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

a technology of quetiapine and fatty acid conjugates, which is applied in the field of fatty acid conjugates of quetiapine, process for making and using the same, can solve the problems of difficult tablets of such a high concentration of active pharmaceutical ingredients (api), and achieve the effects of increasing the relative bioavailability of quetiapine, reducing interindividual variability, and increasing bioavailability

Inactive Publication Date: 2013-06-20
KEMPHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a new way to make a medication called quetiapine, which is used to treat various mental illnesses like schizophrenia and bipolar disorder. The new way involves combining quetiapine with fatty acids to create a prodrug. This prodrug can be taken orally, through the skin, or through the lining of the mouth. The fatty acids can be saturated, monounsaturated, polyunsaturated, or have other rings attached to them. The patent also describes a method for making the prodrug by attaching a fatty acid to quetiapine or its active metabolite. This new method can increase the bioavailability of quetiapine and make it more effective in treating certain mental illnesses.

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

[0125]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.

[0126]In one embodi...

example 1

Oral Pharmacokinetic Data

[0216]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.

[0217]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

[0218]A general synthetic scheme for the synthesis of a prodrug of this invention typically consists of the following steps (See FIG. 5):[0219]1. Protection of a functional moiety on the fatty acid, if applicable.[0220]2. Activation of the carboxylic group, if not already in activated form.[0221]3. Addition of activated fatty acid to quetiapine or vice versa in the presence of base[0222]4. Removal of protecting groups on functional moieties of the fatty acid, if applicable.

[0223]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 is a continuation of and claims priority to U.S. application Ser. No. 13 / 043,764, filed on Mar. 9, 2011 which claims priority to and benefit from U.S. Provisional Application Ser. No. 61 / 312,977, filed on Mar. 11, 2010, the contents of both of which are incorporated herein by their references in their entireties.BACKGROUND OF THE INVENTION[0002]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 a1- and 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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D417/04
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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