Oral delivery of peptide pharmaceutical compositions

Abstract

Bioavailability of peptide active agents to be administered orally is enhanced by a pharmaceutical composition providing targeted release of the peptide to the intestine by combining the composition with an absorption enhancer. Bioavailability is further significantly increased by administering the composition in an acid-resistant protective vehicle which transports components of the invention through the stomach. The composition may optionally further include a sufficient amount of a pH-lowering agent to lower local intestinal pH. All components are released together into the intestine with the peptide.

1 . A pharmaceutical composition for oral delivery of a peptide having analgesic or cardiovascular activity, or a prodrug thereof, said composition comprising: 
 (A) a therapeutically effective amount of a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7; and 
 (B) at least one absorption enhancer effective to promote bioavailability of said dermorphin analog or prodrug thereof.  
   
     
     
         2 . The pharmaceutical composition of  claim 1 , which further comprises at least one additional component selected from the group consisting of: 
 (C) an acid-resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said pharmaceutical composition and stomach proteases; and    (D) at least one pharmaceutically acceptable pH-lowering agent,    wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.    
     
     
         3 . A pharmaceutical composition for oral delivery of a peptide having analgesic or cardiovascular activity, or a prodrug thereof, said composition comprising: 
 (A) a therapeutically effective amount of a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, am idobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7; 
 (B) at least one absorption enhancer effective to promote bioavailability of said dermorphin analog or prodrug thereof; and  
 (C) an acid resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said pharmaceutical composition and stomach proteases.  
   
     
     
         4 . A pharmaceutical composition for oral delivery of a peptide having analgesic or cardiovascular activity, or a prodrug thereof, said composition comprising: 
 (A) a therapeutically effective amount of a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7; and 
 (B) at least one pharmaceutically acceptable pH-lowering agent, wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.  
   
     
     
         5 . A pharmaceutical composition for oral delivery of a peptide having analgesic or cardiovascular activity, or a prodrug thereof said composition comprising: 
 (A) a therapeutically effective amount of a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7; 
 (B) at least one pharmaceutically acceptable pH-lowering agent; and  
 (C) at least one absorption enhancer effective to promote bioavailability of said dermorphin analog or prodrug thereof,  
 wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to ten milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.  
   
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein said dermorphin analog is a peptide selected from the group represented by the formulae: 
 (A) H-Tyrosine-D-Norvaline-Phenylalanine-Ornithine-NH 2 ;    (B) H-Tyrosine-D-Norleucine-Phenylalanine-Ornithine-NH 2 ;    (C) H-Tyrosine-D-Arginine-Phenylalanine-α,γ-diaminobutyric acid-NH 2 ;    (D) H-Tyrosine-D-Arginine-Phenylalanine-Lysine-NH 2 ;    (E) H-Lysine-Tyrosine-D-Arginine-Phenylalanine-Lysine-NH 2 ; and    (F) N′-amidino-Tyrosine-D-arginine-Phenylalanine-Methyl-α-alanine-OH,    or analogs thereof.    
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the dermorphin analog is a peptide of formula II  
         H-Tyrosine-A-Phenylalanine-B-NH 2    
       wherein: 
 A is selected from the group consisting of D-α-amino acids;  
 B is selected from the group consisting of α-amino acids; and  
 an overall net positive charge of the peptide is +2 or greater.  
 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein A is selected from the group consisting of D-norvaline, D-norleucine, D-arginine, D-alanine, D-valine, D-isoleucine, D-leucine, D-serine, D-phenylalanine and D-α,γ-diaminobutyric acid.  
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein B is selected from the group consisting of phenylalanine, para-fluoro phenylalanine, ornithine, α,γ-diaminobutyric acid, lysine, norvaline, arginine, α,β-diaminopropionic acid and homolysine.  
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the overall net positive charge of the peptide is +2 or +3.  
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein said dermorphin analog is an opioid peptide of formula III  
       wherein 
 R 1  is selected from 
 (i) linear or branched C 1 -C 6  alkyl;  
 (ii) C 1 -C 6  alkoxy;  
 
 R 2  is selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
 (iii) C 1 -C 6  alkoxy;  
 
 R 3  and R 4  is each and independently selected from 
 (i) hydrogen;  
                     
 (ii) linear or branched C 1 -C 6  alkyl;  
                     
 
 R 5 , R 6 , R 7 , R 8  and R 9  is each independently selected from 
 (i) hydrogen;  
 (ii) halogen, where “halogen” encompasses chloro, fluoro, bromo and iodo; and  
 (iii) linear or branched C 1 -C 6  alkyl; and  
 n is an integer of from 1 to 5,  
 and wherein the composition further comprises  
 
 (A) an acid-resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said pharmaceutical composition and stomach proteases; and  
 (B) at least one pharmaceutically acceptable pH-lowering agent, wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.  
 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein: 
 R 1  is a linear C 1 -C 6  alkyl;    R 2  is a linear C 1 -C 6  alkyl or hydrogen;    R 3  and R 4  is each and independently selected from a straight C 1 -C 6  alkyl or hydrogen;    R 5 , R 6 , R 7 , R 8  and R 9  is each and independently selected from    (i) hydrogen;    (ii) a halogen selected from chloro, fluoro, bromo and iodo; and    (iii) linear or branched C 1 -C 6  alkyl, and    n is an integer from 1 to 5.    
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein: 
 R 1  is CH 3 ;    R 2  is hydrogen or CH 3 ;    R 3  and R 4  are both hydrogen;    R 5 , R 6 , R 7 , R 8  and R 9  are all hydrogen; and    n=4.    
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein said dermorphin analog is a peptide represented by the formula:  
         H-2,6-dimethyltyrosine-D-Arginine-Phenylalanine-Lysine-NH 2    
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein said dermorphin analog is a peptide of formula IV:  
         Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH 2    wherein Xaa is L- or D-dimethylphenylalanine.    
     
     
         16 . A pharmaceutical composition for oral delivery of a peptide having analgesic or cardiovascular activity, or a prodrug thereof, said composition comprising: 
 (A) a therapeutically effective amount of a deltorphin analog or a prodrug thereof, wherein said deltorphin analog is a peptide of formula V:      Tyrosine-D-alanine-Xaa-Glutamic Acid-Valine-Valine-Glycine-NH 2      wherein Xaa is L-or D-dimethylphenylalanine; and    (B) at least one absorption enhancer effective to promote bioavailability of said deltorphin analog or prodrug thereof.    
     
     
         17 . The pharmaceutical composition of  claim 16 , which further comprises at least one additional component selected from the group consisting of: 
 (C) an acid-resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said pharmaceutical composition and stomach proteases; and    (D) at least one pharmaceutically acceptable pH-lowering agent,    wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5,    
     
     
         18 . A pharmaceutical composition for oral delivery of a compound having analgesic or cardiovascular activity, or a prodrug thereof, said composition comprising: 
 (A) a therapeutically effective amount of a compound which is an agonist or partial agonist of vanilloid receptor VR1; and    (B) at least one absorption enhancer effective to promote bioavailability of said compound.    
     
     
         19 . The pharmaceutical composition of  claim 18 , which further comprises at least one additional component selected from the group consisting of: 
 (C) an acid-resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said pharmaceutical composition and stomach proteases; and    (D) at least one pharmaceutically acceptable pH-lowering agent,    wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.    
     
     
         20 . The pharmaceutical composition of  claim 19  wherein said compound is selected from the group consisting of: 
 (i) N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-[4-(methylsulfonylamino)benzyl]thiourea; and    (ii) N-(4-tert-butylbenzyl)-N′-[3-methoxy-4-(methylsulfonylamino)benzyl]thiourea.    
     
     
         21 . A pharmaceutical composition for oral delivery of a peptide having analgesic or cardiovascular activity, or a prodrug thereof, said composition comprising: 
 (A) a therapeutically effective amount of an enkephalin peptide or a prodrug thereof, wherein said enkephalin peptide is a peptide selected from the group represented by the formulae    (i) H-Tyrosine-Glycine-Glycine-Phenylalanine-Methionine-OH;    (ii) H-Tyrosine-Glycine-Glycine-Phenylalanine-Leucine-OH;    (iii) H-Tyrosine-D-alanine-Glycine-N-methyl-phenylalanine-Glycine-ol; and    (iv) analogs thereof; and    (B) at least one absorption enhancer effective to promote bioavailability of said enkephalin peptide or prodrug thereof.    
     
     
         22 . The pharmaceutical composition of  claim 21 , which further comprises at least one additional component selected from the group consisting of: 
 (C) an acid-resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said pharmaceutical composition and stomach proteases; and    (D) at least one pharmaceutically acceptable pH-lowering agent,    wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.    
     
     
         23 . A pharmaceutical composition for oral delivery of a peptide having analgesic or cardiovascular activity, or a prodrug thereof, said composition comprising: 
 (A) a therapeutically effective amount of a peptide linked to a DMT-Tic-Pharmacophore having the structure 
 H-2′,6′-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, said peptide selected from the group consisting of 
 (i) H-DMT-Tic-Glycine-NH-Benzyl; and  
   
 (ii) H-DMT-Tic-NH—CH(CH 2 —COOH)-1-H-benzimidazole-2-yl; and  
 
   (B) at least one absorption enhancer effective to promote bioavailability of said peptide or prodrug thereof.    
     
     
         24 . The pharmaceutical composition of  claim 23 , which further comprises at least one additional component selected from the group consisting of: 
 (C) an acid-resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said pharmaceutical composition and stomach proteases; and    (D) at least one pharmaceutically acceptable pH-lowering agent,    wherein said pH-lowering agent is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1 M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.    
     
     
         25 . The pharmaceutical composition of  claim 1 , wherein the absorption enhancer is an acyl carnitine.  
     
     
         26 . The pharmaceutical composition of  claim 11 , wherein the absorption enhancer is an acyl carnitine.  
     
     
         27 . The pharmaceutical composition of  claim 25 , further including a sucrose ester.  
     
     
         28 . The pharmaceutical composition of  claim 26 , further including a sucrose ester.  
     
     
         29 . The pharmaceutical composition of  claim 1 , further comprising an amount of a second peptide, that is not a physiologically active peptide, effective to enhance bioavailability of said peptide having analgesic or cardiovascular activity or prodrug thereof.  
     
     
         30 . The pharmaceutical composition of  claim 11 , further comprising an amount of a second peptide, that is not a physiologically active peptide, effective to enhance bioavailability of said peptide having analgesic or cardiovascular activity or prodrug thereof.  
     
     
         31 . The pharmaceutical composition of  claim 1 , further comprising a water-soluble barrier that separates said pH-lowering agent from said protective vehicle.  
     
     
         32 . The pharmaceutical composition of  claim 11 , further comprising a water-soluble barrier that separates said pH-lowering agent from said protective vehicle.  
     
     
         33 . The pharmaceutical composition of  claim 1 , wherein said pharmaceutical composition comprises granules containing a pharmaceutical binder and, uniformly dispersed in said binder, at least one of said pH-lowering agent, said absorption enhancer and said peptide having analgesic or cardiovascular activity, or prodrug thereof.  
     
     
         34 . The pharmaceutical composition of  claim 11 , wherein said pharmaceutical composition comprises granules containing a pharmaceutical binder and, uniformly dispersed in said binder, at least one of said pH-lowering agent, said absorption enhancer and said peptide having analgesic or cardiovascular activity, or prodrug thereof.  
     
     
         35 . The pharmaceutical composition according to  claim 2 , wherein said acid resistant protective vehicle is a viscous protective syrup.  
     
     
         36 . The pharmaceutical composition of  claim 11 , wherein said acid resistant protective vehicle is a viscous protective syrup.  
     
     
         37 . A method for enhancing the bioavailability of a peptide having analgesic or cardiovascular activity or a prodrug thereof delivered orally, said method comprising selectively releasing said peptide or prodrug thereof with at least one absorption enhancer into a patient's intestine following passage of said peptide or prodrug and said at least one absorption enhancer through said patient's mouth and stomach.  
     
     
         38 . The method of  claim 37 , wherein the passage of said peptide or prodrug thereof and said at least one absorption enhancer through said patient's mouth and stomach is under the protection of an acid-resistant protective vehicle which prevents contact between stomach proteases and said peptide or prodrug thereof.  
     
     
         39 . The method of  claim 37 , wherein said peptide or prodrug thereof and said at least one absorption enhancer are released into the patient's intestine in the presence of at least one pH-lowering agent, wherein said pH-lowering agent and other compounds released therewith are released into said intestine in a quantity which, if added to 10 milliliters of 0.1 M aqueous sodium bicarbonate solution, would be sufficient to lower pH of said solution to no higher than 5.5.  
     
     
         40 . A method for enhancing the bioavailability of a peptide having analgesic or cardiovascular activity or a prodrug thereof delivered orally, said method comprising selectively releasing said peptide or prodrug thereof, together with at least one pH-lowering agent and at least one absorption enhancer, into a patient's intestine following passage of said peptide or prodrug thereof, pH-lowering agent and absorption enhancer through said patient's mouth and stomach under protection of an acid-resistant protective vehicle which substantially prevents contact between stomach proteases and said peptide or prodrug thereof, wherein said pH-lowering agent and other compounds released therewith are released into said intestine in a quantity which, if added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5.  
     
     
         41 . The method of  claim 37 , wherein said absorption enhancer is selected from the group consisting of a cationic surfactant and an anionic surfactant that is a cholesterol derivative.  
     
     
         42 . The method of  claim 37 , wherein said pH-lowering agent has a pKa no higher than 4.2 and a solubility in water of at least 30 grams per 100 milliliters of water at room temperature  
     
     
         43 . The method of  claim 37 , wherein a weight ratio of said pH-lowering agent to said absorption enhancer is between 3:1 and 20:1.  
     
     
         44 . The method of  claim 37 , wherein said pH-lowering agent is present in an amount of not less than 300 milligrams.  
     
     
         45 . A method for stimulating a mu, delta, or kappa-opioid receptor in a mammal in need thereof, the method comprising orally administering to the mammal an effective amount of a pharmaceutical composition comprising a peptide, or a prodrug thereof, selected from the group consisting of: 
 (A) a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is    selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7;    (B) an opioid peptide, or an analog thereof, wherein said opioid peptide is a peptide of formula III                          wherein    R 1  is selected from 
 (i) linear or branched C 1 -C 6  alkyl;  
 (ii) C 1 -C 6  alkoxy;  
   R 2  is selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
 (iii) C 1 -C 6  alkoxy;  
   R 3  and R 4  is each and independently selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
                     
 and R 7 , R 8  and R 9  is each independently selected from  
   (i) hydrogen;    (ii) halogen, where “halogen” encompasses chloro, fluoro, bromo and iodo; and    (iii) linear or branched C 1 -C 6  alkyl; and    n is an integer of from 1 to 5,    (C) H-2,6-dimethyltyrosine-D-Arginine-Phenylalanine-Lysine-NH 2 ;    (D) Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH 2  
 wherein Xaa is L- or D-dimethylphenylalanine;  
   (E) a deltorphin analog or a prodrug thereof, wherein said deltorphin analog is a peptide of formula V:      Tyrosine-D-alanine-Xaa-Glutamic Acid-Valine-Valine-Glycine-NH 2      wherein Xaa is L-or D-dimethylphenylalanine;    (F) a compound which is an agonist or partial agonist of vanilloid receptor VR1, including, but not limited to, (i) N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-[4-(methylsulfonylamino)benzyl]thiourea; and 
 (ii) N-(4-tert-butylbenzyl)-N′-[3-methoxy-4-(methylsulfonylamino)benzyl]thiourea;  
   (G) an enkephalin peptide or a prodrug thereof, wherein said enkephalin peptide is a peptide selected from the group represented by the formulae 
 (i) H-Tyrosine-Glycine-Glycine-Phenylalanine-Methionine-OH;  
 (ii) H-Tyrosine-Glycine-Glycine-Phenylalanine-Leucine-OH;  
 (iii) H-Tyrosine-D-alanine-Glycine-N-methyl-phenylalanine-Glycine-ol; and  
 (iv) analogs thereof; and  
   (H) a peptide linked to a DMT-Tic-Pharmacophore having the structure 
 H-2′,6′-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, said peptide selected from the group consisting of 
 (i) H-DMT-Tic-Glycine-NH-Benzyl; and  
 (ii) H-DMT-Tic-NH—CH(CH 2 —COOH)-1-H-benzimidazole-2-yl.  
 
   
     
     
         46 . A method for relieving pain, the method comprising orally administering to a patient in need of pain relief an effective pain-relieving amount of a pharmaceutical composition comprising a peptide, or a prodrug thereof, wherein said peptide is selected from the group consisting of: 
 (A) a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is    selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7; 
 (B) an opioid peptide, or an analog thereof, wherein said opioid peptide is a peptide of formula III  
                     
 wherein  
   R 1  is selected from 
 (i) linear or branched C 1 -C 6  alkyl;  
 (ii) C 1 -C 6  alkoxy;  
   R 2  is selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
 (iii) C 1 -C 6  alkoxy;  
   R 3  and R 4  is each and independently selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
                     
 and R 5 , R 6 , R 7 , R 8  and R 9  is each independently selected from  
   (i) hydrogen;    (ii) halogen, where “halogen” encompasses chloro, fluoro, bromo and iodo; and    (iii) linear or branched C 1 -C 6  alkyl; and    n is an integer of from 1 to 5,    (C) H-2,6-dimethyltyrosine-D-Arginine-Phenylalanine-Lysine-NH 2 ;    (D) Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH 2  
 wherein Xaa is L- or D-dimethylphenylalanine;  
   (E) a deltorphin analog or a prodrug thereof, wherein said deltorphin analog is a peptide of formula V:      Tyrosine-D-alanine-Xaa-Glutamic Acid-Valine-Valine-Glycine-NH 2      wherein Xaa is L-or D-dimethylphenylalanine;    (F) a compound which is an agonist or partial agonist of vanilloid receptor VR1 including, but not limited to, (i) N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-[4-(methylsulfonylamino)benzyl]thiourea; and 
 (ii) N-(4-tert-butylbenzyl)-N′-[3-methoxy-4-(methylsulfonylamino)benzyl]thiourea;  
   (G) an enkephalin peptide or a prodrug thereof, wherein said enkephalin peptide is a peptide selected from the group represented by the formulae 
 (i) H-Tyrosine-Glycine-Glycine-Phenylalanine-Methionine-OH;)  
 (ii) H-Tyrosine-Glycine-Glycine-Phenylalanine-Leucine-OH;  
 (iii) H-Tyrosine-D-alanine-Glycine-N-methyl-phenylalanine-Glycine-ol; and  (iii)  
 (iv) analogs thereof; and  
   (H) a peptide linked to a DMT-Tic-Pharmacophore having the structure 
 H-2′,6′-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, said peptide selected from the group consisting of 
 (i) H-DMT-Tic-Glycine-NH-Benzyl; and  
 (ii) H-DMT-Tic-NH—CH(CH 2 —COOH)-1-H-benzimidazole-2-yl.  
 
   
     
     
         47 . The method of  claim 46 , wherein the pain is due to at least one of labor and delivery  
     
     
         48 . The method of  claim 46 , wherein said pain is due to surgery.  
     
     
         49 . A method for improving myocardial contractile force, the method comprising orally administering to a patient in need of said improvement an effective amount of a pharmaceutical composition comprising a peptide, or a prodrug thereof, wherein said peptide is selected from the group consisting of: 
 (A) a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is    selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7; 
 (B) an opioid peptide, or an analog thereof, wherein said opioid peptide is a peptide of formula III  
                     
 wherein  
   R 1  is selected from 
 (i) linear or branched C 1 -C 6  alkyl;  
 (ii) C 1 -C 6  alkoxy;  
   R 2  is selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
 (iii) C 1 -C 6  alkoxy;  
   R 3  and R 4  is each and independently selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
                     
   and R 5 , R 6 , R 7 , R 8  and R 9  is each independently selected from 
 (i) hydrogen;  
 (ii) halogen, where “halogen” encompasses chloro, fluoro, bromo and iodo; and  
 (iii) linear or branched C 1 -C 6  alkyl; and  
 n is an integer of from 1 to 5; and  
   (C) Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH 2  
 wherein Xaa is L- or D-dimethylphenylalanine.  
   
     
     
         50 . A method for improving cardiac performance of a heart before, during or after cardiac transplantation, the method comprising orally administering to a patient in need of said improvement a cardiac performance-improving effective amount of a pharmaceutical composition comprising a peptide, or a prodrug thereof, wherein said peptide is selected from the group consisting of: 
 (A) a dermorphin analog or a prodrug thereof, wherein said dermorphin analog is a peptide of formula I                          wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 7  branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and nitrobenzyl;    R 2  is hydrogen, methyl, ethyl; or    R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl ring containing 3-5 carbon atoms;    X is selected from the group consisting of C═O, N—H, CH 2 , —O—, C═S and —S—;    Y is selected from the group C═O, N—H, CH 2 , —O—, C═S and —S—; or    X and Y, taken together, represent an olefin linkage wherein X and Y each have a hydrogen atom attached thereto in a cis or trans configuration; and    n is 1-7; 
 (B) an opioid peptide, or an analog thereof, wherein said opioid peptide is a peptide of formula III  
                     
 wherein  
   R 1  is selected from 
 (i) linear or branched C 1 -C 6  alkyl;  
 (ii) C 1 -C 6  alkoxy;  
   R 2  is selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
 (iii) C 1 -C 6  alkoxy;  
   R 3  and R 4  is each and independently selected from 
 (i) hydrogen;  
 (ii) linear or branched C 1 -C 6  alkyl;  
                     
   and R 5 , R 6 , R 7 , R 8  and R 9  is each independently selected from 
 (i) hydrogen;  
 (ii) halogen, where “halogen” encompasses chloro, fluoro, bromo and iodo; and  
 (iii) linear or branched C 1 -C 6  alkyl; and  
 n is an integer of from 1 to 5; and  
   (C) Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH 2  
 wherein Xaa is L- or D-dimethylphenylalanine.