Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydromorphone, prodrugs, methods of making and use thereof
The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydromorphone (4,5-α-epoxy-3-hydroxy-17-methyl morphinan-6-one) to form novel prodrugs/compositions of hydromorphone. The hydromorphone prodrugs of the present technology have decreased side effects and decreased potential for abuse compared to unconjugated hydromorphone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.
1. A compound-having the following structure:
2. A composition comprising a conjugate having the structure of claim 1 , a pharmaceutically acceptable salt thereof, or a combination thereof.
3. The composition of claim 2 , wherein the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof is used to treat narcotic or opioid abuse; to prevent narcotic or opioid withdrawal; to treat moderate to severe pain; to reduce or prevent oral, intranasal or intravenous drug abuse; or to provide oral, intranasal, or parenteral drug abuse resistance.
4. The composition of claim 3 , wherein oral administration of the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof results in an improved rate of release over time when compared to unconjugated hydromorphone over the same time period.
5. The composition of claim 3 , wherein oral administration of the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof results in less variability in the oral PK profile when compared to unconjugated hydromorphone.
6. The composition of 3 , wherein oral administration of the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof results in reduced side effects when compared with unconjugated hydromorphone.
7. The composition of claim 6 , wherein the reduced side effect is reduced opioid induced constipation.
8. The composition of claim 2 , wherein the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof 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, a suspension, a gel, an oral strip, a rectal film, a transdermal patch, a syrup, and an inhalation compound.
9. The composition of claim 3 , wherein oral administration of the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof provides a therapeutically bioequivalent AUC and/or a bioequivalent when compared to an equivalent molar amount of unconjugated hydromorphone.
10. The composition of claim 3 , wherein intranasal or intravenous administration of the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof provides a lower AUC and/or C max when compared to an equivalent molar amount of unconjugated hydromorphone.
11. The composition of claim 3 , wherein oral administration of the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated hydromorphone.
12. The composition of claim 2 , wherein the at least one conjugate and/or at least one pharmaceutically acceptable salt thereof provides an increased tamper resistance when compared to unconjugated hydromorphone.
13. The composition of claim 2 , wherein the conjugate and/or pharmaceutically acceptable salt thereof is a prodrug.
14. The composition of claim 2 , wherein the pharmaceutically acceptable salt of the conjugate is an anionic salt form, amphoteric salt form, zwitterionic salt form or cationic salt form, or salt form mixtures thereof.
15. The composition of claim 14 , wherein the anionic salt form is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.
16. The composition of claim 14 , wherein the cationic salt form is selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium and tromethamine.