Orally Bioavailable Lipid-Based Constructs

Abstract

The present invention is embodied by a composition capable of chaperoning a typically non-orally available therapeutic or diagnostic agent through the environment of the digestive tract such that the therapetuic or diagnostic agent is bioavailable. The composition may or may not be targeted to specific cellular receptors, such as hepatocytes. Therapeutic agents include, but are not limited to, insulin, calcitonin, serotonin, and other proteins. Targeting is accomplished with biotin or metal based targeting agents.

1 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula I, 
       
         
           
           
               
               
           
         
       
       wherein
 “A” is 
 
       
         
           
           
               
               
           
         
       
       or NH 2 NH—;
 “J” corresponds to (CH 2 ) a  or 
 
       
         
           
           
               
               
           
         
         G 1  is either H or SO 3 Na; and 
         “a” is independently, at each occurrence, 1, 2, 3, 4, 5, 6, 7, or 8. 
       
     
     
         2 . The composition according to  claim 1 , wherein the linker precursor according to formula I is N-succinimidyl-3-(2-pyridyldithio)proprionate (“SPDP”), Succinimidyl 6-(3-[2-pyridyldithio]-propionamido)hexanoate (“LC-SPDP”), Sulfosuccinimidyl 6-(3′-[2-pyridyldithio]-propionamido)hexanoate (“Sulfo-LC-SPDP”), 4-Succinimidyloxycarbonyl-methyl-a-[2-pyridyldithio]toluene (“SMPT”), 4-Sulfosuccinimidyl-6-methyl-a-(2-pyridyldithio)toluamido]hexanoate) (“Sulfo-LC-SMPT”), or 3-(2-pyridyldithio)propionyl hydrazide (“PDPH”). 
     
     
         3 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula II, 
       
         
           
           
               
               
           
         
       
       wherein
 G 1  is either H or SO 3 Na; 
 G 2  is maleimidyl, 
 
       
         
           
           
               
               
           
         
       
       —HNC(O)CH 2 I, —CH 2 NHC(O)(CH 2 ) a NHC(O)CH 2 I, —CH 2 HNC(O)CH 2 I;
 “Q” is optional and, when present, is C(O)(CH 2 ) a NH; 
 “K” is optional and, when present, is —(CH 2 ) a —; and 
 wherein “a” is independently, at each occurrence 1, 2, 3, 4, 5, 6, 7, or 8. 
 
     
     
         4 . The composition according to  claim 3 , wherein the linker precursor according to formula II is Succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (“SMCC”), Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (“Sulfo-SMCC”), m-Maleimidobenzoyl-N-hydroxysuccinimide ester (“MBS”), m-Maleimidobenzoyl-N-hydroxysulfosuccinimide ester (“Sulfo-MBS”), N-Succinimidyl[4-iodoacetyl]aminobenzoate (“SIAB”), N-Sulfosuccinimidyl[4-iodoacetyl]aminobenzoate (“Sulfo-SIAB”), succinimidyl-4-(((iodoacetyl)amino)methyl)cyclohexane-1-carboxylate (“SIAC”), succinimidyl 4-[p-maleimidophenyl]butyrate (“SMPB”), sulfosuccinimidyl 4-[p-maleimidophenyl]butyrate (“Sulfo-SMPB”), or succinimidyl-6-((((4-(iodoacetyl)amino)methyl)cyclohexane-1-carbonyl)amino)-hexanoate (“SIACX”). 
     
     
         5 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula III, 
       
         
           
           
               
               
           
         
       
       wherein
 G 1  is either H or SO 3 Na; 
 G 4  is maleimidyl, —HNC(O)CH 2 I, or NHC(O)(CH 2 ) a NHC(O)CH 2 I; and 
 “a” is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, or 8. 
 
     
     
         6 . The composition according to  claim 5 , wherein the linker precursor according to formula III is N-[g-maleimidobutyryloxy]succinimide ester (“GMBS”), N-[g-maleimidobutyryloxy]sulfosuccinimide ester (“Sulfo-GMBS”), succinimidyl-6-((iodoacetyl)amino)hexanoate (“SIAX”), or succinimidyl-6-(6-(((iodoacetyl)amino)hexanoyl)amino)hexanoate (“SIAXX”). 
     
     
         7 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula IV, 
       
         
           
           
               
               
           
         
       
     
     
         8 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula V, 
       
         
           
           
               
               
           
         
       
       wherein
 Z is independently optional at each occurrence, and, when present, (CH 2 ) a ; and 
 wherein “a” is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, or 8. 
 
     
     
         9 . The composition according to  claim 8 , wherein the linker precursor according to formula V is 4-(4-N-Maleimidophenyl)butyric acid hydrazide hydrochloride (“MBPH”), or 4-(N-maleimidophenyl)cyclohexane-1-carbonyl-hydrazide hydrochloride (“M 2 C 2 H”). 
     
     
         10 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula VI, 
       
         
           
           
               
               
           
         
       
       wherein
 G 5  is selected from the group consisting of —C(O)G 7 , —C(O)NHNH 2 , —C(O)C(O)H, —C(O)NH(CH 2 ) a NH 2 , —C(O)NH(CH 2 ) a NHC(O)CH 2 I, —C(O)NH(CH 2 ) a C(O)G 7 , —NO 2 , —(CH 2 ) a NHC(O)G 7 , —NH(CH 2 ) a C(O)G 7 , —(CH 2 ) a SSC(O)G 7 , —C(O)NH(CH 2 ) a SS(CH 2 ) a C(O)G 7 , —(CH 2 ) a C(O)G 7 , and —C(O)NH(CH 2 ) a NHC(O)(CH 2 ) a G 9 ; 
 “a” is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; 
 G 6  is selected from the group consisting —OH, —NO 2 , —H, and —C(O)G 7 ; 
 G 7  is 
 
       
         
           
           
               
               
           
         
       
       wherein G 1  is either H or —SO 3 Na; and
 G 9  is 
 
       
         
           
           
               
               
           
         
       
       with the proviso that is G 6  is —C(O)G 7  only when G 5  is —NO 2  and that G 5  is —NO 2  only when G 6  is —C(O)G 7 . 
     
     
         11 . The composition according to  claim 10 , wherein the linker precursor according to formula VI is N-Hydroxysuccinimidyl-4-azidosalicylic acid (“NHS-ASA”), N-hydroxysulfosuccinimidyl-4-azidosalicylic acid (“Sulfo-NHS-ASA”), sulfosuccinimidyl[4-azidosalicylamido]-hexanoate (“Sulfo-NHS-LC-ASA”), N-hydroxysuccinimidyl-4-azidobenzoate (“HSAB”), N-hydroxysulfosuccinimidyl-4-azidobenzoate (“Sulfo-HSAB”), N-5-azido-2-nitrobenzoyloxysuccinimide (“ANB-NOS”), N-succinimidyl-6-(4′-azido-2′-nitrophenylamino)hexanoate (“SANPAH”), N-sulfosuccinimidyl-6-(4′-azido-2′-nitrophenylamino)hexanoate (“Sulfo-SANPAH”), N-succinimidyl(4-azidophenyl)-1,3′-dithioproprionate (“SADP”), N-Sulfosuccinimidyl(4-azidophenyl)-1,3′-dithioproprionate (“Sulfo-SADP”), sulfosuccinimidyl-2-(p-azidosalicylamido)-ethyl-1,3′-dithiopropionate (“SASD”), 1-(p-azidosalicylamido)-4-(iodoacetamido)butane (“ASIB”), N-[4-(p-azidosalicylamido)butyl]-3′-(2′-pyridyldithio)propionamide (“APDP”), p-azidobenzoyl hydrazide (“ABH”), 4-[p-azidosalicylamido]butylamine (“ASBA”), p-azidophenyl glyoxal (“APG”), or sulfosuccinimidyl-4-(p-azidophenyl)butyrate (“Sulfo-SAPB”). 
     
     
         12 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula VIII, 
       
         
           
           
               
               
           
         
       
       wherein
 G′ is either H or SO 3 Na; 
 G 8  is selected from the group consisting of 2-nitrophenyl-5-azido and 
 
       
         
           
           
               
               
           
         
       
       wherein “a” is independently, at each occurrence, 1, 2, 3, 4, 5, 6, 7, or 8. 
     
     
         13 . The composition according to  claim 12 , wherein the linker precursor according to formula VII is sulfosuccinimidyl-2-(m-azido-o-nitrobenzamido)-ethyl-1,3′-proprionate (“SAND”) or sulfosuccinimidyl 2-[7-amino-4-methylcoumarin-3-acetamido]ethyl-1,3′dithiopropionate (“SAED”). 
     
     
         14 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula VIII, 
       
         
           
           
               
               
           
         
       
       wherein
 G 1  is either H or SO 3 Na; 
 G 8  is selected from the group consisting of 2-nitrophenyl-5-azido and 
 
       
         
           
           
               
               
           
         
       
     
     
         15 . The composition according to  claim 14 , wherein the linker precursor according to formula VIII is sulfo-succinimidyl 7-azido-4-methylcoumarin-3-acetate (“Sulfo-SAMCA”). 
     
     
         16 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula IX, 
       
         
           
           
               
               
           
         
       
       wherein
 G 10  is selected from the group consisting of maleimidyl and NC(O)CH 2 I. 
 
     
     
         17 . The composition according to  claim 16 , wherein the linker precursor according to formula IX is benzophenone-4-iodoacetamide or benzophenone-4-maleimide. 
     
     
         18 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3 aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional reticuloendothelial system (“RES”) masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids through a linker derived from a linker precursor according to formula X, 
       
         
           
           
               
               
           
         
       
       wherein G 11  is selected from the group consisting of C(O)C(N 2 )H and C(N 2 )CF 3 . 
     
     
         19 . The composition of  claim 1 , wherein said therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, parathyroid hormone, calcitonin, serotonin, rituximab, trastuzumab, uricase, tissue plasminogen activator, thymoglobin, a vaccine, heparin or a heparin analog, antithrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide, antivenins, IgG, IgM, HGH, thyroxine, GLP-1, blood clotting Factors VII and VIII, IX, X, a monoclonal antibody, and glycolipids that act as therapeutic agents. 
     
     
         20 . The composition of  claim 1  wherein the lipids are 1,2 distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol. 
     
     
         21 . The composition of  claim 20  wherein said 1,2 distearoyl-sn-glycero-3-phosphocholine is present in approximately 62 mole percent, said dihexadecyl phosphate is present in approximately 22 mole percent, and said cholesterol is present in approximately 16 mole percent, wherein, optionally, at least about 25% of the cholesterol is thiocholesterol. 
     
     
         22 . A method of preparing an orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate;   at least one therapeutic or diagnostic agent;   an optional RES masking agent; and   an optional targeting agent,   
       wherein said at least one therapeutic or diagnostic agent is covalently bound to one or more of said one or more lipids either directly or through a linker derived from a linker precursor according to formula I, said method comprising the steps of:
 a. selecting one or more of said lipids; 
 b. mixing said lipids to form a mixture of lipid-based constituents; 
 c. selecting said therapeutic agent; 
 d. reacting said therapeutic agent with a linker-precursor of formula I to form a therapeutic agent/linker conjugate; and 
 e. adding said conjugate to said mixture to form said composition. 
 
     
     
         23 . An orally bioavailable composition comprising:
 one or more lipids selected from the group consisting of MCC-PE, MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, thiocholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phospho-2-mercaptoethanol, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2-(5-((3 aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate; and   at least one therapeutic agent selected from the group consisting of blood clotting factors VII, VIII, IX, Kallikrein, Kininogen, Hageman Factor (XII), plasma thromboplastin antecedent Factor (XI), tissue factor, Stuart Factor (X), accelerin (V), prothrombin (II), and fibrin stabilizing Factor (XIII).