Phenylethanoic Acid, Phenylpropanoic Acid and Phenylpropenoic Acid Conjugates and Prodrugs of Hydrocodone, Methods of Making and Use Thereof
The presently described technology provides phenylethanoic acid, phenylpropanoic acid, phenylpropenoic acid, a salt thereof, a derivative thereof or a combination thereof chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs or compositions of hydrocodone which have a decreased potential for abuse of hydrocodone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.
1 . A composition comprising at least one conjugate, the conjugate comprising hydrocodone and at least one of phenylethanoic acid, phenylpropanoic acid, phenylpropenoic acid, a salt thereof, a derivative thereof or a combination thereof.
2 . The composition of claim 1 , wherein the conjugate comprises at least one phenylethanoic acid, a salt thereof, a derivative thereof or a combination thereof having the formula I:
wherein,
X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH 2 ) x —;
R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, aromatic, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
o, p, q are independently selected from 0 or 1;
x is an integer between 1 and 10;
Alk is an alkyl chain —(CH 2 ) n — wherein n is 0 or 1; and
R 6 is H, OH or carbonyl.
3 . The composition of claim 2 , wherein the phenylethanoic acid or derivative thereof is a profen.
4 . The composition of claim 2 , wherein the phenylethanoic acid or derivative thereof is a tyrosine metabolite.
5 . The composition of claim 1 , wherein the conjugate comprises at least one phenylpropenoic acid, phenylpropanoic acid, a salt thereof, a derivative thereof or a combination thereof having the formula II or formula III:
wherein,
X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH 2 ) x —;
R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, aromatic, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
o, p, q are independently selected from 0 or 1;
x is an integer between 1 and 10;
R 4 is H or OH; and
R 5 is H, OH or carbonyl.
6 . The composition of claim 1 , wherein the conjugate comprises at least one phenylethanoic acid or derivative selected from the group consisting of: phenylacetic acid (hydratropic acid), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillic acid, homoveratric acid, atropic acid, D,L-tropic acid, diclofenac, D,L-mandelic acid, 3,4-dihydroxy-D,L-mandelic acid, vanillyl-D,L-mandelic acid, isovanillyl-D,L-mandelic acid, ibuprofen, fenoprofen, carprofen, flurbiprofen, ketoprofen, naproxen, derivatives thereof and combinations thereof.
7 . The composition of claim 1 , wherein the conjugate comprises at least one phenylpropanoic acid or derivative selected from the group consisting of:
benzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid, 4-hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid, D,L-phenyllactic acid, o,m,p-hydroxy-D,L-phenyllacetic acid, phenylpyruvic acid, derivatives thereof and combinations thereof.
8 . The composition of claim 1 , wherein the conjugate comprises at least one phenylpropenoic acid or derivative selected from a group consisting of: cinnamic acid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapic acid, 2-hydroxy-3-phenylpropenoic acid, derivatives thereof and combinations thereof.
9 . The composition of claim 1 , wherein at least one conjugate is ibuprofen-hydrocodone, cinnamate-hydrocodone, or naproxen-hydrocodone.
10 . The composition of claim 1 , wherein at least one conjugate is a treatment or preventative composition for treating narcotic or opioid abuse or prevent withdrawal.
11 . The composition of claim 1 , wherein at least one conjugate reduces or prevents oral, intranasal or intravenous drug abuse.
12 . The composition of claim 1 , wherein at least one conjugate is a pain treatment composition.
13 . The composition of claim 1 , wherein at least one conjugate exhibits a slower rate of release over time and a higher AUC when compared to unconjugated hydrocodone over that same time period.
14 . The composition of claim 1 , wherein at least one conjugate exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone.
15 . The composition of claim 1 , wherein at least one conjugate is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a thin strip, a slurry, and a suspension.
16 . The composition of claim 1 , wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone.
17 . The composition of claim 1 , wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and C max when compared to unconjugated hydrocodone.
18 . The composition of claim 1 , wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone but does not provide an equivalent C max .
19 . A method for treating a patient having a disease, disorder or condition mediated by binding between an opioid and opioid receptors of the patient, comprising orally administering to the patient a pharmaceutically effective amount of a composition of claim 1 or claim 9 .
20 . The method of claim 19 , wherein the conjugate comprises at least one acid, a salt thereof, a derivative thereof or a combination thereof having the formula I, II, or III:
wherein,
X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH 2 ) x —;
R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, aromatic, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
o, p, q are independently selected from 0 or 1;
x is an integer between 1 and 10;
Alk is an alkyl chain —(CH 2 ) n —, wherein n, is 0 or 1;
R 4 is H or OH;
R 5 is H, OH or carbonyl; and
R 6 is H, OH or carbonyl.
21 . A prodrug comprising a conjugate, the conjugate comprising hydrocodone and at least one acid, a salt thereof, a derivative thereof or a combination thereof having the formula I, II, or III:
wherein,
X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH 2 ) x —;
R 1 , R 2 and R 3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, aromatic, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
o, p, q are independently selected from 0 or 1;
x is an integer between 1 and 10;
Alk is an alkyl chain —(CH 2 ) n —, wherein n is 0 or 1;
R 4 is H or OH;
R 5 is H, OH or carbonyl; and
R 6 is H, OH or carbonyl.
22 . The prodrug of claim 21 , wherein the conjugate comprises ibuprofen-hydrocodone, cinnamate-hydrocodone, or naproxen-hydrocodone.