SO 2 and provided that when M 1 is SO 2 and R 1 is phenyl, 4-methylphenyl, or 2,4,6-trimethylphenyl, then R 2 is not alkyl, 2-phenethyl, benzyl, or 2-methoxy-2-oxoethyl, and M1 is CO, and R 1 is 2-furyl, 4-pyridyl, or 3,5-dinitrophenyl, then R 2 is not alkyl, benzyl, or 2-(1H-indol-2-yl)ethyl, M 2 is absent or CH 2 and M 3 and M 4 are absent, M 5 is (CR 11 R 12 ), R 11 is hydrogen, R 12 is hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 , CONR 22 R 23 , COOR 24 , O(CH 2 CH 2 O) S R 24 , hydroxyalkyl, and alkoxyalkyl, and is selected from the group consisting of R 21 and R 22 are, when present, independently selected from the group consisting of hydrogen and C 1 ~C 6 alkyl, R 23 and R 24 each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, s is an integer from 1 to 6, M 6 is (CH 2 ) q and q is an integer from 0 to 6, R 3 is NR 15 COOR 16 NR 15 COR 16 NR 15 CONR 13 R 14 and NR 15 SO 2 R 16 selected from the group consisting of, R 13 when present, is hydrogen and C 1 ~C 6 alkyl, independently selected from the group consisting of, R 14 R 15 and R 16 each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, R 1 R 2 R 3 R 12 R 14 R 15 R 16 R 23 and R 24 when present, are independently unsubstituted or alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azide, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO 2 (alkyl), -NHSO 2 (aryl), -NHSO 2either substituted with one or more substituents selected from the group consisting of (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), and -OCO(dialkylamino), or their pharmaceutically acceptable salts, or their mixtures.

[0044] In some embodiments, a chemical compound having the general formula (I), wherein R 1 is aryl or aralkyl, R 2 is alkyl, aryl, or aralkyl, M 1 is CH 2 and M 2 is CO, M 3 is absent, M 4 is absent or CH 2 and M 5 is (CR 11 R 12 ) and M 6 is (CH 2 ) q where q is an integer from 0 to 6, R 11 is hydrogen, R 12 is hydrogen, NR 21 CONR 22 R 23 NR 21 COR 24 NR 21 SO 2 R 24 NR 21 COOR 24 OCOR 24 OR 24 SCOR 24 SR 24 N 3 CN, and O(CH 2 CH 2 O) S R 24 selected from the group consisting of, s is an integer from 1 to 6, and R 21 and R 22 , when present, are independently selected from the group consisting of hydrogen, lower alkyl, or aralkyl, R23 is, when present, selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl, and alkoxycarbonylalkyl, R 24 is, when present, selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, provided that M 3 and M 4 is absent, R 12 is not the following formula, J || A-C-E-C(MX)-T-L-R 25 wherein A is selected from the group consisting of -O-, -S-, and -NR 26 -, E is selected from the group consisting of -CH 2 -, -O-, -S-, and -NR 27 -, J is selected from the group consisting of -O-, -S-, and -NR 28 -, T is selected from the group consisting of CO and (CH 2 ) b selected from the group consisting of, b is an integer from 0 to 3, L is --(CH 2 )--, --O--, --S--, and --NR 29 -- selected from the group consisting of, n is an integer from 0 to 3, M is CR 30 R 31 and (CH 2 ) u selected from the group consisting of, u is an integer of 0 or 1, X is CO 2 B, PO 3 H 2 , SO 3 H, OPO 3 H 2 , CONHCOR 32 , CONHSO 2 R 33 , selected from the group consisting of oxazolyl, tetrazolyl, and hydrogen, B, R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R32 and R 33 is hydrogen, haloalkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, --CF 3 , nitro, amino, cyano, N(C 1 ~C 3 alkyl)CO(C 1 ~C 3 alkyl), C 1 ~C 3 alkylamino, alkenylamino, alkynylamino, di(C 1 ~C 3 alkyl)amino, CO 2 (C 1 ~C 3 alkylamino), CONH(C 1 ~C 3 alkylamino), CH=NOH, PO 3 H 2 , OPO 3 H 2 , CON(C 1 ~C 3 alkyl) 2 , haloalkyl, alkoxycarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclic alkyl (heterocyclycalkyl), sulfonyl, sulfonamide, carbamate, aryloxyalkyl, carboxyl, and CONH(benzyl), independently selected from the group consisting of, B, X, R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 is unsubstituted or substituted with at least one electron donating group or electron withdrawing group, R 3 is hydrogen, NR 15 COOR 16 , NR 15COR 16 、 NR 15 CONR 13 R 14 、 NR 15 SO 2 R 16 、 OCOR 16 、 COOR 16 、 alkyl, SR 16 、 selected from the group consisting of heterocyclyl, hydroxyl, hydroxyalkyl, guanidino, and aryl, R 13 and R 15 are, when present, independently hydrogen, lower alkyl, or aralkyl, R 14 and R 16 are, when present, independently selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, provided that when R 3 is hydrogen, alkyl, or aryl, R 12 is not hydrogen, provided that when R 1 is phenyl, R 3 is benzyloxycarbonylamino, R 12 is hydrogen, R 2 is not 2-methoxybenzyl, R 1 、 R 2 、 R 3 、 R 12 、 R 13 、 R 14 、 R 15 、 R 16 、 R 21 、 R 22 、 R 23 、 and R 24which, when present, is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azide, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO 2 (alkyl), -NHSO 2 (aryl), -NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), -OCO(dialkylamino), and may be either of them substituted with one or more substituents selected from the group consisting of A chemical compound is provided.

[0045] In other embodiments, the integrin activating pharmaceutical agent is defined by the composition of formula (II). Q 1 -R a -Z-R b -Q 2 (II) Wherein Q 1 group and Q 2 group are independently R 1 R 2 N-group, R 1 R 2 NC(=O)-group, R 1 R 2 NC(=O)N(R 3 )-group, R 1 R 2 NC(=O)O-group, or R 1 R 2 NSO 2 -group, and R 1 group and R 2The groups may independently be a hydrocarbyl group, a heterohydrocarbyl group, an aryl-containing hydrocarbyl group, a heteroaryl-containing hydrocarbyl group, an aryl-containing heterohydrocarbyl group, a heteroaryl-containing heterohydrocarbyl group, a fused heterocyclic group, or any combination thereof. R 3 The groups may be a hydrocarbyl group or a heterohydrocarbyl group. R a The groups and R b The groups may independently be a hydrocarbenyl linking group in which one or more carbon atoms may be replaced by oxygen atoms, such as an alkylene oxide linking group such as a methylene oxide-containing linking group or an ethylene oxide-containing linking group. The Z group may be a hydrocarbenyl linking group or a heterohydrocarbenyl linking group and contains one or more protonatable moieties.

[0046] In certain embodiments, one or more protonatable moieties are protonated at biological pH and / or are protonated and contain a pharmaceutically acceptable counterion. In certain embodiments, R 1 The groups and R 2 The groups are selected from the group consisting of 2-thienylalkyl groups, 3-alkoxybenzyl groups, 4-alkoxybenzyl groups, pyridin-2-ylalkyl, pyridin-4-ylalkyl groups, pyridin-4-ylalkyl groups, 4-dialkylaminobenzyl groups, 3-dialkylaminobenzyl groups, and mixtures or combinations thereof, and the alkyl group or alkoxy group independently contains 1 to 6 carbon atoms.

[0047] In other embodiments, R 1 The groups and R 2The base is selected from the group consisting of 2-thienylmethyl group, 2-(2-thienyl)ethyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, pyridin-2-ylmethyl group, pyridin-4-ylmethyl group, pyridin-4-ylmethyl group, 4-dimethylaminobenzyl group, 3-dimethylaminobenzyl, carbazole, 3,6-dimethoxycarbazole, and mixtures or combinations thereof. In certain embodiments, R a group and R b group are independently -O(R c O) n -, -R d O(R c O) n - group, -O(R c O) n R e - group, -R d O(R c O) n R e - group, or R aa group, wherein R c , R d , R e , and R aa are independently optionally hydrocarbyl linking groups, and each n is independently an integer having a value of 1 to 6. In other embodiments, the R a group and the R b group are independently optionally -O((CH 2 ) m O) n -, m is an integer having a value of 1 to 3, and n is an integer having a value of 1 to 6.

[0048] In other embodiments, the R a group and the R b group are independently optionally -O((CH 2 ) m1 )((CH 2 ) m2 O) n (CH 2 ) m3 - group, wherein m1, m2, and m3 are integers having a value of 1 to 3, and n is an integer having a value of 1 to 8. In other embodiments, the R a group and Rb The group is independently -((CH 2 ) m1 )((CH 2 ) m2 O) n (CH 2 ) m3 - group or -(CH 2 ) m1 - and may be, wherein m1, m2, and m3 are integers having values of 1 to 3, and n is an integer having a value of 1 to 6. Exemplary examples include, but are not limited to, -O(CH 2 O) n - group, -O(CH 2 CH 2 O) n - group, -O(CH 2 CH 2 CH 2 O) n - group, -CH 2 O(CH 2 O) n - group, -O(CH 2 O) n CH 2 - group, -CH 2 O(CH 2 O) n CH 2 - group, -CH 2 O(CH 2 CH 2 O) n - group, -O(CH 2 CH 2 O) n CH 2 - group, -CH 2 O(CH 2 CH 2 O) n CH 2 - group, -CH 2 CH 2 O(CH 2 CH 2 O) n - group, -O(CH 2 CH 2 O) n CH 2 CH 2 - group, -CH 2 CH 2 O(CH 2 CH 2 O)n CH 2 CH 2 - group, or a higher analog, or -(CH 2 ) n - group may be, where n is an integer having a value of 1 to 6. R a and R b are selected such that the agonist does not contain certain moieties such as a -C-N-O- moiety, an -O-O- moiety, or other linking moieties that are unstable or decompose into undesirable by-products. It should be recognized that the selection of Q 1 and Q 2 will depend on this.

[0049] In certain embodiments, the Z group is -R f N(R 4 )R g - group, -R f N + (R 4 R 5 A - )R g - group, -R f C(R 6 )(N(R 4 R 5 ))R g - group, -R f C(R 6 )(N(R 4 R 5 R 7 A - ))R g - group, -R f C(R 6 )(R h N(R 4 R 5 ))R g - group, or -R f C(R 6 )(R h N(R 4 R 5 R 7 A - ))R g - group, where (a) the R 4 , R 5 , R 6 , and R 7 groups are independently a hydrocarbyl group or a heterohydrocarbyl group, and (b) Rf Group and R g The group is independently C 1 ~C 3 is an alkenyl linking group, (c) A - The group is independently a counter ion.

[0050] In other embodiments, the Z group is -G 1 -J-G 2 - group, wherein (a) the J group contains an arylene group or a heteroarylene group, (b) G 1 group and G 2 The group is independently -R f -(R 8 )N - group, -R f -(R 8 )N-R g - group, -R f -O- group, -R f -O-R g - group, -C(=O)- group, -C(=O)-R g - group, -C(=O)N(R 8 )- group, -C(=O)N(R 8 )-R g - group, -C(=O)O- group, -C(=O)O-R g - group, -R f -(R 8 )NC(=O)- group, -R f -(R 8 )NC(=O)-R g - group, -R f -(R 8 )NC(=O)N(R 8 )- group, -R f -(R 8 )NC(=O)N(R 8 )-R g - group, -R f -(R 8 )NC(=O)O- group, -R f -(R 8 )NC(=O)O-R g - group, -R f -OC(=O)- group, -R f -OC(=O)-R g - group, -R f -OC(=O)N(R 8 )- group, -Rf -OC(=O)N(R 8 )-R g -group, -R f -OC(=O)O-group, or -R f -OC(=O)O-R g -group, and (c)R f group and R g group are, independently, C 1 ~C 3 alkenyl linking group, and (d)R 8 group are, independently, a hydrogen atom or C 1 ~C 8 hydrocarbyl group, and (e)A - groups each independently contain a counterion. In certain embodiments, the Z group may comprise a hydrocarbyl or heterohydrocarbyl linking group comprising any of the hydrocarbyl or heterohydrocarbyl linking groups disclosed herein.

[0051] In other embodiments, the Z group comprises a hydrocarbyl or heterohydrocarbyl group, which hydrocarbyl or heterohydrocarbyl group is protonated at biological pH and / or is charged and comprises one or more moieties associated with an acceptable counterion. Representative examples of Z groups that comprise a hydrocarbyl group or heterohydrocarbyl group that is protonated at biological pH and / or is charged and comprises at least one moiety associated with an acceptable counterion include, but are not limited to, pyrrole, pyrrole-2,3-dicarboxylic acid, pyridine, pyridine-2,3-dicarboxylic acid, pyridine-2,4-dicarboxylic acid, pyridine-2,5-dicarboxylic acid, pyridine-3,4-dicarboxylic acid, pyridine-2,4-dicarboxylic acid, pyridine-2,5-dicarboxylic acid, pyridine-2,6-dicarboxylic acid, pyridine-3,4-dicarboxylic acid, pyridine-3,5-dicarboxylic acid, or groups derived from other heterohydrocarbyl groups. In other embodiments, the Z group includes, but is not limited to, 1-amino-benzene-2,4-dicarboxylic acid, 1-amino-benzene-2,5-dicarboxylic acid, 1-amino-benzene-2,6-dicarboxylic acid, 1-amino-benzene-3,4-dicarboxylic acid, 1-amino-benzene-3,5-dicarboxylic acid, 1,2,3-trihydroxybenzene, 1,2,4-trihydroxybenzene, 1,2,5-trihydroxybenzene, 1,3,4-trihydroxybenzene, 1,3,5-trihydroxybenzene, 1-amino-2,3-dihydroxybenzene, 1-amino-2,4-dihydroxybenzene, 1-amino-2,5-dihydroxybenzene, 1-amino-3,4-dihydroxybenzene, 1-amino-3,5-dihydroxybenzene, orthoformic acid, glycerol, 2-amino-1,3-dihydroxypropane, diethanolamine, N-methyldiethanolamine, dipropanolamine, N-methyldipropanolamine, diisopropanolamine, N-methyldiisopropanolamine, higher dialkanolamines, higher N-methyldialkanolamines, or may be derived from other hydrocarbyl groups.

[0052] In certain embodiments, R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 groups are present and, when not a hydrogen atom, are independently unsubstituted or substituted with one or more substituents selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclylaryl group, a hydroxy group, an alkoxy group, an azide group, a haloalkoxy group, a hydroxyalkyl group, an aryloxy group, a hydroxyaryl group, an alkoxyaryl group, a halogen atom, a haloalkyl group, a haloaryl group, an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, -NHC(=O)(alkyl) group, -NHC(=O)(aryl) group, -NHC(=O)(aralkyl) group, -NHC(=O)(haloalkyl) group, -NHSO 2 (alkyl) group, -NHSO 2 (aryl) group, -NHSO 2 (aralkyl) group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, -OC(=O)(alkylamino) group, and -OC(=O)(dialkylamino) group, may be either unsubstituted or substituted with one or more substituents selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclylaryl group, a hydroxy group, an alkoxy group, an azide group, a haloalkoxy group, a hydroxyalkyl group, an aryloxy group, a hydroxyaryl group, an alkoxyaryl group, a halogen atom, a haloalkyl group, a haloaryl group, an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, -NHC(=O)(alkyl) group, -NHC(=O)(aryl) group, -NHC(=O)(aralkyl) group, -NHC(=O)(haloalkyl) group, -NHSO

[0053] Certain integrin activating pharmaceutical agents of formula (I) In some embodiments, the integrin agonist of formula (I) includes the following: N,N,N’,N’-tetrakis(2-thienylmethyl)pentanediamide, N-(3-methoxybenzyl)-N,N’,N’-tris(2-thienylmethyl)pentanediamide, N,N,N’-tris(2-thienylmethyl)pentanediamide, N’-[2-(2-thienyl)ethyl]-N,N-bis(2-thienylmethyl)pentanediamide, N-[2-(2-thienyl)ethyl]-N,N’,N’-tris(2-thienylmethyl)pentanediamide, N,N-bis(pyridin-4-ylmethyl)-N’,N’-bis(2-thienylmethyl)pentanediamide, N,N-bis(pyridin-3-ylmethyl)-N’,N’-bis(2-thienylmethyl)pentanediamide, N,N-bis(3-methoxybenzyl)-N’,N’-bis(2-thienylmethyl)pentanediamide, N,N,N’,N’-tetrakis(4-methoxybenzyl)pentanediamide, N,N,N’,N’-tetrakis(2-thienylmethyl)hexanediamide, N,N,N’,N’-tetrakis(4-methoxybenzyl)hexanediamide, N,N,N’,N’-tetrakis(3-methoxybenzyl)hexanediamide, N,N,N’,N’-tetrakis(2-thienylmethyl)heptanediamide, 2,2’-(1,3-phenylene)bis[N,N-bis(2-thienylmethyl)acetamide], N,N,N’,N’-tetrakis(4-methoxybenzyl)heptanediamide, N,N,N’,N’-tetrakis(2-thienylmethyl)octanediamide, (3E)-N,N,N’,N’-tetrakis(2-thienylmethyl)hexa-3-enediamide, 2,2’-oxybis[N,N-bis(2-thienylmethyl)acetamide], 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,10-trioxa-2-azadodecan-12-yl bis(2-thienylmethyl)carbamate (7HP349), 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7-dioxa-2-azanonan-9-yl bis(2-thienylmethyl)carbamate (7HP577), N,N,N’,N’-tetrakis(4-methoxybenzyl)succinamide ethane-1,2-diylbis[bis(2-thienylmethyl)carbamate], N,N,N’,N’-tetrakis(4-methoxybenzyl)octanediamide, N,N,N’,N’-Tetrakis(2-thienylmethyl)pyridine-3,5-dicarboxamide, N,N,N’,N’-Tetrakis(2-thienylmethyl)pyridine-2,6-dicarboxamide, N,N,N’,N’-Tetrakis(2-thienylmethyl)pyridine-2,4-dicarboxamide, 2,2’-(1,4-Phenylene)bis[N,N-bis(2-thienylmethyl)acetamide], 8-{2-[Bis(2-thienylmethyl)amino]-2-oxoethoxy}-N,N-bis(2-thienylmethyl)quinoline-2-carboxamide, N,N’-Bis(4-methoxybenzyl)-N,N’-bis(2-thienylmethyl)hexanediamide, and tert-butyl {(2S)-1,6-bis[bis(2-thienylmethyl)amino]-1,6-dioxohexan-2-yl}carbamate.

[0054] Specific integrin activating pharmaceutical agent of formula (II) R a ZR b =(OCH 2 ) n N(CH 3 )(CH 2 O) class In certain embodiments, the integrin agonist of formula (II) comprises one or more agonists, wherein R a ZR b group is -(OCH 2 ) n N(CH 3 )(CH 2 O) n -, and n is an integer from 1 to 6. In other embodiments, the agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,6-diaza-6-methyl-heptan-7-yl-bis(2-thienylmethyl)carbamate or 3,9-dioxo-1,11-bis(2-thienyl)-2,10-bis(2-thienylmethyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane, (b) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undecan-11-yl-bis(2-thienylmethyl)carbamate or 3,13-dioxo-1,15-bis(2-thienyl)-2,14-bis(2-thienylmethyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane, (c) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecane-15-yl-bis(2-thienylmethyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(2-thienylmethyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecane, (d) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4-oxa-2,6-diaza-6-methyl-heptan-7-yl-bis(3-methoxybenzyl)carbamate or 3,9-dioxo-1,11-bis(3-methoxyphenyl)-2,10-bis(3-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane, (e) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undecan-11-yl-bis(3-methoxybenzyl)carbamate or 3,13-dioxo-1,15-bis(3-methoxyphenyl)-2,14-bis(3-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane, (f) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecane-15-yl-bis(3-methoxybenzyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(3-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecane, (g) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,6-diaza-6-methyl-heptane-7-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,9-dioxo-1,11-bis(3-methoxyphenyl)-2,10-bis(3-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane, (h) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undecane-11-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,13-dioxo-1,15-bis(3-methoxyphenyl)-2,14-bis(3-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane, (i) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecane-15-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(3-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecane, (j) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4-oxa-2,6-diaza-6-methyl-heptan-7-yl-bis(4-methoxybenzyl)carbamate or 3,9-dioxo-1,11-bis(4-methoxyphenyl)-2,10-bis(4-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane, (k) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undecan-11-yl-bis(4-methoxybenzyl)carbamate or 3,13-dioxo-1,15-bis(4-methoxyphenyl)-2,14-bis(4-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane, (l) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecane-15-yl-bis(4-methoxybenzyl)carbamate or 3,17-dioxo-1,19-bis(4-methoxyphenyl)-2,18-bis(4-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecane, (m) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,6-diaza-6-methyl-heptan-7-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,9-dioxo-1,11-bis(4-methoxyphenyl)-2,10-bis(4-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane, (n) 3-Oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undecan-11-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,13-dioxo-1,15-bis(4-methoxyphenyl)-2,14-bis(4-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane, (o) 3-Oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecane-15-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(4-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecane, (p) N-Methylbis[(9-carbazolylcarbonyloxy)methyl]amine, (q) N-Methylbis{[(9-carbazolylcarbonyloxy)methoxy]methyl}amine, (r) N-Methylbis({[(9-carbazolylcarbonyloxy)methoxy]methoxy}methyl)amine, (s) N-Methylbis[(3,6-dimethoxy-9-carbazolylcarbonyloxy)methyl]amine, (t) N-Methylbis{[(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methyl}amine, (u) N-Methylbis({[(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}methyl)amine, (v) higher analogs, or (w) mixtures and combinations thereof.

[0055] In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-bis(2-thienylmethyl)carbamate or 3,11-dioxo-1,13-bis(2-thienyl)-2,11-bis(2-thienylmethyl)-4,10-dioxa-2,6,12-triaza-7-methyl-tridecane, (b) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecane-15-yl-bis(2-thienylmethyl)carbamate, (c) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-henicosane-21-yl-bis(2-thienylmethyl)carbamate, (d) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-bis(3-methoxybenzyl)carbamate, (e) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecane-15-yl-bis(3-methoxybenzyl)carbamate, (f) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-henicosane-21-yl-bis(3-methoxybenzyl)carbamate, (g) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate, (h) 3-oxo-l-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecane-15-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate, (i) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-henicosan-21-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate, (j) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-bis(4-methoxybenzyl)carbamate, (k) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecane-15-yl-bis(4-methoxybenzyl)carbamate, (l) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-henicosan-21-yl-bis(4-methoxybenzyl)carbamate, (m) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate, (n) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecane-15-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate, (o) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-henicosan-21-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate, (p) 2-{[2-(9H-carbazol-9-ylcarbonyloxy)ethyl]-N-methylamino}ethyl 9H-carbazole-9-carboxylate, (q) 2-[2-({2-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]ethyl}-N-methylamino)ethoxy]ethyl 9H-carbazole-9-carboxylate, (r) 2-(2-{2-[(2-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}ethyl)-N-methylamino]ethoxy}ethoxy)ethyl 9-carbazolecarboxylate, (s) 2-{[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethyl]-N-methylamino}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (t) 2-[2-({2-[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]ethyl}-N-methylamino)ethoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (u) 2-(2-{2-[(2-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}ethyl)-N-methylamino]ethoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (v) higher analogs, or, (w) mixtures and combinations thereof.

[0056] R a and R b =(OCH 2 ) n or (CH 3 )(CH 2 O) n and the class where Z = 2,6-dihydroxypyridine In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a group and R b group are (OCH 2 ) n or (OCH 2 CH 2 ) nincluding, where n is an integer from 1 to 6, and the Z group is derived from 2,6-dihydroxypyridine. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds: (a) 2-[bis(tenyl)aminocarbonyloxy],6-[bis(tenyl)aminocarbonyloxy]pyridine, (b) 2-[bis(3-methoxybenzyl)aminocarbonyloxy],6-[bis(3-methoxybenzyl)aminocarbonyloxy]pyridine, (c) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine, (d) 2-[bis(4-methoxybenzyl)aminocarbonyloxy],6-[bis(4-methoxybenzyl)aminocarbonyloxy]pyridine, (e) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],6-[(4-methoxybenzyl)(4-dimethylaminobenzyl(aminocarbonyloxy]pyridine, (f) 6-(9H-carbazol-9-ylcarbonyloxy)-2-pyridyl 9H-carbazole-9-carboxylate, (g) 6-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)-2-pyridyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or (h) mixtures and combinations thereof.

[0057] In other embodiments, the integrin activating compound includes one or more of the following integrin activating compounds: (a) 2-[bis(tenyl)aminocarbonyloxymethoxy],6-[bis(tenyl)aminocarbonyloxymethoxy]pyridine, (b) 2-[bis(tenyl)aminocarbonyloxymethoxymethoxy],6-[bis(tenyl)aminocarbonyloxymethoxymethoxy]pyridine, (c) 2 - [Bis(3 - methoxybenzyl)aminocarbonyloxymethoxy], 6 - [bis(3 - methoxybenzyl)aminocarbonyloxymethoxy]pyridine, (d) 2 - [Bis(3 - methoxybenzyl)aminocarbonyloxymethoxymethoxy], 6 - [bis(3 - methoxybenzyl)aminocarbonyloxymethoxyemthyloxy(amino carbonyloxymethoxyemthyloxy)]pyridine, (e) 2 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxy], 6 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxy]pyridine, (f) 2 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 6 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine, (g) 2 - [Bis(4 - methoxybenzyl)aminocarbonyloxymethoxy], 6 - [bis(4 - methoxybenzyl)aminocarbonyloxymethoxy]pyridine, (h) 2 - [Bis(4 - methoxybenzyl)aminocarbonyloxymethoxymethoxy], 6 - [bis(4 - methoxybenzyl)aminocarbonyloxymethoxymethoxy]pyridine, (i) 2 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxy], 6 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxy]pyridine, (j) 2 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 6 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine, (k) 2 - {6 - [2 - (9H - carbazol - 9 - ylcarbonyloxy)methoxy] - 2 - pyridyloxy}methyl 9H - carbazole - 9 - carboxylate, (l) 2-[2-(6-{2-[2-(9-carbazolylcarbonyloxy)methoxy]methoxy}-2-pyridyloxy)methoxy]methyl 9-carbazolecarboxylate, (m) 2-{6-[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)methoxy]-2-pyridyloxy}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(6-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}-2-pyridyloxy)methoxy]methyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) higher analogs, or, (p) mixtures and combinations thereof.

[0058] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 2-[bis(tenyl)aminocarbonyloxyethoxy],6-[bis(tenyl)aminocarbonyloxyethoxy]pyridine, (b) 2-[bis(tenyl)aminocarbonyloxyethoxyethoxy],6-[bis(tenyl)aminocarbonyloxyethoxyethoxy]pyridine, (c) 2-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy],6-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]pyridine, (d) 2-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy],6-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (e) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy],6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine, (f) 2-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (g) 2-[Bis(4-methoxybenzyl)aminocarbonyloxyethoxy], 6-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]pyridine, (h) 2-[Bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy], 6-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (i) 2-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine, (j) 2-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (k) 2-{6-[2-(9H-Carbazol-9-ylcarbonyloxy)ethoxy]-2-pyridyloxy}ethyl 9H-carbazole-9-carboxylate, (l) 2-[2-(6-{2-[2-(9-Carbazolylcarbonyloxy)ethoxy]ethoxy}-2-pyridyloxy)ethoxy]ethyl 9-carbazolecarboxylate, (m) 2-{6-[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]-2-pyridyloxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(6-{2-[2-(3,6-Dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}-2-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) Higher analogs, or, (p) Their mixtures and combinations.

[0059] R a and R b =(OCH 2 ) n or CH 3 )(CH 2 O) n and Z = a class of 2,6-dimethanol pyridine In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a group and R b group are (OCH 2 ) n or (OCH 2 CH 2 ) n n is an integer from 1 to 6, and Z is derived from 2,6-dimethanol pyridine. In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) 2-({bis[(2-thienyl)methyl]aminocarbonyl-oxy}methyl)-6-({bis[(2-thienyl)methyl]aminocarbonyl-oxy}methyl)pyridine, (b) 2-({bis(3-methoxybenzyl)aminocarbonyl-oxy}methyl)-6-({bis(3-methoxybenzyl)aminocarbonyl-oxy}methyl)pyridine, (c) 2-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl-oxy}methyl)-6-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl-oxy}methyl)pyridine, (d) 2-({bis(4-methoxybenzyl)aminocarbonyl-oxy}methyl)-6-({bis(4-methoxybenzyl)aminocarbonyl-oxy}methyl)pyridine, (e) 2-(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl-oxy}methyl)-6-(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl-oxy}methyl)pyridine, (f) {6-[(9H-Carbazol-9-ylcarbonyloxy)methyl]-2-pyridyl}methyl 9H-carbazole-9-carboxylate, (g) {6-[(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)methyl]-2-pyridyl}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or (h) mixtures and combinations thereof.

[0060] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 2-{Bis[(2-thienyl)methyl]aminocarbonyloxy}methoxy)methyl]-6-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxy)methyl]pyridine, (b) 2-{Bis[(2-thienyl)methyl]aminocarbonyloxy}methoxymethoxy)methyl]-6-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxymethoxy)methyl]pyridine, (c) 2-{Bis(3-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]-6-{bis(3-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]pyridine, (d) 2-{Bis(3-methoxybenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-6-{bis(3-methoxybenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine, (e) 2-(3-Methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]-6-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]pyridine, (f) 2-(3-Methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-6-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxyemthoxy)methyl]pyridine, (g) 2-{(Bis(4-methoxybenzyl)aminocarbonyloxy)methoxy}methyl]-6-{(bis(4-methoxybenzyl)aminocarbonyloxy)methoxy}methyl]pyridine, (h) 2-{(Bis(4-methoxybenzyl)aminocarbonyloxy)methoxymethoxy}methyl]-6-{(bis(4-methoxybenzyl)aminocarbonyloxy)methoxymethoxy}methyl]pyridine, (i) 2-(4-Methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]-6-(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]pyridine, (j) 2-(4-Methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-6-(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine, (k) 2-[(6-{[2-(9H-Carbazol-9-ylcarbonyloxy)methoxy]methyl}-2-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate, (l) 2-(2-{[6-({2-[2-(9H-Carbazolylcarbonyloxy)methoxy]methoxy}methyl)-2-pyridyl]methoxy}ethoxy)ethyl 9-carbazolecarboxylate, (m) 2-[(6-{[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)methoxy]methyl}-2-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-(2-{[6-({2-[2-(3,6-Dimethoxy-9H-carbazolylcarbonyloxy)methoxy]methoxy}methyl)-2-pyridyl]methoxy}methoxy)ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) Higher analogs, or, (p) Mixtures and combinations thereof.

[0061] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 2-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxy)methyl]-6-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxy)methyl]pyridine, (b) 2-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxyethoxy)methyl]-6-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (c) 2-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]-6-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]pyridine, (d) 2-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]-6-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (e) 2-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxy)methyl]-6-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxy)methyl]pyridine, (f) 2-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]-6-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (g) 2-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]-6-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]pyridine, (h) 2-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]-6-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (i) 2-({[4-Methoxybenzyl,4-dimethylaminobenzyl]aminocarbonyl}oxy)ethoxy)methyl]-6-({[4-methoxybenzyl,4-dimethylaminobenzyl]aminocarbonyl}oxy)ethoxy)methyl]pyridine, (j) 2-({[4-Methoxybenzyl,4-dimethylaminobenzyl]aminocarbonyl}oxyethoxyethoxy)methyl]-6-({[4-methoxybenzyl,4-dimethylaminobenzyl]aminocarbonyl}oxyethoxyethoxy)methyl]pyridine, (k) 2-[(6-{[2-(9H-Carbazol-9-ylcarbonyloxy)ethoxy]methyl}-2-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate, (l) 2-(2-{[6-({2-[2-(9H-Carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-2-pyridyl]methoxy}ethoxy)ethyl 9-carbazolecarboxylate, (m) 2-[(6-{[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-2-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-(2-{[6-({2-[2-(3,6-Dimethoxy-9H-carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-2-pyridyl]methoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) Higher analogs, or, (p) Mixtures and combinations thereof.

[0062] R a and R b =(OCH 2 ) n or CH 3 )(CH 2 O) n as well as the class where Z = 3,5-dihydroxypyridine In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a group and R bThe base contains (OCH 2 ) n or (OCH 2 CH 2 ) n where n is an integer from 1 to 6 and Z is derived from 3,5-dihydroxypyridine. In other embodiments, the integrin agonist of formula (II) contains one or more of the following integrin activating compounds: (a) 3-[Bis(tenyl)aminocarbonyloxy],5-[bis(tenyl)aminocarbonyloxy]pyridine, (b) 3-[Bis(3-methoxybenzyl)aminocarbonyloxy],5-[bis(3-methoxybenzyl)aminocarbonyloxy]pyridine, (c) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine, (d) 3-[Bis(4-methoxybenzyl)aminocarbonyloxy],5-[bis(4-methoxybenzyl)aminocarbonyloxy]pyridine, (e) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine, (f) 5-(9H-Carbazol-9-ylcarbonyloxy)-3-pyridyl 9H-carbazole-9-carboxylate, (g) 5-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)-3-pyridyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or (h) mixtures and combinations thereof.

[0063] In other embodiments, the integrin activating compound contains one or more of the following integrin activating compounds: (a) 3-[Bis(tenyl)aminocarbonyloxymethoxy],5-[bis(tenyl)aminocarbonyloxymethoxy]pyridine, (b) 3 - [Bis(tenyl)aminocarbonyloxymethoxymethoxy], 5 - [bis(tenyl)aminocarbonyloxymethoxymethoxy]pyridine, (c) 3 - [Bis(3 - methoxybenzyl)aminocarbonyloxymethoxy], 5 - [bis(3 - methoxybenzyl)aminocarbonyloxymethoxy]pyridine, (d) 3 - [Bis(3 - methoxybenzyl)aminocarbonyloxymethoxymethoxy], 5 - [bis(3 - methoxybenzyl)aminocarbonyloxymethoxymethoxy]pyridine, (e) 3 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxy], 5 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxy]pyridine, (f) 3 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine, (g) 3 - [Bis(4 - methoxybenzyl)aminocarbonyloxymethoxy], 5 - [bis(4 - methoxybenzyl)aminocarbonyloxymethoxy]pyridine, (h) 3 - [Bis(3 - methoxybenzyl)aminocarbonyloxymethoxymethoxy], 5 - [bis(3 - methoxybenzyl)aminocarbonyloxymethoxymethoxy]pyridine, (i) 3 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxy], 5 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl(aminocarbonyloxymethoxy]pyridine, (j) 3 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine, (k) 2 - {5 - [2 - (9H - carbazol - 9 - ylcarbonyloxy)methoxy] - 3 - pyridyloxy}ethyl 9H - carbazole - 9 - carboxylate, (l) 2-[2-(5-{2-[2-(9-Carbazolylcarbonyloxy)methoxy]methoxy}-3-pyridyloxy)ethoxy]ethyl 9-carbazolecarboxylate, (m) 2-{5-[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)methoxy]-3-pyridyloxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(5-{2-[2-(3,6-Dimethoxy-9H-carbazolylcarbonyloxy)methoxy]methoxy}-3-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) Higher analogs, or, (p) Mixtures and combinations thereof.

[0064] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-[Bis(tenyl)aminocarbonyloxyethoxy], 5-[bis(tenyl)aminocarbonyloxyethoxy]pyridine, (b) 3-[Bis(tenyl)aminocarbonyloxyethioxyethoxy(aminocarbonyloxyethyoxyethoxy)], 5-[bis(tenyl)aminocarbonyloxyethioxyethoxy]pyridine, (c) 3-[Bis(3-methoxybenzyl)aminocarbonyloxyethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]pyridine, (d) 3-[Bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (e) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine, (f) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine, (g) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (h) 3-[Bis(4-methoxybenzyl)aminocarbonyloxyethoxy], 5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]pyridine, (i) 3-[Bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (j) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine, (k) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (l) 2-{5-[2-(9H-Carbazol-9-ylcarbonyloxy)ethoxy]-3-pyridyloxy}ethyl 9H-carbazole-9-carboxylate, (m) 2-[2-(5-{2-[2-(9-Carbazolylcarbonyloxy)ethoxy]ethoxy}-3-pyridyloxy)ethoxy]ethyl 9-carbazolecarboxylate, (n) 2-{5-[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]-3-pyridyloxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (o) 2-[2-(5-{2-[2-(3,6-dimethoxy-9H-carbazolylcarbonyloxy)ethoxy]ethoxy}-3-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (p) higher analogs, or (q) mixtures and combinations thereof.

[0065] R a and R b =(OCH 2 ) n or CH 3 )(CH 2 O) n and Z = 3,5-dimethanolpyridine class In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a groups and R b groups are (OCH 2 ) n or (OCH 2 CH 2 ) n n is an integer from 1 to 6, and Z is derived from 3,5-dimethanolpyridine. In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) 3-({bis[(2-thienyl)methyl]aminocarbonyloxy}methyl)-5-({bis[(2-thienyl)methyl]amino(carbonyloxy}methyl)pyridine, (b) 3-({bis(3-methoxybenzyl)aminocarbonyloxy}methyl)-5-({bis(3-methoxybenzyl)aminocarbonyloxy}methyl)pyridine, (c) 3-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methyl)-5-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methyl)pyridine, (d) 3-({bis(4-methoxybenzyl)aminocarbonyloxy}methyl)-5-({bis(4-methoxybenzyl)aminocarbonyloxy}methyl)pyridine, (e) 3-({[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyl}oxy)methyl)-5-({[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyl}oxy)methyl)pyridine, (f) {5-[(9H-carbazol-9-ylcarbonyloxy)methyl]-3-pyridyl}methyl 9H-carbazole-9-carboxylate, (g) {5-[(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)methyl]-3-pyridyl}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or (h) mixtures and combinations thereof.

[0066] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)methoxy)methyl]-5-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)methoxy)methyl]pyridine, (b) 3-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)methoxymethoxy)methyl]-5-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)methoxymethoxy)methyl]pyridine, (c) 3-({bis(3-methoxybenzyl)aminocarbonyl}oxy)methoxy)methyl]-5-({bis(3-methoxybenzyl)aminocarbonyl}oxy)methoxy)methyl]pyridine, (d) 3-({bis(3-methoxybenzyl)aminocarbonyl}oxy)methoxymethoxy)methyl]-5-({bis(3-methoxybenzyl)aminocarbonyl}oxy)methoxymethoxy)methyl]pyridine, (e) 3-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)methoxy)methyl]-5-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)methoxy)methyl]pyridine, (f) 3-{(3-Methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-5-{(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine, (g) 3-{Bis(4-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]-5-{bis(4-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]pyridine, (h) 3-{Bis(4-methoxybenzyl)aminocarbonyloxy}methoxyethoxy)methyl]-5-{bis(4-methoxybenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine, (i) 3-(4-Methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]-5-(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]pyridine, (j) 3-(4-Methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-5-(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine, (k) 2-[(5-{[2-(9H-Carbazol-9-ylcarbonyloxy)methoxy]methyl}-3-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate, (l) 2-(2-{[5-({2-[2-(9-Carbazolylcarbonyloxy)methoxy]methoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 9-carbazolecarboxylate, (m) 2-[(5-{[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)methoxy]methyl}-3-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-(2-{[5-({2-[2-(3,6-Dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) higher analogs, or, (p) mixtures and combinations thereof.

[0067] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxy)methyl]-5-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxy)methyl]pyridine, (b) 3-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxymethoxy)methyl]-5-({bis[(2-thienyl)methyl]aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (c) 3-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]-5-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]pyridine, (d) 3-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]-5-({bis(3-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (e) 3-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxy)methyl]-5-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxy)methyl]pyridine, (f) 3-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxymethoxy)methyl]-5-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (g) 3-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]-5-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxy)methyl]pyridine, (h) 3-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]-5-({bis(4-methoxybenzyl)aminocarbonyl}oxy)ethoxyethoxy)methyl]pyridine, (i) 3-({4-methoxybenzyl,4-dimethylaminobenzyl}aminocarbonyloxy}ethoxy)methyl]-5-({4-methoxybenzyl,4-dimethylaminobenzyl}aminocarbonyloxy}ethoxy)methyl]pyridine, (j) 3-({4-methoxybenzyl,4-dimethylaminobenzyl}aminocarbonyloxy}ethoxyethoxy)methyl]-5-({4-methoxybenzyl,4-dimethylaminobenzyl}aminocarbonyloxy}ethoxyethoxy)methyl]pyridine, (k) 2-[(5-{[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-3-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate, (l) 2-(2-{[5-({2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 9-carbazolecarboxylate, (m) 2-[(5-{[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-3-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-(2-{[5-({2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) higher analogs, or, (p) mixtures and combinations thereof. R a and R b =(OCH 2 ) n or (CH 3 )(CH 2 O) n as well as the class of Z = 3,5-dihydroxy-dimethylaniline In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a groups and R b groups are (OCH2 ) n or (OCH 2 CH 2 ) n and n is an integer from 1 to 6, and Z is derived from 3,5-dihydroxy-dimethylaniline. In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) 3-[bis(tenyl)aminocarbonyloxy],5-[bis(tenyl)aminocarbonyloxy]dimethylaminobenzene, (b) 3-[bis(3-methoxybenzyl)aminocarbonyloxy],5-[bis(3-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzene, (c) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzene, (d) 3-[bis(4-methoxybenzyl)aminocarbonyloxy],5-[bis(4-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzene, (e) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzene, (f) 3-(9H-carbazol-9-ylcarbonyloxy)-5-(dimethylamino)phenyl 9H-carbazole-9-carboxylate, (g) 3-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)-5-(dimethylamino)phenyl-3,6-dimethoxy-9H-carbazole-9-carboxylate, or (h) mixtures and combinations thereof.

[0068] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-[Bis(tenyl)aminocarbonyloxymethoxy], 5-[bis(tenyl)aminocarbonyloxymethoxy]dimethylaminobenzene, (b) 3-[Bis(tenyl)aminocarbonyloxymethoxymethoxy], 5-[bis(tenyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene, (c) 3-[Bis(3-methoxybenzyl)aminocarbonyloxymethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene, (d) 3-[Bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene, (e) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene, (f) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene, (g) 3-[Bis(4-methoxybenzyl)aminocarbonyloxymethoxy], 5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene, (h) 3-[Bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy], 5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene, (i) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene, (j) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene, (k) 2-{3-[2-(9H-Carbazol-9-ylcarbonyloxy)methoxy]-5-(dimethylamino)phenoxy}methyl 9H-carbazole-9-carboxylate, (l) 2-[2-(3-{2-[2-(9-Carbazolylcarbonyloxy)methoxy]methoxy}-5-(dimethylamino)phenoxy)methoxy]ethyl 9-carbazolecarboxylate, (m) 2-{3-[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)methoxy]-5-(dimethylamino)phenoxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(3-{2-[2-(3,6-Dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}-5-(dimethylamino)phenoxy)methoxy]methyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) Higher analogs, or, (p) Mixtures and combinations thereof.

[0069] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-[Bis(tenyl)aminocarbonyloxyethoxy], 5-[bis(tenyl)aminocarbonyloxyethoxy]dimethylaminobenzene, (b) 3-[Bis(tenyl)aminocarbonyloxyethoxyethoxy], 5-[bis(tenyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene, (c) 3-[Bis(3-methoxybenzyl)aminocarbonyloxyethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene, (d) 3 - [Bis(3 - methoxybenzyl)aminocarbonyloxyethoxyethoxy], 5 - [bis(3 - methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene, (e) 3 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxy], 5 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene, (f) 3 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5 - [(3 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene, (g) 3 - [Bis(4 - methoxybenzyl)aminocarbonyloxyethoxy], 5 - [bis(4 - methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene, (h) 3 - [Bis(4 - methoxybenzyl)aminocarbonyloxyethoxyethoxy], 5 - [bis(4 - methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene, (i) 3 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxy], 5 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene, (j) 3 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5 - [(4 - methoxybenzyl)(4 - dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene, (k) 2 - {3 - [2 - (9H - carbazol - 9 - ylcarbonyloxy)ethoxy] - 5 - (dimethylamino)phenoxy}ethyl 9H - carbazole - 9 - carboxylate, (l) 2 - [2 - (3 - {2 - [2 - (9 - carbazolylcarbonyloxy)ethoxy]ethoxy} - 5 - (dimethylamino)phenoxy)ethoxy]ethyl 9 - carbazolecarboxylate, (m) 2-{3-[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]-5-(dimethylamino)phenoxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}-5-(dimethylamino)phenoxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) higher analogs, or, (p) mixtures and combinations thereof.

[0070] R a and R b =(OCH 2 ) n or CH 3 )(CH 2 O) n and the class where Z = 3,5-dihydroxy-dimethylbenzylamine In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein the R a group and the R b group are (OCH 2 ) n or (OCH 2 CH 2 ) n and n is an integer from 1 to 6, and Z is derived from 3,5-dihydroxy-dimethyl-benzylamine. In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-[bis(tenyl)aminocarbonyloxy],5-[bis(tenyl)aminocarbonyloxy]dimethylaminobenzylamine, (b) 3-[bis(3-methoxybenzyl)aminocarbonyloxy],5-[bis(3-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzylamine, (c) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzylamine, (d) 3-[Bis(4-methoxybenzyl)aminocarbonyloxy], 5-[bis(4-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzylamine, (e) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzylamine, (f) 3-(9H-Carbazol-9-ylcarbonyloxy)-5-[(methylamino)methyl]phenyl 9H-carbazole-9-carboxylate, (g) 3-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)-5-[(dimethylamino)methyl]phenyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or (h) A mixture and combination thereof.

[0071] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-[Bis(tenyl)aminocarbonyloxymethoxy], 5-[bis(tenyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine, (b) 3-[Bis(tenyl)aminocarbonyloxymethoxymethoxy], 5-[bis(tenyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzylamine, (c) 3-[Bis(3-methoxybenzyl)aminocarbonyloxymethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine, (d) 3-[Bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzylamine, (e) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine, (f) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], dimethylaminobenzylamine, (g) 3-[Bis(4-methoxybenzyl)aminocarbonyloxymethoxy], 5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine, (h) 3-[Bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy], 5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxymethoxy]dimethylaminobenzylamine, (i) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine, (j) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzylamine, (k) 2-{3-[2-(9H-Carbazol-9-ylcarbonyloxy)methoxy]-5-[(dimethylamino)methyl]phenoxy}methyl 9H-carbazole-9-carboxylate, (l) 2-[2-(3-{2-[2-(9-Carbazolylcarbonyloxy)methoxy]methoxy}-5-[(dimethylamino)methyl]phenoxy)methoxy]methyl 9-carbazolecarboxylate, (m) 2-{3-[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]-5-[(dimethylamino)methyl]phenoxy}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(3-{2-[2-(3,6-Dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}-5-[(dimethylamino)methyl]phenoxy)methoxy]methyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) Higher analogs, or, (p) Mixtures and combinations thereof.

[0072] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 3-[Bis(tenyl)aminocarbonyloxyethoxy],5-[bis(tenyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine, (b) 3-[Bis(tenyl)aminocarbonyloxyethoxyethoxy],5-[bis(tenyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine, (c) 3-[Bis(3-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine, (d) 3-[Bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine, (e) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine, (f) 3-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(3-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], dimethylaminobenzylamine, (g) 3-[Bis(4-methoxybenzyl)aminocarbonyloxyethoxy], 5-[Bis(4-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine, (h) 3-[Bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy], 5-[Bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine, (i) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine, (j) 3-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-Methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine, (k) 2-{3-[2-(9H-Carbazol-9-ylcarbonyloxy)ethoxy]-5-[(dimethylamino)methyl]phenoxy}ethyl 9H-carbazole-9-carboxylate, (l) 2-[2-(3-{2-[2-(9-Carbazolylcarbonyloxy)ethoxy]ethoxy}-5-[(dimethylamino)methyl]phenoxy)ethoxy]ethyl 9-carbazolecarboxylate, (m) 2-{3-[2-(3,6-Dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]-5-[(dimethylamino)methyl]phenoxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}-5-[(dimethylamino)methyl]phenoxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, (o) higher analogs, or, (p) mixtures and combinations thereof.

[0073] R a and R b =(OCH 2 ) n or CH 3 )(CH 2 O) n as well as the class of Z = 2,6-pyridinedicarboxylic acid chloride In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein the R a group and the R b group are (OCH 2 ) n or (OCH 2 CH 2 ) n n is an integer from 1 to 6, and Z is derived from 2,6-pyridinedicarboxylic acid chloride. In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) N,N,N,N-tetra(2-thienylmethyl)-2,6-pyridinedicarboxamide, (b) N,N,N,N-tetra(3-methoxybenzyl)-2,6-pyridinedicarboxamide, (c) N,N-bis(3-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-2,6-pyridinedicarboxamide, (d) N,N,N,N-tetra(4-methoxybenzyl)-2,6-pyridinedicarboxamide, (e) N,N-bis(4-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-2,6-pyridinedicarboxamide, or (f) mixtures and combinations thereof.

[0074] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) Bis(2-{bis(2-thienylmethyl)aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate, (b) Bis(2-{bis(2-thienylmethyl)aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate, (c) Bis(2-{bis[3-methoxybenzyl]aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate, (d) Bis(2-{bis[3-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate, (e) Bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate, (f) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate, (g) Bis(2-{bis[4-methoxybenzyl]aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate, (h) Bis(2-{bis[4-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate, (i) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate, (j) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate, (k) Higher analogs, or (l) Mixtures and combinations thereof.

[0075] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) Bis(2-{bis(2-thienylmethyl)aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate, (b) Bis(2-{bis(2-thienylmethyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (c) Bis(2-{bis[3-methoxybenzyl]aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate, (d) Bis(2-{bis[3-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (e) Bis(2-{(3-methoxybenzyl)(4-dimethyl(aminobenzyl)aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate, (f) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (g) Bis(2-{bis[4-methoxybenzyl]aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate, (h) Bis(2-{bis[4-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (i) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate, (j) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (k) Higher analogs, or (l) Mixtures and combinations thereof.

[0076] R a and R b =(OCH 2 ) n or CH 3 )(CH 2 O) n and the class of Z = 3,5-pyridinedicarboxylic acid chloride In one embodiment, the integrin agonist of formula (II) comprises one or more integrin agonists, and R a group and R b group comprise (OCH 2 ) n or (OCH 2 CH 2 ) n wherein n is an integer from 1 to 6, and Z is derived from 3,5-pyridinedicarboxylic acid chloride. In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) N,N,N,N-tetra(2-thienylmethyl)-3,5-pyridinedicarboxamide, (b) N,N,N,N-tetra(4-methoxybenzyl)-3,5-pyridinedicarboxamide, (c) N,N-bis(3-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-3,5-pyridinedicarboxamide, (d) N,N,N,N-tetra(4-methoxybenzyl)-3,5-pyridinedicarboxamide, (e) N,N-bis(4-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-3,5-pyridinedicarboxamide, or (f) mixtures and combinations thereof.

[0077] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) bis(2-{bis(2-thienylmethyl]aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate, (b) bis(2-{bis(2-thienylmethyl]aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate, (c) bis(2-{bis(3-methoxybenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate, (d) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate, (e) Bis(2-{(3-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate, (f) Bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate, (g) Bis(2-{bis(4-methoxybenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate, (h) Bis(2-{bis[4-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate, (i) Bis(2-{bis(4-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate, (j) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate, (k) Higher analogs, or (l) Mixtures and combinations thereof.

[0078] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) Bis(2-{bis(2-thienylmethyl]aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate, (b) Bis(2-{bis(2-thienylmethyl]aminocarbonyloxyethoxy}ethyl) 3,5-pyridinedicarboxylate, (c) Bis(2-{bis(3-methoxybenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate, (d) Bis(2-{bis[3-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (e) Bis(2-{(3-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate, (f) Bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (g) Bis(2-{bis(4-methoxybenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate, (h) Bis(2-{bis[4-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 3,5-pyridinedicarboxylate, (i) Bis(2-{bis(4-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate, (j) Bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate, (k) Higher analogs, or (l) Mixtures and combinations thereof.

[0079] R a and R b = (OCH 2 ) n or CH 3 )(CH 2 O) n and Z = 3-dimethylamino-1,5-pentanediol class In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, and the R a group and the R b group comprise (OCH 2 ) n or (OCH 2 CH 2 ) n where n is an integer from 1 to 6, and Z is derived from 3-dimethylamino-1,5-pentanediol. In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) 1-[Bis(2-thienylmethyl)aminocarbonyloxy]-5-[bis(2-thienylmethyl)aminocarbonyloxy]-3-(dimethylamino)pentane, (b) 1-[Bis(3-methoxybenzyl)aminocarbonyloxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane, (c) 1-[(3-Methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-5-[bis(3-methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane, (d) 1-[Bis(4-methoxybenzyl)aminocarbonyloxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane, (e) 1-[(4-Methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-5-[bis(4-methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane, or (f) A mixture and combination thereof.

[0080] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 1-[Bis(2-thienylmethyl)aminocarbonyloxymethoxy]-5-[bis(2-thienylmethyl)aminocarbonyloxymethoxy]-3-(dimethylamino)pentane, (b) 1-[Bis(2-thienylmethyl)aminocarbonyloxymethoxymethoxy]-5-[bis(2-thienylmethyl)aminocarbonyloxymethoxymethoxy]-3-(dimethylamino)pentane, (c) 1-[Bis(3-methoxybenzyl)aminocarbonyloxymethoxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]-3-(dimethylamino)pentane, (d) 1-[Bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-3-(dimethylamino)pentane, (e) 1-{[(3-Methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-5-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-3-(dimethylamino)pentane, (f) 1-{[(3-Methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-5-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-3-(dimethylamino)pentane, (g) 1-[Bis(4-methoxybenzyl)aminocarbonyloxymethoxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]-3-(dimethylamino)pentane, (h) 1-[Bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-3-(dimethylamino)pentane, (i) 1-{[(4-Methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-3-(dimethylamino)pentane, (j) 1-{[(4-Methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-3-(dimethylamino)pentane, (k) Higher analogs, or (l) Mixtures and combinations thereof.

[0081] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 1 - [Bis(2 - thienylmethyl)aminocarbonyloxyethoxy] - 5 - [bis(2 - thienylmethyl)aminocarbonyloxyethoxy] - 3 - (dimethylamino)pentane, (b) 1 - [Bis(2 - thienylmethyl)aminocarbonyloxyethoxyethoxy] - 5 - [bis(2 - thienylmethyl)aminocarbonyloxyethoxyethoxy] - 3 - (dimethylamino)pentane, (c) 1 - [Bis(3 - methoxybenzyl)aminocarbonyloxyethoxy] - 5 - [bis(3 - methoxybenzyl)aminocarbonyloxyethoxy] - 3 - (dimethylamino)pentane, (d) 1 - [Bis(3 - methoxybenzyl)aminocarbonyloxyethoxyethoxy] - 5 - [bis(3 - methoxybenzyl)aminocarbonyloxyethoxyethoxy] - 3 - (dimethylamino)pentane, (e) 1 - {[(3 - Methoxybenzyl)(4 - dimethylaminobenzyl)amino]carbonyloxyethoxy} - 5 - {[(3 - methoxybenzyl)(4 - dimethylaminobenzyl)amino]carbonyloxyethoxy} - 3 - (dimethylamino)pentane, (f) 1 - {[(3 - Methoxybenzyl)(4 - dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy} - 5 - {[(3 - methoxybenzyl)(4 - dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy} - 3 - (dimethylamino)pentane, (g) 1 - [Bis(4 - methoxybenzyl)aminocarbonyloxyethoxy] - 5 - [bis(4 - methoxybenzyl)aminocarbonyloxyethoxy] - 3 - (dimethylamino)pentane, (h) 1 - [Bis(4 - methoxybenzyl)aminocarbonyloxyethoxyethoxy] - 5 - [bis(4 - methoxybenzyl)aminocarbonyloxyethoxyethoxy] - 3 - (dimethylamino)pentane, (i) 1-{[(4-Methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxy}-3-(dimethylamino)pentane, (j) 1-{[(4-Methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy}-3-(dimethylamino)pentane, (k) Higher analogs, or (l) mixtures and combinations thereof.

[0082] R a =(OCH 2 ) n or CH 3 )(CH 2 O) n and the class where Z = 3-dimethylamine In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, and the R a group comprises (OCH 2 ) n or (OCH 2 CH 2 ) n n is an integer from 1 to 6, and Z is dimethylamine. In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds: (a) 5-Oxo-7-(2-thienyl)-6-(2-thienylmethyl)-2,4-dioxa-6-aza-heptanyl-N,N-dimethylamine, (b) 5-Oxo-7-(3-methoxyphenyl)-6-(3-methoxybenzyl)-2,4-dioxa-6-aza-heptanyl-N,N-dimethylamine, (c) 5-Oxo-7-(3-methoxyphenyl)-6-(4-dimethylaminobenzyl)-2,4-dioxa-6-aza-heptanyl-N,N-dimethylamine, (d) 5-Oxo-7-(4-methoxyphenyl)-6-(4-methoxybenzyl)-2,4-dioxa-6-aza-heptanyl-N,N-dimethylamine, (e) 5-Oxo-7-(4-methoxyphenyl)-6-(4-dimethylaminobenzyl)-2,4-dioxa-6-aza-heptanyl-N,N-dimethylamine, (f) 7-Oxo-9-(2-thienyl)-8-(2-thienylmethyl)-2,4,6-trioxa-8-aza-nonyl-N,N-dimethylamine, (g) 7-Oxo-9-(3-methoxyphenyl)-8-(3-methoxybenzyl)-2,4,6-trioxa-8-aza-undecyl-N,N-dimethylamine, (h) 7-Oxo-9-(3-methoxyphenyl)-8-(4-dimethylaminobenzyl)-2,4,6-trioxa-8-aza-dodecyl-N,N-dimethylamine, (i) 7-Oxo-9-(3-methoxyphenyl)-8-(3-methoxybenzyl)-2,4,6-trioxa-8-aza-dodecyl-N,N-dimethylamine, (j) 7-Oxo-9-(3-methoxyphenyl)-8-(4-dimethylaminobenzyl)-2,4,6-trioxa-8-aza-dodecyl-N,N-dimethylamine, (k) 9-Oxo-11-(2-thienyl)-10-(2-thienylmethyl)-2,4,6,8-tetraoxa-10-aza-undecyl-N,N-dimethylamine, (l) 9-Oxo-11-(3-methoxyphenyl)-10-(3-methoxybenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine, (m) 9-Oxo-11-(3-methoxyphenyl)-10-(4-dimethylaminobenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine, (n) 9-Oxo-11-(4-methoxyphenyl)-10-(4-methoxybenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine, (o) 9-oxo-11-(3-methoxyphenyl)-10-(4-dimethylaminobenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine, (p) higher analogs, or (q) mixtures and combinations thereof.

[0083] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds: (a) 7-oxo-9-(2-thienyl)-8-(2-thienylmethyl)-3,6-dioxa-8-aza-nonanil-N,N-dimethylamine, (b) 7-oxo-9-(3-methoxyphenyl)-8-(3-methoxybenzyl)-3,6-dioxa-8-aza-nonanil-N,N-dimethylamine, (c) 7-oxo-9-(3-methoxyphenyl)-8-(4-dimethylaminobenzyl)-3,6-dioxa-8-aza-nonanil-N,N-dimethylamine, (d) 7-oxo-9-(4-methoxyphenyl)-8-(4-methoxybenzyl)-3,6-dioxa-8-aza-nonanil-N,N-dimethylamine, (e) 7-oxo-9-(4-methoxyphenyl)-8-(4-dimethylaminobenzyl)-3,6-dioxa-8-aza-nonanil-N,N-dimethylamine, (f) 10-oxo-12-(2-thienyl)-11-(2-thienylmethyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine, (g) 10-oxo-12-(3-methoxyphenyl)-11-(3-methoxybenzyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine, (h) 10-oxo-12-(3-methoxyphenyl)-11-(4-dimethylaminobenzyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine, (i) 10-oxo-12-(3-methoxyphenyl)-11-(3-methoxybenzyl)-3,6,9-trioxa-11-azadodecyl-N,N-dimethylamine, (j) 10-oxo-12-(3-methoxyphenyl)-11-(4-dimethylaminobenzyl)-3,6,9-trioxa-11-azadodecyl-N,N-dimethylamine, (k) 13-oxo-15-(2-thienyl)-14-(2-thienylmethyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine, (l) 13-oxo-15-(3-methoxyphenyl)-14-(3-methoxybenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine, (m) 13-oxo-15-(3-methoxyphenyl)-14-(4-dimethylaminobenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine, (n) 13-oxo-15-(4-methoxyphenyl)-14-(4-methoxybenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine, (o) 13-oxo-15-(3-methoxyphenyl)-14-(4-dimethylaminobenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine, (p) higher analogs, or (q) mixtures and combinations thereof.

[0084] Suitable agents and substances Surfactants zwitterionic surfactants Suitable zwitterionic surfactants for use in the present disclosure include, but are not limited to, phospholipids, betaines, sultaines, sulfobetaines, amide betaines, imidazoline betaines, or any combination thereof.

[0085] Suitable zwitterionic compounds include, but are not limited to, the following: (1) general structure R6 R 7 R 8 N + -R 9 -CO 2 - having, wherein R 6 , R 7 , and R 8 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups, or mixtures thereof, and R 9 is an alkenyl group, an alkenyl oxide group, or a mixture thereof, any compound; (2) general structure R 10 (R 7 R 8 N + -R 9 -CO 2 - ) n having, wherein, R 7 and R 8 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups, or mixtures thereof, and R 9 is an alkenyl group, an alkenyl oxide group, or a mixture thereof, and R 10 is a polyvalent substituent having a valence n of from 2 to about 6, for example, when n is 2 it is a CH 2 moiety, when n is 3 it is a CH moiety, and when n is 4 it is a C atom, any compound; (3) general structure R 12 -C(O)-N(R 11 )-R 13 -N + (R 7 R 8 )-R 9 -CO 2 - having, wherein, R 7 , R 8 , R 11 , and R 12 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups, or mixtures thereof, and R 9 and R 13 are the same or different alkenyl groups, alkenyl oxide groups, or mixtures thereof, any compound. (4) general structure R 14 -[R 15 -C(O)-N(R11 )-R 13 -N + (R 7 R 8 )-R 9 -CO 2 - m having, wherein R 7 , R 8 , and R 11 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups, or mixtures thereof, and R 9 , R 13 , and R 15 are the same or different alkenyl groups, alkenyl oxide groups, or mixtures thereof, and R 14 is a polyvalent substituent having a valence m of 2 to about 6, any compound; other similar ammonium acid zwitterionic agents; or mixtures or combinations thereof. Preferred zwitterionic compounds are betaines such as cocamidopropyl betaine, 5-(1-piperidinomethyl)-1H-tetrazolide, or similar zwitterionic compounds. Other zwitterionic compounds for use in the present invention include, but are not limited to, phospholipids capable of assuming a zwitterionic state, such as phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and other ceramides, as well as various other zwitterionic phospholipids. Preferred sulfo-betaines and related zwitterionic compounds include, but are not limited to, N-decyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, dimethylbenzyl-(3-sulfopropyl)ammonium, dimethylethyl-(3-sulfopropyl)ammonium, dimethyl-(2-hydroxyethyl)-(3-sulfopropyl)ammonium, 4-n-hexylbenzoylamide-propyl-dimethylammoniosulfobetaine, -methyl-N-(3-sulfopropyl)morpholinium, 4-n-octylbenzoylamide-propyl-dimethylammoniosulfobetaine, 1-(3-sulfopropyl)pyridium, or N-tetradecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, etc., or mixtures or combinations thereof.

[0086] ​ Representative examples of phospholipids include, but are not limited to, the following: phosphatidylcholine, 1-lyso-phosphatidylcholine, alkyl glycerol monooxygenase, cardiolipin, dinogrelin, 1,2-dioleoyl-sn-glycero-phosphoethanolamine, dipalmitoyl phosphatidylcholine, dolichyl beta-d-glucosyl phosphate, edelfosine, egg lecithin, soy lecithin, endothelial lipase, glycerophospholipid, hydroxylated lecithin, lecithin, lysophosphatidic acid, lysophosphatidylethanolamine, lysophosphatidylinositol, monolysocardiolipin, myo-inositol trisphosphate, periphos, phosphatidylethanol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol (3,4,5)-trisphosphate, phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-bisphosphate, phosphatidylinositol 3,5-bisphosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol phosphate, phosphatidylinositol-4-phosphate 5-kinase, phosphatidyl myo-inositol mannoside, phosphatidylserine, phosphorylcholine, phytosome, PIP2 (disambiguation), POPC, SignaFresh, sphingomyelin, sphingosylphosphatide, or any mixture thereof.

[0087] Representative examples of sulfobetaines include, but are not limited to, sulfobetaine 8 (SB-8), sulfobetaine 10 (SB-10), sulfobetaine 12 (SB-12), sulfobetaine 14 (SB-14), sulfobetaine 16 (SB-16), and / or sulfobetaine 18 (SB-18) available from Taiwan Hopax Chemicals Mfg. Co., Ltd.

[0088] Nonionic surfactant Suitable nonionic surfactants are classified by their hydrophilic-lipophilic balance (HLB) number, with lower values (≦10) corresponding to higher lipophilicity and higher values (≧10) corresponding to higher hydrophilicity. Examples of low HLB (<10) emulsifiers include, but are not limited to, the following: (a) phosphatidylcholine and phosphatidylcholine / solvent mixtures, such as phosphatidylcholine, phosphatidylcholine in propylene glycol, phosphatidylcholine in medium-chain triglycerides, and phosphatidylcholine in safflower oil; (b) unsaturated polyglycolated glycerides, such as oleoyl macrogol glyceride and linoleoyl macrogol glyceride; (c) sorbitan esters, such as sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, and sorbitan monopalmitate; or (d) mixtures or combinations thereof. Examples of high HLB (>10) emulsifiers include, but are not limited to, the following: (a) polyoxyethylene sorbitan esters, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; (b) polyoxyl castor oil derivatives, such as polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil; (c) polyoxyethylene polyoxypropylene block copolymers, such as poloxamer 188 and poloxamer 407; (d) saturated polyglycolated glycerides, such as lauroyl macrogol glyceride and stearoyl macrogol glyceride; (e) PEG-8 caprylic / capric glyceride, such as caprylocapryl macrogol glyceride; (f) vitamin E derivatives, such as tocopherol PEG succinate; or (g) mixtures or combinations thereof. Other suitable nonionic surfactants include, but are not limited to, polyol esters, cyclic polyol esters, polyethylene glycol (PEG) esters, or mixtures and combinations thereof.Representative examples include, but are not limited to, the following: sorbitan mono- and / or poly-fatty acid esters, sorbitol mono- and / or poly-fatty acid esters, monoglyceride fatty acids, polyethylene glycol (PEG) ester surfactants (hydrophilic and / or hydrophobic gelucire, e.g., hydrophilic GELUCIRE® 44 / 14, lauroyl macrogol glyceride type 1500, hydrophobic GELUCIRE® 43 / 01, GELUCIRE® 39 / 01, GELUCIRE® 33 / 01, or other gelucire); polyglycol-modified castor oil, e.g., polyoxyl 35 hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil; polysorbates, e.g., polysorbate 20, 40, 60, 80, etc., and TWEEN® surfactants; and mixtures or combinations thereof.

[0089] Sorbitan and sorbitol esters Suitable sorbitan and / or sorbitol esters for use in the present disclosure include, but are not limited to, the following: sorbitan monoesters, such as sorbitan caprylate, sorbitan undecylenate, sorbitan laurate, sorbitan palmitate, sorbitan isostearate, sorbitan oleate, sorbitan stearate, etc.; sorbitan sesquiesters, such as sesquicaprylate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, etc.; sorbitan diesters, such as sorbitan diisostearate, sorbitan dioleate, sorbitan distearate, etc.; (2002)sorbitan triesters, such as sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate, etc.; mixed-chain sorbitan esters, such as sorbitan cocoate, sorbitan olivate, sorbitan palmate, sorbitan theobroma grandiflorum seedate, etc.; or mixtures and combinations thereof.Examples of other sorbitan or sorbitol esters include, but are not limited to, the following: PEG-20 sorbitan cocoate, PEG-40 sorbitan diisostearate, PEG-2 sorbitan isostearate, PEG-5 sorbitan isostearate, PEG-20 sorbitan isostearate, PEG-40 sorbitan lanolate, PEG-75 sorbitan lanolate, PEG-10 sorbitan laurate, PEG-40 sorbitan laurate, PEG-44 sorbitan laurate, PEG-75 sorbitan laurate, PEG-80 sorbitan laurate, PEG-3 sorbitan oleate, PEG-6 sorbitan oleate, PEG-80 sorbitan palmitate, PEG-40 sorbitan persostearate, PEG-40 sorbitan peroelate, PEG-3 sorbitan stearate, PEG-6 sorbitan stearate, PEG-40 sorbitan stearate, PEG-60 sorbitan stearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan tetraoleate, PEG-60 sorbitan tetraoleate, PEG-60 sorbitan tetrastearate, PEG-160 sorbitan triisostearate; PEG-20 sorbitan triisostearate, Sorbeth-40 hexaoleate, Sorbeth-50 hexaoleate, Sorbeth-30 tetraoleate laurate, Sorbeth-60 tetrastearate, and PEG sorbitan and sorbitol fatty acid esters including any mixtures thereof. Such PEG sorbitan or sorbitol can vary from brown waxy solids and amber pastes to clear yellow liquids.Examples of other exemplary nonionic surfactants include, but are not limited to, the following: polyoxyethylene surfactants such as POE sorbitan monolaurate (Tween 20, HLB 17), POE sorbitan monopalmitate (Tween 40, HLB 15.6), POE sorbitan monostearate (Tween 60, HLB 15.0), POE sorbitan monooleate (Tween 80, HLB 15.0), POE sorbitan tristearate (Tween 65, HLB 10.5), POE sorbitan trioleate (Tween 85, HLB 11.0), POE glycerol trioleate (Tagat TO, HLB 11.5), POE-40-hydrogenated castor oil (solid) Cremophore RH40, HLB 14.0 - 16.0), POE-35-castor oil (Cremophore EL (liquid), HLB 12.0 - 14.0), POE(10) oleyl ether (Brij 96, HLB 12.4), POE(23) lauryl ether (Brij 35, HLB 16.9), POE-vitamin E (alpha-tocopherol TPGS, HLB 13.0), and mixtures or combinations thereof.

[0090] Poloxamer Suitable poloxamers include, but are not limited to, nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Poloxamers are also known by the trade names Synperonics, Pluronics, and Kolliphor. Since the lengths of the polymer blocks can be customized, there are various poloxamers with slightly different properties. In the case of the general term "poloxamer", such copolymers are generally named with three numbers following the letter P (which refers to the poloxamer). Multiplying the first two numbers by 100 gives the approximate molecular weight of the polyoxypropylene core, and multiplying the last number by 10 gives the percentage of polyoxyethylene content (e.g., P407 is a poloxamer with a polyoxypropylene molecular mass of 4000 g / mol and a 70% polyoxyethylene content). In the case of the trade names Pluronic and Synperonic, the codes for such copolymers start with a letter (L = liquid, P = paste, F = flake (solid)) that defines the physical form at room temperature, followed by two or three numbers. Multiplying the first number of the number designation (two numbers in the case of a three-digit number) by 300 gives the approximate molecular weight of the hydrophobic substance, and the last number × 10 indicates the percentage of polyoxyethylene content (e.g., L61 indicates a polyoxypropylene molecular mass of 1800 g / mol and a 10% polyoxyethylene content). In a given example, poloxamer 181 (P181) = Pluronic L61 and Synperonic PE / L61.

[0091] Nonionic neutral polymer Suitable nonionic neutral polymers include, but are not limited to, pH-responsive nonionic polymers and temperature-sensitive nonionic polymers. Representative examples of such pH-responsive nonionic polymers include, but are not limited to, pH-responsive dendrimers such as poly-amidoamine (PAMAM), dendrimers, poly(propyleneimine) dendrimers, poly(l-lysine) esters, poly(hydroxyproline), poly(propylacrylic acid), poly(methacrylic acid), Carbopol®, Eudragit® S-100, Eudragit® L-100, chitosan, poly(methacrylic acid) (PMMA), PMAA-PEG copolymer, N,N-dimethylaminoethyl methacrylate (DMAEMA), and any mixtures thereof. Representative examples of temperature-sensitive polymers include, but are not limited to, poloxamers (Pluronics®), prolactin, poly(n-substituted acrylamide), poly(organic phosphazene), cyclotriphosphazene of poly(ethylene glycol) and amino acid ester, block copolymer of poly(ethylene glycol) / poly(lactic acid-co-glycolic acid), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), PMAA, poly(vinyl alcohol) (PVA), various silk elastin-like polymers, poly(silamine), poly(vinyl methyl ether) (PVME), poly(vinyl methyl oxazolidone) (PVMO), poly(vinyl pyrrolidone) (PVP), poly(n-vinyl caprolactam), poly(N-vinyl isobutylamide), poly(vinyl methyl ether), poly(N-vinyl caprolactam) (PVCL), poly(siloxyethylene glycol), poly(dimethylaminoethyl methacrylate), triblock copolymer poly(DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA), cellulose derivatives, alginate, gellan, xyloglucan, and any mixtures thereof.

[0092] Anionic surfactant Suitable anionic surfactants include, but are not limited to, anionic sulfate surfactants, alkyl ether sulfonates, alkyl aryl sulfonates, or mixtures or combinations thereof. Preferred sodium or ammonium alcohol ether sulfate surfactants include those having the general formula R 1 O-(CH 2 CH 2 O) n SO 3 NH 4 wherein R 1 is a carbon-containing group including an alkyl group, an aryl group, an alkaryl group, an aralkyl group, or mixtures thereof. Particularly preferred sodium or ammonium alcohol ether sulfate surfactants include short-chain sodium or ammonium alcohol ether sulfate surfactants having 2 to about 10 carbon atoms, particularly about 4 to 10 carbon atoms, and long-chain sodium or ammonium alcohol ether sulfate surfactants having about 10 to about 24 carbon atoms, more particularly about 12 to about 18 carbon atoms, especially about 12 to about 14 carbon atoms. The sodium or ammonium alcohol ether sulfate surfactants are prepared by reacting 1 to 10 moles of ethylene oxide per mole of alkanol, preferably by reacting 3 moles of ethylene oxide per mole of alkanol.

[0093] Preferred alkyl aryl sulfonates include, but are not limited to, alkyl benzene sulfonic acids and their salts, dialkyl benzene disulfonic acids and their salts, dialkyl benzene sulfonic acids and their salts, alkyl toluene / alkyl xylene sulfonic acids and their salts, alkyl naphthalene sulfonic acids / condensed alkyl naphthalene sulfonic acids and their salts, alkyl phenol sulfonic acids / condensed alkyl phenol sulfonic acids and their salts, or mixtures or combinations thereof.

[0094] Preferred alkyl ether sulfonates include, but are not limited to, those having the general formula R 2[-(O-R 3 O)m-(R 4 O)n-(R 5 )] y having the formula, wherein R 2 = alkyl, alkenyl, amine, alkylamine, dialkylamine, trialkylamine, aromatic, polycyclic aromatic, cycloalkane, cycloalkene, and R 3 , R 4 = C 2 H 4 or C 3 H 6 or C 4 H 8 and when y = 1, R 4 = linear or branched C 7 H 14 SO 3 X~C 30 H 60 SO 3 X, and when y> 1, R 5 = linear or branched C 7 H 14 SO 3 X~C 30 H 60 SO 3 X or H, provided that at least one R 4 is linear or branched C 7 H 14 SO 3 X~C 30 H 60 SO 3 X, M is 1 or more, n is 0 or more, n + m = 1 to 30 +, y is 1 or more, and X is an alkali metal or alkaline earth metal or ammonium or amine, and examples include alkyl ether sulfonates.

[0095] Cationic surfactant Suitable cationic surfactants include, but are not limited to, Gemini, bis-, or diquaternary ammonium surfactants, such as bisquaternary ammonium halides of bis-halogenated ethane, propane, butane, or higher halogenated alkanes, such as dichloroethane or dibromoethane, or bis-halogenated ethers, such as dichloroethyl ether (DCEE). Preferred bisquaternary ammonium halides are substituted dimethyl tertiary amines, wherein the substituents contain from about 4 to about 30 carbon atoms, preferably from about 6 to about 24 carbon atoms, particularly from about 8 to about 24 carbon atoms, one or more of the carbon atoms may be replaced by oxygen atoms in the form of ether and / or hydroxyl moieties, and / or the nitrogen atom is in the form of an amide moiety, and are prepared from substituted dimethyl tertiary amines. Particularly preferred bisquaternary ammonium halide hydrocarbons are prepared from natural acids such as fatty acids, synthetic acids, modified natural acids, or mixtures or combinations thereof. Preferred natural acids are those found in natural oils such as coconut oil, palm oil, palm kernel oil, soybean oil, safflower oil, sunflower oil, peanut oil, canola oil, or those derived from animals such as tallow oil and its derivatives. Preferred bisquaternary ammonium halides are disubstituted methyl tertiary amines, wherein the substituents contain from about 4 to about 30 carbon atoms, preferably from about 6 to about 24 carbon atoms, particularly from about 8 to about 24 carbon atoms, one or more of the carbon atoms may be replaced by oxygen atoms in the form of ether and / or hydroxyl moieties, and / or the nitrogen atom is in the form of an amide moiety, and are prepared from amidepropyl tertiary amines derived from the reaction of dimethylaminopropylamine (DMAPA) or similar end-capped primary to tertiary diamines with the oils or their corresponding fatty acids or hydroxy acids mentioned above. Other preferred cationic surfactants include dimer acids or anhydrides containing alkyl-substituted maleic anhydride, alkyl-substituted diethyl malonate, or alkyl-substituted higher dibasic acids such as azelaic acid (C9), trimer acids such as NTA (nitrilotriacetic acid), and aconitic acid and trimellitic anhydride are useful but produce higher trimers.Tertiary amines can be achieved by reacting diamines with fatty acids or oils to react with one amine, and then adding tetrahydrofuran, ethylene oxide, propylene oxide, butylene oxide, epichlorohydrin, etc. to convert the other primary amine into a tertiary amine. Furthermore, the terminal hydrogen of the primary amine can be alkylated using a formaldehyde / formic acid mixture.

[0096] Neutral lipid Fatty acid ester Suitable neutral lipids for use in the present disclosure include, but are not limited to, fatty acid esters, such as alkyl fatty acid esters, and / or polyalkylene oxide fatty acid esters. Representative examples of fatty acid esters include esters of any of the fatty acids listed above, and include, but are not limited to, monoalcohol esters, where the monoalcohol or polyol contains from 1 to 20 carbon atoms, and one or more of the carbon atoms may be replaced by O, NR (R is a carbyl or hydrocarbyl group having 1 to 5 carbon atoms), or S. Examples of exemplary monoalcohols used to form free fatty acid esters include methanol, ethanol, propanol, butanol, pentanol, or mixtures thereof.

[0097] Representative examples of fatty acid esters include (a) short-chain fatty acid esters (SCFE) containing all esters of fatty acids having less than 6 carbons, (b) medium-chain fatty acid esters (MCFE) containing all esters of fatty acids having 6 to 12 carbons, (c) long-chain fatty acid esters (LCFE) containing all esters of fatty acids having 13 to 21 carbons, and (d) very-long-chain fatty acid esters (VLCFE) containing all esters of fatty acids having more than 22 carbons.

[0098] Fatty acid glycerol ester Suitable monoglycerides, diglycerides, and / or triglycerides include monoglycerides, diglycerides, and / or triglycerides derived from animals or plants (animal and vegetable oils). Exemplary animal oils include, but are not limited to, adipose tissue oil, tallow, fat, bone oil, bandicoot oil, butter, butterfat, chicken fat, cod liver oil, fish oil, ghee, goose fat, seal oil, lard, lanolin, lard, lard oil, lipid, lipoma, margarine, neat s-foot oil, oleo, oleo oil, oleomargarine, dolphin oil, salmon oil, sardine oil, seal oil, shark oil, shortening, sperm whale oil, suet, tallow, tallow oil, tuna oil, whale oil, wool fat or wool wax, wool oil, or any combination thereof. Exemplary vegetable oils include, but are not limited to, coconut oil, corn oil, canola oil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil, almond oil, beech nut oil, Brazil nut oil, cashew nut oil, hazelnut oil, macadamia oil, mongongo nut oil, pecan oil, pine nut oil, pistachio oil, walnut oil, pumpkin seed oil, grapefruit seed oil, lemon oil, orange oil, bitter melon oil, bottle gourd oil, buffalo pumpkin oil, buttercup squash seed oil, pumpkin seed oil, watermelon seed oil, or any mixture thereof.

[0099] Representative examples of monoglycerides include (a) short-chain monoglycerides (SCM) containing all glycerol esters of fatty acids having less than 6 carbons, (b) medium-chain monoglycerides (MCM) containing all glycerol esters of fatty acids having 6 to 12 carbons, (c) long-chain fatty acid monoglycerides (LCM) containing all glycerol esters of fatty acids having 13 to 21 carbons, and (d) very-long-chain fatty acid monoglycerides (VLCM) containing all glycerol esters of fatty acids having more than 22 carbons. Representative examples of diglycerides include (a) short-chain diglycerides (SCD) containing all glycerol esters of fatty acids having less than 6 carbons, (b) medium-chain diglycerides (MCD) containing all glycerol esters of fatty acids having 6 to 12 carbons, (c) long-chain fatty acid diglycerides (LCD) containing all glycerol esters of fatty acids having 13 to 21 carbons, and (d) very-long-chain fatty acid diglycerides (VLCD) containing all glycerol esters of fatty acids having more than 22 carbons.

[0100] Representative examples of triglycerides include (a) short-chain triglycerides (SCT) containing all glycerol esters of fatty acids having less than 6 carbons, (b) medium-chain triglycerides (MCT) containing all glycerol esters of fatty acids having 6 to 12 carbons, (c) long-chain fatty acid triglycerides (LCT) containing all glycerol esters of fatty acids having 13 to 21 carbons, and (d) very-long-chain fatty acid triglycerides (VLCT) containing all glycerol esters of fatty acids having more than 22 carbons.

[0101] Biocompatible oil Suitable biocompatible oils include, but are not limited to, any oil approved by the FDA or other government agency for human consumption, mammalian consumption, or animal consumption. Exemplary biocompatible oils include, but are not limited to, plant-derived oils or animal-derived oils or derivatives thereof or synthetic oils. In certain embodiments, the natural oil is an oil rich in phospholipids, such as lecithin oil derived from soybeans. Representative examples of plant-derived oils or animal-derived oils or derivatives thereof or synthetic oils include, but are not limited to, essential oils, vegetable oils, hydrogenated vegetable oils, such as peanut oil, canola oil, avocado oil, safflower oil, olive oil, corn oil, soybean oil, sesame oil, vitamin A, vitamin D, or vitamin E, animal oils, fish oils, or krill oil, or mixtures thereof. In certain embodiments, the biocompatible oil is a neutral lipid. Suitable neutral lipids include, but are not limited to, any neutral lipid such as triglycerides. For a partial list of representative neutral lipids such as triglycerides, see in particular U.S. Patent Nos. 4,950,656 and 5,043,329. Both saturated and unsaturated triglycerides can be used in the present composition, and examples of saturated and unsaturated triglycerides include triglycerides such as tripalmitin (saturated), triolein, and trilinolein (unsaturated). However, these specific triglycerides are merely representative examples of useful triglycerides.

[0102] Animal fats include, but are not limited to, lard, duck fat, butter, or mixtures or combinations thereof. Plant fats include, but are not limited to, coconut oil, palm oil, cottonseed oil, wheat germ oil, soybean oil, olive oil, corn oil, sunflower oil, safflower oil, sesame oil, canola oil / rapeseed oil, or mixtures and combinations thereof.

[0103] Gelatin Suitable gelatins include chemical substances having ATC (Anatomical Therapeutic Chemical Classification) registration number B05AA06 and CAS (Chemical Abstracts Service) registration number 0009000-70-8. Suitable gelatins have a chemical description of a purified protein obtained by any of partial acid hydrolysis (type A), partial alkaline hydrolysis (type B), or enzymatic hydrolysis of collagen derived from animals. Also, suitable gelatins may be mixtures of different types. These gelatins are described under the following foreign names: Gelatina (Latin), Gelatine (German), Gelatine (French), and Gelatina (Spanish).

[0104] Gelatin is sold under the following common names: Gelatin (official synonym: Japanese Approved Name), Gelatine (official synonym: Denomination Commune Francaise), Gelatina alba (unofficial synonym), Gelatina animalis (unofficial synonym), UNII-2G86QN327L (unofficial synonym), Gelatin (Pharmacopoeial name: BP 2018, JP XVII, National Formulary 33, Ph.Eur.9.3, Ph.Int.7), Gelatina (Pharmacopoeial name: Ph.Eur.9.3, Ph.Int.7), Gelatine (Pharmacopoeial name: Ph.Eur.9.3), Gelatine (Pharmacopoeial name: Ph.Eur.9), Purified Gelatin (Pharmacopoeial name: JP XVII), Absorbable Gelatin (Pharmacopoeial name: USP 41), Gelatine Polysuccinat zur parenteralen Anwendung (unofficial synonym), Gelofusin (unofficial synonym), Modified Fluid Gelatin (unofficial synonym), and Modifizierte Gelatine (unofficial synonym).

[0105] Gelatin is sold under the following trade names: Colagenan by Herbarium Laboratorio Botanico in Brazil, Gelatina Pharma Arte by Pharma Arte in Paraguay, Gelfilm by Pfizer in New Zealand, Gelfoam by Pfizer in New Zealand, Gelofusine by B. Braun in France, B. Braun in Hungary [+ sodium chloride]; B. in LatviaManufactured by Braun Medical; Gelofusine manufactured by JV Healthcare Limited in Malta, manufactured by Fresenius Kabi in Estonia; manufactured by Fresenius Kabi in Romania; manufactured by Fresenius Kabi Austria in Austria; Geloplasma manufactured by Fresenius-Kabi in Argentina, Geloplasma manufactured by Fresenius Kabi in Latvia [+ magnesium chloride, + potassium chloride, + sodium chloride, + sodium lactate], Glycerin AD manufactured by Pharco in Egypt [+ glycerol], Glycerin Inf manufactured by Pharco in Egypt [+ glycerol], Glycerin Pharco manufactured by Pharco in Kuwait [+ glycerol], Glycerol Adult manufactured by Sedico in Egypt [+ glycerol], Glycerol Infant manufactured by Sedico in Egypt [+ glycerol], Intragel manufactured by Zoetis in the United States [+ sodium chloride] [for veterinary use], Stomahesive manufactured by Bristol-Myers Squibb in Uruguay [+ pectin, + carmellose], Tego manufactured by Armstrong Laboratorios de Mexico in Mexico, Valcatil manufactured by Panalab in Argentina; manufactured by Panalab in Paraguay [+ cysteine, + methionine], Gelfilm manufactured by Pfizer Japan in Japan, manufactured by Pfizer in Singapore; Gelfoam manufactured by Pfizer Japan in Japan, Spongel manufactured by Astellas in Japan, Eufusin manufactured by Medacta Italia in Italy, Galafundin manufactured by Braun in Kuwait [+ calcium chloride, + sodium chloride], manufactured by Buminusantara Bestari Perkasa / B Braun in Indonesia; Gelafundin manufactured by Pisa in Mexico, Gelafundin 4% manufactured by B. Braun in Germany, Gelafundin ISO manufactured by B. Braun in Germany, B. in SpainGelafundina manufactured by Braun Medical, manufactured by Biomed in New Zealand; Gelafusal manufactured by Serumwerk Bernburg in Germany, manufactured by B. Braun Medical in Spain; manufactured by B. Braun B.Braun Melsungen in Romania; Gelaspan manufactured by Braun in Norway, Gelaspan 4% manufactured by B. Braun Medical in Estonia, manufactured by B. Braun in Italy; manufactured by B. Braun Medical in Denmark; manufactured by Braun Medical in Ecuador; manufactured by B. Braun Medical in the Netherlands; manufactured by B. Braun Melsungen in Serbia; manufactured by B. Braun B.Braun Melsungen in Romania; Gelofusine manufactured by Biomed in New Zealand, manufactured by B. Braun in Bulgaria; manufactured by B. Braun in the Czech Republic, B. Braun Austria in Austria, B. Braun Medical in Hong Kong, Gelofusine [+ sodium chloride] manufactured by Braun in Sweden, Geloplasma manufactured by Fresenius Kabi in Spain, manufactured by Fresenius Kabi in the Czech Republic; Geloplasma [+ magnesium chloride, + potassium chloride, + sodium chloride, + sodium lactate] manufactured by Fresenius Kabi France in Slovenia, Infuplas manufactured by Fresenius Kabi in Italy, Isoplex 4% manufactured by Beacon Pharmaceuticals in the UK, manufactured by Beacon in Malta; Volplex 4% manufactured by Beacon Pharmaceuticals in the UK.

[0106] Excipient or adjuvant In addition, the formulations or compositions of the present disclosure may contain other chemical substances, such as antioxidants (e.g., vitamins A, C, D, E, etc.), trace metals and / or polyvalent cations (aluminum, gold, copper, zinc, calcium, etc.), surfactants and / or solvents (e.g., propylene glycol / PPG, dimethyl sulfoxide / DMSO, medium-chain triglycerides / MCT, etc.). Non-toxic dyes and flavor enhancers may be added to the formulations during preparation to improve stability, fluidity / spreadability, permeability, efficacy, and consumer acceptability. Such additives, excipients, and / or adjuvants may also function as active agents. Suitable organic solvents for use in the present disclosure include, but are not limited to, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, or any combination thereof.

Examples

[0107] Experiment of the present invention Capsule filling formulation Example 1 Preferred capsule filling formulation Table 5 shows a preferred capsule solution containing a 50 mg dosage form suitable for encapsulation in soft gelatin or two-piece capsules of 7HP349. The capsule filling formulation contains 5 mass / mass% 7HP349 + 14 mass / mass% ethanol + 81 mass / mass% Phosal 53 MCT, a soybean phosphatidylcholine (PC)-containing oil, and the same excipients as those present in the 7HP349 capsule drug product. All substances used in formulation development and those intended for use in the placebo are GMP-compliant, approved official inactive ingredients.

Table 5

[0108] Phosal 53 MCT soybean lecithin-containing oil has been shown to improve the oral bioavailability of hydrophobic small molecules. The components and official status are summarized in Table 6.

Table 6

[0109] Formulation Development Example 2 Physical Stability of 7HP349 Filled Formulations The physical stability of various 7HP349 filled formulations containing Phosal 53 MCT was tested at Eurofins Advinus Limited for 3 months under storage conditions of 2 - 8°C (long term), 25 ± 2°C @ 60 ± 5% RH (ambient temperature), and 40 ± 2°C @ 75 ± 5% RH (accelerated). The test conditions for physical stability are outlined in Table 7. The compositions of the various 7HP349 formulations tested are shown in Table 8. [Table 7] [Table 8]

[0110] Overview of Physical Stability All formulation samples were examined for precipitation, color change, and phase separation during the storage period. In summary, all formulation samples stored under ambient conditions (25 ± 2°C, 60 ± 5% RH) were stable for 3 months and no changes in physical appearance were found. Some formulation samples stored under refrigeration (2 - 8°C) and accelerated conditions (40 ± 2°C @ 75 ± 5% RH) showed phase separation with globules and precipitates, but became clear solutions after vortexing and sonication. [Table 9]

[0111] Example 3 Characterization of Dosage Form Table 10 shows an overview of the initial assay values and impurity levels in the various filled formulations and various filled shell (two-piece capsule) combinations tested. The initial assay values and impurity levels in two development batches of 7HP349 capsules 50 mg are shown in Tables 11 and 12. In all formulations, 7HP349 remained stable. No new impurities were identified.

Table 10

[0112] Example 4 The following examples illustrate compositions that can be administered to a patient parenterally, for example, by intravenous, intraarterial, intramuscular, or injection, and the compositions have anti-solid tumor activity, improve antigen presentation before, during, and / or after antigen administration, enhance antigen-presenting cell (APC) activity, enhance the immune response to a vaccine before, during, and / or after vaccine administration, enhance T cell activity, natural or antigen-activated T cells, enhance therapeutic antibody activity before, during, and / or after administration of a therapeutic antibody, enhance checkpoint inhibitor activity therapy with a checkpoint inhibitor antibody, and / or enhance hematopoietic stem cell engraftment before, during, and / or after administration of hematopoietic stem cells.

[0113] The composition includes the following component ranges:

Table 11

[0114] Phosal 53 MCT includes components in the following ranges:

Table 12

[0115] In certain embodiments, the composition includes the following component ranges:

Table 13

[0116] In certain embodiments, the ZIS comprises about 90% by weight phosphatidylcholine and about 10% by weight lysophosphatidylcholine, the organic solvent comprises alcohol, and the NL comprises from about 94.12% to about 99.56% by weight triglyceride, from about 2.94% to about 0.22% by weight ascorbyl fatty acid ester, and from about 2.94% to about 0.22% by weight α-tocopherol. In other embodiments, the organic solvent comprises ethanol.

[0117] In certain embodiments, the carrier comprises from about 30.76% to about 28.71% by weight of one or more ZIS, from about 28.91% to about 20.35% by weight of one or more NL, from about 9.56% to about 16.18% by weight of one or more organic solvents, from about 23.05% to about 21.71% by weight of one or more gelatins, and from about 7.72% to about 13.05% by weight of a blend of sorbitol and glycerin.

[0118] When added to an aqueous, injectable, pharmaceutically acceptable carrier, the composition forms a stable emulsion.

[0119] Pharmacokinetics Example Example 5 Several target 7HP349 solutions suitable for use in liquid-filled capsules were tested. Non-lipid-based solutions with high surfactant levels, such as "Solution", provided limited bioavailability. The use of medium-chain triglycerides and high surfactants provided higher absorbability (Formulation Q), but in U28, the addition of phospholipids to MCT further improved bioavailability. [Table 14]

[0120] Preferred lipid-based formulations based on U28 provided appropriate exposure in humans. Optimal PK exposure for engaging integrins and improving adjuvant activity is a systemic plasma exposure of AUC0-t of about 50 ng / mL / hour to about 100 ng / mL / hour. [Table 15]

[0121] Embodiments of the present disclosure Embodiment 1 One or more surfactants (SRF), and One or more neutral lipids (NL) A carrier composition comprising the same Embodiment 2 One or more SRF, and One or more NL A carrier composition comprising the same, and One or more poorly water-soluble pharmaceutical agents A pharmaceutical composition comprising the same

[0122] Embodiment 3 A soft gel capsule, comprising One or more SRF, and One or more NL A carrier composition comprising the same, and One or more poorly water-soluble pharmaceutical agents A soft gel capsule filled with a filling composition comprising the same A pharmaceutical composition comprising the same Embodiment 4 One or more organic solvents Embodiments 1, 2, or 3 further comprising the same

[0123] Embodiment 5 One or more SRF are One or more zwitterionic surfactants (ZIS), or One or more nonionic surfactants (NIS), or Any mixture or combination thereof Embodiments 1, 2, 3, or 4 comprising the same Embodiment 6 One or more SRF are One or more ionic surfactants (IS) Embodiment 5 further comprising the same

[0124] Embodiment 7 One or more SRFs one or more ZISs in one, two, three, or four embodiments. Embodiment 8 One or more SRFs one or more NISs in one, two, three, or four embodiments. Embodiment 9 One or more SRFs one or more ZISs, and one or more NISs in one, two, three, or four embodiments. Embodiment 10 One or more SRFs one or more ZISs, one or more NISs, and one or more ISs in six embodiments.

[0125] Embodiment 11 One or more SRFs are present in an amount of about 5 wt% to about 95 wt% or any sub-range thereof, one or more NLs are present in an amount of about 95 wt% to about 5 wt% or any sub-range thereof, in any of the preceding embodiments. Embodiment 12 Their SRF / NL mixtures containing about 99 wt% to about 75 wt% or any sub-range thereof of one or more SRFs and one or more NLs, and about 1 wt% to about 25 wt% or any sub-range thereof of one or more organic solvents in any of the preceding embodiments. Embodiment 13 One or more SRFs an SRF mixture containing about 99 wt% to about 90 wt% or any sub-range thereof, including one or more ZISs, one or more NISs, or any mixture thereof, and about 1 wt% to about 10 wt% or any sub-range thereof of one or more ISs Any of the preceding embodiments, including

[0126] Embodiment 14 The carrier composition is present in an amount of about 75% to about 97% by mass or any sub-range thereof, One or more poorly water-soluble pharmaceutical agents are present in an amount of about 25% to about 1% by mass or any sub-range thereof. Any of the preceding embodiments. Embodiment 15 One or more NLs are An SC mixture of about 0% to about 20% by mass or any sub-range thereof, including one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, and An NL mixture of about 100% to about 80% by mass or any sub-range thereof, including one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof Any of the preceding embodiments, including

[0127] Embodiment 16 One or more NLs are An SC mixture of about 0% to about 20% by mass or any sub-range thereof, including one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, and An MC mixture of about 100% to about 80% by mass or a sub-range thereof, including one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof Any of the preceding embodiments, including Embodiment 17 One or more NLs are An SC mixture of about 0 wt% to about 20 wt% or any sub-range thereof, comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, and An LC mixture of about 100 wt% to about 80 wt% or any sub-range thereof, comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof Comprising any of the preceding embodiments.

[0128] Embodiment 18 One or more NLs are An SC mixture of about 0 wt% to about 20 wt% or any sub-range thereof, comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, and A VLC mixture of about 100 wt% to about 80 wt% or any sub-range thereof, comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof Comprising any of the preceding embodiments. Embodiment 19 One or more NLs are An MC mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any sub-range thereof Comprising any of the preceding embodiments.

[0129] Embodiment 20 One or more NLs are An LC mixture comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof Comprising any of the preceding embodiments. Embodiment 21 One or more NLs are A VLC mixture comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any partial range thereof Comprising any of the preceding embodiments.

[0130] Embodiment 22 One or more NLs are One or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any partial range thereof, and One or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any partial range thereof Comprising any of the preceding embodiments.

[0131] Embodiment 23 One or more NLs are One or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any partial range thereof, and One or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any partial range thereof Comprising any of the preceding embodiments.

[0132] Embodiment 24 One or more NLs are One or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any partial range thereof, One or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any partial range thereof, and One or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any partial range thereof comprising any of the preceding embodiments.

[0133] Embodiment 25 One or more NLs are one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any partial range thereof, and one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any partial range thereof comprising any of the preceding embodiments.

[0134] Embodiment 26 One or more poorly water-soluble pharmaceutical active agents are one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical active agents comprising any of the preceding embodiments. Embodiment 27 One or more poorly water-soluble pharmaceutical active agents have an n-octanol to water LogP value greater than 5 (LogP > 5), Embodiment 26. Embodiment 28 One or more ZISs of about 30.76% to 28.71% by mass, one or more NLs of about 28.91% to 20.35% by mass, one or more organic solvents of about 9.56% to 16.18% by mass, one or more gelatins of about 23.05% to 21.71% by mass, and a blend of sorbitol and glycerin of about 7.72% to 13.05% comprising a carrier comprising a pharmaceutical carrier composition.

[0135] Embodiment 29 One or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents from about 1.50% to about 4.20% by mass, One or more ZIS from about 30.30% to about 27.50% by mass, One or more NL from about 28.48% to about 19.50% by mass, One or more organic solvents from about 9.42% to about 15.50% by mass, One or more gelatins from about 22.70% to about 20.80% by mass, Containing a mixture of sorbitol and glycerin from about 7.60% to about 12.50% by mass, Essentially free of water Carrier Pharmaceutically acceptable aqueous injection system A pharmaceutical composition comprising: The composition comprises a stable injectable emulsion, Pharmaceutical composition.

[0136] Embodiment 30 One or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents from about 1.50% to about 4.20% by mass, One or more ZIS from about 30.30% to about 27.50% by mass, One or more NL from about 28.48% to about 19.50% by mass, One or more organic solvents from about 9.42% to about 15.50% by mass, One or more gelatins from about 22.70% to about 20.80% by mass, Containing a mixture of sorbitol and glycerin from about 7.60% to about 12.50% by mass, Essentially free of water, Carrier A pharmaceutical system comprising, and Pharmaceutically acceptable aqueous injection system An injectable pharmaceutical composition comprising: The composition comprises a stable injectable emulsion, Injectable pharmaceutical composition.

[0137] Embodiment 31 Embodiments 28, 29, or 30, where the mass ratio of the pharmaceutical and pharmaceutically acceptable aqueous injection systems is from about 1:2 to 1:10. Embodiment 32 Lecithin is one or more ZIS, and one or more NL in embodiments 28, 29, 30, or 31.

[0138] Embodiment 33 One or more SRF are one or more zwitterionic surfactants (ZIS), one or more nonionic surfactants (NIS), or contain any combination thereof, One or more NL are one or more short-chain monoglycerides (SCM), one or more medium-chain monoglycerides (MCM), one or more long-chain monoglycerides (LCM), one or more very long-chain monoglycerides (VLCM), one or more short-chain diglycerides (SCD), one or more medium-chain diglycerides (MCD), one or more long-chain diglycerides (LCD), one or more very long-chain monoglycerides (VLCD), one or more short-chain triglycerides (SCT), one or more medium-chain triglycerides (MCT), one or more long-chain triglycerides (LCT), one or more very long-chain triglycerides (VLCT), one or more short-chain fatty acid esters (SCFE), one or more medium-chain fatty acid esters (MCFE), one or more long-chain fatty acid esters (LCFE), One or more very long chain fatty acid esters (VLCFEs), or comprising any mixture thereof, or one or more organic solvents are one or more alcohols, one or more non-alcoholic organic solvents, or any mixture thereof, any of the preceding embodiments.

[0139] Embodiment 34 One or more poorly water-soluble pharmaceutical agents comprise one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents, any of the preceding embodiments.

[0140] Embodiment 35 One or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents are one or more compounds of formula (I), one or more compounds of formula (II), or any mixture thereof of two or more compounds of formula (I) and (II), Embodiment 34.

[0141] Embodiment 36 A method of administering to a human or animal a pharmaceutical composition corresponding to any of the pharmaceutical compositions described in any of the above embodiments.

[0142] Final Paragraph - Incorporation by Reference in its Entirety All references cited herein are incorporated by reference. Although the invention has been disclosed with reference to preferred embodiments, those skilled in the art will understand that upon reading this description, changes and modifications can be made without departing from the scope and spirit of the invention as described above and claimed below.

Claims

1. One or more surfactants (SRF), and one or more neutral lipids (NL) A carrier composition comprising the same.

2. One or more SRF, and one or more NL A carrier composition comprising the same, and one or more poorly water-soluble pharmaceutical agents A pharmaceutical composition comprising the same.

3. A soft gel capsule, comprising one or more SRF, and one or more NL A carrier composition comprising the same, and one or more poorly water-soluble pharmaceutical agents A soft gel capsule filled with a filling composition comprising the same A pharmaceutical composition comprising the same.

4. One or more organic solvents The composition according to claim 1, 2, or 3, further comprising the same.

5. The one or more SRF are one or more zwitterionic surfactants (ZIS), or one or more nonionic surfactants (NIS), or Any mixture or combination thereof The composition according to claim 1, 2, 3, or 4, comprising the same.

6. The one or more SRF are one or more ionic surfactants (IS) The composition according to claim 5, further comprising the same.

7. The one or more SRF are one or more ZIS The composition according to claim 1, 2, 3, or 4, comprising the same.

8. The one or more SRF are one or more NIS The composition according to claim 1, 2, 3, or 4, comprising the same.

9. The one or more SRF are one or more ZIS, and one or more NIS The composition according to claim 1, 2, 3, or 4, comprising the same.

10. The one or more SRF are one or more ZIS, one or more NIS, and one or more IS The composition according to claim 6, comprising the same.

11. The one or more SRF are present in an amount of about 5% to about 95% by mass or any sub-range thereof, The one or more NL are present in an amount of about 95% to about 5% by mass or any sub-range thereof, The composition according to any one of claims 1 to 10.

12. An SRF / NL mixture of about 99% to about 75% by mass or any sub-range thereof, comprising the one or more SRF and the one or more NL, and About 1% to about 25% by mass or any sub-range thereof of the one or more organic solvents The composition according to any one of claims 1 to 11, comprising the same.

13. The one or more SRF are An SRF mixture comprising one or more ZISs, one or more NISs, or any mixture thereof, in an amount of about 99% to about 90% by mass or any sub-range thereof, and said one or more ISs in an amount of about 1% to about 10% by mass or any sub-range thereof The composition according to any one of claims 1 to 12.

14. The carrier composition is present in an amount of about 75% to about 97% by mass or any sub-range thereof, said one or more poorly water-soluble pharmaceutical agents are present in an amount of about 25% to about 1% by mass or any sub-range thereof, The composition according to any one of claims 1 to 13.

15. Said one or more NLs are An SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, in an amount of about 0% to about 20% by mass or any sub-range thereof, and An NL mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, in an amount of about 100% to about 80% by mass or any sub-range thereof The composition according to any one of claims 1 to 14.

16. Said one or more NLs are An SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, in an amount of about 0% to about 20% by mass or any sub-range thereof, and An MC mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, in an amount of about 100% to about 80% by mass or a sub-range thereof The composition according to any one of claims 1 to 15.

17. Said one or more NLs are An SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, in an amount of about 0% to about 20% by mass or any sub-range thereof, and An LC mixture of about 100% by mass to about 80% by mass or any sub-range thereof, comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LC FEs, or any mixture thereof The composition according to any one of claims 1 to 16, comprising the same

18. Said one or more NLs are An SC mixture of about 0% by mass to about 20% by mass or any sub-range thereof, comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SC FEs, or any mixture thereof, and A VLC mixture of about 100% by mass to about 80% by mass or any sub-range thereof, comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLC FEs, or any mixture thereof The composition according to any one of claims 1 to 17, comprising the same

19. Said one or more NLs are An MC mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MC FEs, or any mixture thereof, or any sub-range thereof The composition according to any one of claims 1 to 18, comprising the same

20. Said one or more NLs are An LC mixture comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LC FEs, or any mixture thereof, or any sub-range thereof The composition according to any one of claims 1 to 19, comprising the same

21. Said one or more NLs are A VLC mixture comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLC FEs, or any mixture thereof, or any sub-range thereof The composition according to any one of claims 1 to 20, comprising the same

22. Said one or more NLs are One or more MCMs, one or more MCDs, one or more MCTs, one or more MC FEs, or any combination thereof, or any sub-range thereof, and One or more LCMs, one or more LCDs, one or more LCTs, one or more LC FEs, or any mixture thereof, or any sub-range thereof The composition according to any one of claims 1 to 21, comprising the same

23. The one or more NLs are one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any partial range thereof, and one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any partial range thereof The composition according to any one of claims 1 to 22, comprising.

24. The one or more NLs are one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any partial range thereof, one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any partial range thereof, and one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any partial range thereof The composition according to any one of claims 1 to 23, comprising.

25. The one or more NLs are one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any partial range thereof, and one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any partial range thereof The composition according to any one of claims 1 to 24, comprising.

26. The one or more poorly water-soluble pharmaceutical active agents are one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical active agents The composition according to any one of claims 1 to 25, comprising.

27. The one or more poorly water-soluble pharmaceutical active agents have an n-octanol to water LogP value (LogP > 5) greater than 5, The composition according to claim 26.

28. About 30.76% to 28.71% by mass of one or more ZISs, About 28.91% to 20.35% by mass of one or more NLs, About 9.56% to 16.18% by mass of one or more organic solvents, One or more gelatins from about 23.05% to 21.71% by mass, and A blend of sorbitol and glycerin from about 7.72% to 13.05% by mass A carrier containing A pharmaceutical carrier composition containing

29. One or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents from about 1.50% to about 4.20% by mass, One or more ZISs from about 30.30% to about 27.50% by mass, One or more NLs from about 28.48% to about 19.50% by mass, One or more organic solvents from about 9.42% to about 15.50% by mass, One or more gelatins from about 22.70% to about 20.80% by mass, Containing a mixture of sorbitol and glycerin from about 7.60% to about 12.50% by mass, Essentially free of water, A carrier, A pharmaceutically acceptable aqueous injection system A pharmaceutical composition containing The composition contains a stable injectable emulsion, A pharmaceutical composition.

30. One or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents from about 1.50% to about 4.20% by mass, One or more ZISs from about 30.30% to about 27.50% by mass, One or more NLs from about 28.48% to about 19.50% by mass, One or more organic solvents from about 9.42% to about 15.50% by mass, One or more gelatins from about 22.70% to about 20.80% by mass, Containing a mixture of sorbitol and glycerin from about 7.60% to about 12.50% by mass, Essentially free of water, A carrier, A pharmaceutical system containing, and A pharmaceutically acceptable aqueous injection system An injectable pharmaceutical composition containing The composition contains a stable injectable emulsion, An injectable pharmaceutical composition.

31. The mass ratio of the pharmaceutical system and the pharmaceutically acceptable aqueous injection system is about 1:2 to 1:10, the composition according to claim 28, 29, or 30.

32. Lecithin is One or more ZISs, and One or more NLs The composition according to claim 28, 29, 30, or 31 containing.

33. The one or more SRFs are One or more zwitterionic surfactants (ZISs), One or more nonionic surfactants (NISs), or Any combination thereof, or The one or more NLs are One or more short-chain monoglycerides (SCMs), One or more medium-chain monoglycerides (MCMs), One or more long-chain monoglycerides (LCM), One or more very-long-chain monoglycerides (VLCM), One or more short-chain diglycerides (SCD), One or more medium-chain diglycerides (MCD), One or more long-chain diglycerides (LCD), One or more very-long-chain diglycerides (VLCD), One or more short-chain triglycerides (SCT), One or more medium-chain triglycerides (MCT), One or more long-chain triglycerides (LCT), One or more very-long-chain triglycerides (VLCT), One or more short-chain fatty acid esters (SCFE), One or more medium-chain fatty acid esters (MCFE), One or more long-chain fatty acid esters (LCFE), One or more very-long-chain fatty acid esters (VLCFE), or comprises any mixture thereof, or said one or more organic solvents are one or more alcohols, one or more non-alcohol organic solvents, or any mixture thereof, A composition according to any one of claims 1 to 32.

34. Said one or more poorly water-soluble pharmaceutical agents comprise one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents, A composition according to any one of claims 1 to 33.

35. Said one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents comprise one or more compounds of formula (I), one or more compounds of formula (II), or any mixture thereof of two or more compounds of formula (I) and (II), A composition according to claim 34.

36. A method of administering a pharmaceutical composition corresponding to any of the pharmaceutical compositions according to any one of claims 1 to 35 to a human or an animal.

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