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Tazarotene derivatives

a technology of tazarotene and derivatives, which is applied in the field of derivatives of tazarotene, can solve the problems of difficult formulation chemists, retinoids and antibiotics are often readily degraded,

Inactive Publication Date: 2012-05-10
STIEFEL LABORATORIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]According to another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
[0015]In a further embodiment, the present invention provides a method of treating a skin disorder in a subject, the method comprising administering a composition comprising a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, to a subject in need thereof.

Problems solved by technology

However, this presents challenges to the formulation chemist insofar as retinoids and antibiotics often readily degrade in the presence of benzoyl peroxide.

Method used

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Examples

Experimental program
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Effect test

example 1

Degradation of Tazarotene in the Presence of Benzoyl Peroxide

[0177]DUAC® gel (1% clindamycin and 5% benzoyl peroxide marketed by Stiefel Laboratories, Inc.) and TAZORAC® cream (0.1% tazarotene marketed by Allergan, Inc.) have been successfully used to treat facial acne. However, these topical treatments are not approved for concomitant use. To study whether tazarotene is susceptible to oxidative decomposition by benzoyl peroxide, an in vitro laboratory study was conducted wherein a mixture of DUAC gel and TAZORAC cream was prepared.

[0178]Samples were prepared by taking equal portions of DUAC gel and TAZORAC cream and mixing them thoroughly at room temperature with a spatula in a suitable container to form a uniform mixture. The initial samples were analyzed immediately by HPLC. The other samples were placed into an oven at 35° C. and removed for analysis after one, two, four, six and eight hours. An allowance was made for product evaporation over the course of the study.

[0179]FIG. 1...

example 2

Further Study of Tazarotene and its Metabolites

[0181]An in vitro study was conducted to assess the formation of tazarotene degradants following the application of a mixture of DUAC gel and TAZORAC cream to human skin.

[0182]Equal portions of DUAC gel and TAZORAC cream were dispensed into a glass vial and mixed for approximately three minutes with a metal spatula to ensure a homogenous mixture. Samples of European DUAC gel and US DUAC gel were used in separate experiments. The products differ inasmuch as European DUAC gel does not contain paraben preservatives. The test mixtures were then applied to the surface of split-thickness skin (˜0.25 mm) at a dose of 15.6 mg / cm2 and spread evenly using a positive displacement pipette.

[0183]After 2 and 6 hours, the skin samples were washed, tape stripped twice, and then the epidermis was peeled from the dermis using a heat block. The skin samples were then extracted with acetonitrile overnight at 4° C. The distribution of tazarotene and its deg...

example 3

Retinoid Activity of Tazarotene, Tazarotene Benzoate and Tazarotene Metabolites

[0189]A study was conducted to evaluate the retinoid activity of tazarotene, tazarotene benzoate and tazarotene metabolites (tazarotenic acid, tazarotene sulfone, tazarotenic acid sulfone and tazarotenic acid sulfoxide).

[0190]SkinEthic RHE cultures were transferred into 6-well plates containing 1.0 mL / well growth media. The cultures were equilibrated at 37° C. and the media was changed daily. The cultures were subsequently placed in 60 mm petri dishes containing 3.5 mL growth media. 6 μl aliquots of the Test Articles shown in Table 3 were applied to duplicate cultures. The cultures were incubated at 37° C. for 72 hours. At the end of the incubation period, the growth media was collected and stored at −20° C. The tissues were cut in half and one half was placed in 10% NBF for histology, while the other half was placed in RNAlater™ solution (Ambion). The following analyses were performed: a) IL-1α and IL-8 ...

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Abstract

The presently described subject matter relates to new derivatives of tazarotene that also exhibit retinoid activity, pharmaceutical compositions comprising the derivatives, method of treating skin disorders with the pharmaceutical compositions, and process of making the derivatives.

Description

FIELD OF THE INVENTION[0001]The present invention relates to derivatives of tazarotene.BACKGROUND OF THE INVENTION[0002]Tazarotene has the chemical name: ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl nicotinate. Tazarotene is a retinoid prodrug which is converted to its active form, tazarotenic acid, by rapid de-esterification in most biological systems. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family; RARα, RARβ and RARγ, but has relative selectivity for RARβ and RARγ, and may modify gene expression.[0003]Allergan, Inc. market TAZORAC® (tazarotene) cream and TAZORAC® (tazarotene) gel for the treatment of acne and psoriasis.[0004]The treatment of skin disorders using a retinoid or an antibiotic in combination with benzoyl peroxide is of great interest to dermatologists. However, this presents challenges to the formulation chemist insofar as retinoids and antibiotics often readily degrade in the presence of benzoyl peroxide. Accordingly, the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4436A61P17/10A61P17/06A61K31/4545A61P17/12A61P17/00C07D409/14A61K31/444C07D409/10A61P17/08
CPCA61K9/0014A61K31/444A61K31/38A61K31/593A61K45/06C07D409/06C07D409/14A61K31/05A61K31/4436A61K31/327A61K2300/00A61P17/00A61P17/06A61P17/08A61P17/10A61P17/12A61P43/00A61K31/4535
Inventor GE, XUEWONG, HANSENCHERN, WENDY HUANGHOFLAND, HANSBISHOP, MICHAEL J.CAI, XIN FRANKCOLBORN, ALAN
Owner STIEFEL LABORATORIES
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