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.

1 . A composition for treating a psychiatric disorder in a subject, comprising:
 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol (quetiapine) conjugated to capric acid, a salt of the conjugate or their combination.   
     
     
         2 . The composition of  claim 1 , wherein the composition has a higher relative bioavailability than non-conjugated quetiapine when administered orally. 
     
     
         3 . The composition of  claim 1 , wherein the salt of the conjugate is selected from the group consisting of an 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, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, 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 or a mixture thereof. 
     
     
         4 . The composition of  claim 1 , wherein the composition is formulated for oral, sublingual, transdermal, suppository, or intrathecal administration. 
     
     
         5 . The composition of  claim 4 , 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). 
     
     
         6 . The composition of  claim 1 , wherein the conjugate of quetiapine is present in an amount per unit dose of between about 1 mg and about 2000 mg per unit dose wherein the amount per unit dose is based on the content of quetiapine. 
     
     
         7 . The composition of  claim 6 , wherein the conjugate of quetiapine is present in an amount per unit dose of between about 150 mg and about 800 mg per unit dose wherein the amount per unit dose is based on the content of quetiapine. 
     
     
         8 . 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. 
     
     
         9 . The composition of  claim 1 , wherein the subject is a mammal subject. 
     
     
         10 . The composition of  claim 9 , wherein the mammal subject is a human. 
     
     
         11 . The composition of  claim 1 , wherein the subject has been diagnosed with schizophrenia or bipolar disorder. 
     
     
         12 . 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. 
     
     
         13 . A method of treating a psychiatric disorder involving the binding of an agent to dopamine receptor(s), serotonin receptor(s), or both in a subject, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol (quetiapine) conjugated to capric acid, a salt of the conjugate or their combination, resulting in the agent binding to a dopamine receptor, a serotonin receptor, or both, wherein the composition has a higher relative bioavailability than non-conjugated quetiapine when administered orally. 
     
     
         14 . The method of  claim 13 , wherein the salt of the conjugate is selected from the group consisting of an 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, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, 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 or a mixture thereof. 
     
     
         15 . The method of  claim 13 , wherein the composition is formulated for oral, sublingual, transdermal, suppository, or intrathecal administration. 
     
     
         16 . The method of  claim 15 , 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). 
     
     
         17 . The method of  claim 13 , wherein the conjugate of quetiapine is present in an amount per unit dose of between about 1 mg and about 2000 mg per unit dose wherein the amount per unit dose is based on the content of quetiapine. 
     
     
         18 . The method of  claim 17 , wherein the conjugate of quetiapine is present in an amount per unit dose of between about 150 mg and about 800 mg per unit dose wherein the amount per unit dose is based on the content of quetiapine. 
     
     
         19 . The method of  claim 13 , 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 method of  claim 13 , wherein the subject is a mammal subject. 
     
     
         21 . The method of  claim 20 , wherein the mammal subject is a human.