Fatty Acid Conjugates of Quetiapine, Process for Making and Using the Same
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 - 170 . (canceled)
171 . A composition for treating a psychiatric disorder in a subject, comprising a conjugate of 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine), an active metabolite or derivative thereof and at least one fatty acid, a salt thereof, a derivative thereof or a combination thereof.
172 . The composition of claim 171 , wherein the at least one fatty acid is a saturated fatty acid, a monounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenic fatty acid, a substituted fatty acid, a heteroatom containing fatty acid, a ring containing fatty acid or a combination thereof.
173 . The composition of claim 172 , wherein the substituted fatty acid is an alkyl-substituted fatty acid, hydroxy-substituted fatty acid, carboxy-substituted fatty acid, halogenated fatty acid, sulfate-substituted fatty acid, methoxy-substituted fatty acid, acetoxy-substituted fatty acid, aldehyde-substituted fatty acid, nitro-substituted fatty acid, or keto-substituted fatty acid.
174 . The composition of claim 172 , wherein the heteroatom containing fatty acid comprises a carbon chain containing a divinyl ether function or a carbon chain containing a sulfur function.
175 . The composition of claim 172 , wherein the ring containing fatty acid is a fatty acid containing at least one three-membered ring, a fatty acid containing at least one five-membered ring, a fatty acid containing at least one six-membered ring, a fatty acid containing ladderanes, a fatty acid containing at least one furan ring or a combination thereof.
176 . The composition of claim 171 , wherein the at least one fatty acid is selected from the group consisting of any one of the fatty acid compounds set forth in Tables I-VII.
177 . The composition of claim 171 , wherein the composition has a higher relative bioavailability than non-conjugated quetiapine when administered orally.
178 . The composition of claim 171 , wherein the salt of the conjugate of quetiapine, an active metabolite thereof or an active derivative thereof and a fatty acid is 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(mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate(enanthate), 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.
179 . The composition of claim 171 , wherein the composition is formulated for oral, sublingual, transdermal, suppository, or intrathecal administration.
180 . The composition of claim 179 , 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).
181 . The composition of claim 171 , wherein the conjugate of quetiapine, an active metabolite thereof or an active derivative thereof and a fatty acid, a salt thereof, a derivative thereof or their combination is present in an amount per unit dose of between about 1 mg and about 2000 mg per unit dose.
182 . The composition of claim 181 , wherein the conjugate of quetiapine, an active metabolite thereof or an active derivative thereof and a fatty acid, a salt thereof, a derivative thereof or their combination is present in an amount per unit dose of between about 150 mg and about 800 mg per unit dose.
183 . The composition of any one of claim 181 or 182 , wherein the amount per unit dose is based on the content of quetiapine, an active metabolite thereof or an active derivative thereof in the conjugate of quetiapine, an active metabolite thereof or an active derivative thereof and at least one fatty acid, a salt thereof, a derivative thereof or their combination.
184 . The composition of claim 171 , 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.
185 . The composition of claim 171 , wherein the subject is a human or a mammal subject.
186 . The composition of claim 171 , wherein the subject has not been diagnosed with schizophrenia or bipolar disorder.
187 . The composition of claim 171 , 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.
188 . A composition for treating a psychiatric disorder in a subject comprising, a conjugate of quetiapine, an active metabolite thereof or an active derivative thereof and a saturated fatty acid, a monounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenic fatty acid, a substituted fatty acid, a heteroatom containing fatty acid, a ring containing fatty acid or a combination thereof wherein the composition is represented by any one of the following structures of general formulas I-IV:
a pharmaceutically acceptable salt thereof, a derivative thereof or a combination thereof, wherein “R” is a fatty acid side-chain selected from the group consisting at least one of the fatty acids set forth in Tables I-VII.
189 . 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 quetiapine, an active metabolite thereof or an active derivative thereof, conjugated to at least one fatty acid, a pharmaceutically acceptable salt thereof or derivative thereof, resulting in the agent binding to a dopamine receptor, a serotonin receptor, or both.
190 . The method of claim 189 , wherein the at least one fatty acid is selected from the group consisting of any one of the fatty acid compounds set forth in Tables I-VII.