Fatty Acid Conjugates of Quetiapine, Process for Making and Using the Same

Abstract

The presently described technology provides a novel class of prodrugs of quetiapine that can be synthesized by chemically conjugating fatty acids to quetiapine. Pharmaceutical compositions and methods of synthesizing conjugates of the present technology are also provided. Methods of treating patients with the compositions of the present technology are also provided.

What is claimed is: 
     
         1 . A composition for treating a psychiatric disorder in a subject, comprising a prodrug conjugate of 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol (quetiapine) and a straight chain, saturated fatty acid having the general formula of C n H 2n+1 —CO 2 H, wherein n is 1-7. 
     
     
         2 . The composition of  claim 1 , wherein the prodrug conjugate has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The composition of  claim 1 , wherein n is 1. 
     
     
         4 . The composition of  claim 1 , wherein n is 4. 
     
     
         5 . The composition of  claim 1 , wherein n is 7. 
     
     
         6 . The composition of  claim 1 , wherein the straight chain, saturated fatty acid is acetate or ethanoate. 
     
     
         7 . The composition of  claim 6 , wherein the prodrug conjugate has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The composition of  claim 1 , wherein the straight chain, saturated fatty acid is valerate or pentanoate. 
     
     
         9 . The composition of  claim 8 , wherein the prodrug conjugate has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The composition of  claim 1 , wherein the straight chain, saturated fatty acid is caprylate or octanoate. 
     
     
         11 . The composition of  claim 10 , wherein the prodrug conjugate has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The composition of  claim 1 , wherein the composition has a higher relative bioavailability than non-conjugated quetiapine when administered orally. 
     
     
         13 . The composition of  claim 1 , wherein the prodrug conjugate is in a salt form 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, methylsufate, 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 (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), 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, undecylenate; and a mixture thereof. 
     
     
         14 . The composition of  claim 1 , wherein the composition is formulated for oral, sublingual, transdermal, suppository, or intrathecal administration. 
     
     
         15 . The composition of  claim 14 , wherein the composition formulated for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid solution, suspension, emulsion, elixir or oral thin film (OTF). 
     
     
         16 . The composition of  claim 1 , wherein the prodrug conjugate is present in an amount per unit dose of between about 1 mg and about 2000 mg per unit dose of the composition. 
     
     
         17 . The composition of  claim 16 , wherein the prodrug conjugate is present in an amount per unit dose of between about 150 mg and about 800 mg per unit dose of the composition. 
     
     
         18 . The composition of  claim 16 , wherein the amount per unit dose is based on the amount of quetiapine present in the prodrug conjugate; or wherein the amount per unit dose is based on the amount of quetiapine in a salt of the prodrug conjugate. 
     
     
         19 . The composition of  claim 1 , wherein the psychiatric disorder is at least one of schizophrenia, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder, restless legs syndrome, autism, alcoholism, depression, insomnia, Tourette syndrome or a combination thereof. 
     
     
         20 . The composition of  claim 1 , wherein the subject is a human or a mammal subject. 
     
     
         21 . The composition of  claim 1 , wherein the subject has not been diagnosed with schizophrenia or bipolar disorder. 
     
     
         22 . The composition of  claim 1 , further comprising one or more of: lithium, divalproex, adjuvants, antiadherents, binders, coatings, disintegrants, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents, sweeteners or a combination thereof. 
     
     
         23 . The composition of  claim 1  wherein the composition is a combination of the prodrug conjugate and a salt of the prodrug conjugate.