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

Inactive Publication Date: 2011-09-15
KEMPHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]In one embodiment, the invention provides a method of increasing the relative bioavailability of quetiapine or an active metabolite thereof such as norQTP or 7-OH-QTP, comprising the step of conjugating quetiapine or its active metabolite to at least one fatty acid such as a saturated fatty acid such as valproic acid, a monounsaturated fatty acid such as palmitoleic acid, a polyunsaturated fatty acid such as DHA or EPA, or a combination thereof, thereby modulating the hydrophobicity, solubility, improving absorption, altering metabolic pathways or their combination of the conjugated quetiapine or the active metabolite thereof, resulting in certain embodiments, in a higher maximum observed blood plasm

Problems solved by technology

Making tablets of such a high concentration of the active pharmaceutical ingredient (API) is difficult, particularly due to the bad tabletting properties of the API.

Method used

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

Examples

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formulation examples

[0152]In one embodiment, the composition comprising the conjugate of quetiapine or an active metabolite and / or 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 is formulated for oral administration. In another aspect, the composition comprising the conjugate of quetiapine or an active metabolite and / or 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 is formulated for sublingual, or transdermal, intrathecal or a suppository administration in other discrete formulation embodiments of the compositions provided herein and are used in the systems and methods described herein.

[0153]In one embodi...

example 1

Oral Pharmacokinetic Data

[0242]Prodrug conjugates described herein were dosed as oral solutions in rats and compared to an equimolar solution of quetiapine dihydrochloride. Although the commercial form of quetiapine (Seroquel®) is a fumarate salt, the dihydrochloride salt was used as comparator because the fumarate is not soluble enough to be dosed efficiently via oral gavage in rats.

[0243]Generally and as shown in FIGS. 1-4, plasma concentrations of quetiapine released from the prodrugs described herein were compared to plasma concentrations generated by an equimolar amount of quetiapine hydrochloride salt. Overall, plasma concentrations of released quetiapine varied depending on the attached fatty acid. Exposure ranged from 34-121%-AUC compared to quetiapine hydrochloride salt.

example 2

General Synthesis of Fatty Acid-Quetiapine Conjugates

[0244]A general synthetic scheme for the synthesis of a prodrug of this invention typically consists of the following steps (See FIG. 5):[0245]1. Protection of a functional moiety on the fatty acid, if applicable.[0246]2. Activation of the carboxylic group, if not already in activated form.[0247]3. Addition of activated fatty acid to quetiapine or vice versa in the presence of base[0248]4. Removal of protecting groups on functional moieties of the fatty acid, if applicable.

[0249]To a solution of quetiapine freebase (1 mmol) in anhydrous THF (20 mL) was added TEA (3 mmol) and DMAP (0.1 mmol). The solution was stirred and the fatty acid chloride (1.5 mmol) was added drop wise at room temperature. After 2-6 hours, depending on the fatty acid derivative, solvents were evaporated to dryness and the residue was dissolved in ethyl acetate (400 mL). The organic phase was washed with aqueous NH4Cl (2×250 mL) and aqueous NaHCO3 (2×250 mL), ...

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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.

Description

RELATED APPLICATIONS[0001]This application claims priority to and benefit from U.S. Provisional Application Ser. No. 61 / 312,977, filed on Mar. 11, 2010, the content of which is incorporated herein by reference in its entirety.FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002][Not Applicable]BACKGROUND OF THE INVENTION[0003]Quetiapine has been used in the treatment of severe mental illness in approximately 70 countries including the US, Canada, most Western European countries, and Japan. Quetiapine is a dibenzothiazepine derivative with a relatively broad receptor binding profile: It has major affinity to cerebral serotonergic (5-HT2A), histaminergic (H1), and dopaminergic D1 and D2 receptors, moderate affinity to α1- und α2-adrenergic receptors, and minor affinity to muscarinergic M1 receptors; it demonstrates a substantial selectivity for the limbic system. This receptor avidity profile with relatively higher affinity for the 5-HT2A receptor compared to the D2 receptor is considered...

Claims

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Application Information

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IPC IPC(8): A61K31/554A61K9/00A61K33/00A61P25/18
CPCA61K31/554A61K47/48046A61K47/48038A61K45/06C07D417/04A61K47/542A61K47/543A61P25/18C07D285/36C07D417/14A61K9/0053A61K39/39
Inventor MICKLE, TRAVISGUENTHER, SVENBERA, SANJIB
Owner KEMPHARM INC
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