STABILIZED COMPOSITIONS OF VOLATILE

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EP 1 858 864 B1

EUROPEAN PATENT SPECIFICATION

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(45) Date of publication and mention

(51) Int Cl.:

A61K 31/50 (2006.01) A61K 31/16 (2006.01)

of the grant of the patent: 04.07.2012 Bulletin 2012/27

A61K 31/13 (2006.01) A61P 17/06 (2006.01)

(86) International application number:

(21) Application number: 06738150.9

PCT/US2006/009060

(22) Date of filing: 14.03.2006

(87) International publication number: WO 2006/099385 (21.09.2006 Gazette 2006/38)

(54) STABILIZED COMPOSITIONS OF VOLATILE ALKYLATING AGENTS AND METHODS OF USING THEREOF STABILISIERTE ZUSAMMENSETZUNGEN VON FLUCHTINGEN ALKYLIERUNGSMITTELN UND VERFAHREN DERER VERWENDUNG COMPOSITIONS STABILISEES D’AGENTS D’ALKYLATION VOLATILS ET METHODES D’UTILISATION DE CES COMPOSITIONS (56) References cited:

(84) Designated Contracting States: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

EP-A- 0 317 281 WO-A-03/037380 US-A- 3 904 766 US-A- 5 229 422

WO-A-87/04154 WO-A-2004/050057 US-A- 4 853 388 US-A1- 2002 146 692

(30) Priority: 14.03.2005 US 661356 P 16.12.2005 US 751128 P 07.03.2006 US 369305

• TANG LIREN ET AL: "Topical mechlorethamine restores autoimmune-arrested follicular activity in mice with an alopecia areata-like disease by targeting infiltrated lymphocytes." JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 120, no. 3, March 2003 (2003-03), pages 400-406, XP002471996 ISSN: 0022-202X • FOULC P ET AL: "Evaluation of a 1-h exposure time to mechlorethamine in patients undergoing topical treatment." BRITISH JOURNAL OF DERMATOLOGY, vol. 147, no. 5, November 2002 (2002-11), pages 926-930, XP002471997 ISSN: 0007-0963 • TAYLOR R.J. ET AL.: ’Mechlorethamine Hydrochloride Solutions and Ointment Prolonged Stability and Biological Activity’ ARCHIVES OF DERMATOLOGY vol. 116, no. 7, July 1980, pages 783 - 785, XP008079021

(43) Date of publication of application: 28.11.2007 Bulletin 2007/48

(73) Proprietor: Ceptaris Therapeutics, Inc. Malvern, PA 19355 (US)

(72) Inventors: • CROOKS, Peter, Univ. Kentucky, College of Pharmacy Lexington, Kentucky 40536-0082 (US) • PIMLEY, Mark, A. Westchester, PA 19382 (US) • ALONSO, Robert Philadelphia, PA 19118-4007 (US)

EP 1 858 864 B1

(74) Representative: Watson, Robert James et al Mewburn Ellis LLP 33 Gutter Lane London EC2V 8AS (GB)

Remarks: The file contains technical information submitted after the application was filed and not included in this specification

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). Printed by Jouve, 75001 PARIS (FR)

EP 1 858 864 B1 Description 1. Field of the Invention 5

[0001] The present invention relates generally to a composition for topical treatment of skin disease, and more specifically to a stabilized Nitrogen Mustard composition for topically treating the skin disease. BACKGROUND

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[0002] Cutaneous T-cell lymphoma (CTCL) is a malignancy of the T-helper (CD4+) cells of the immune system. CTCL, also known as mycosis fungoides (MF), is a cancer of the white blood cells that primarily affects the skin and only secondarily affects other sites. This disease involves the uncontrolled proliferation of T-lymphocytes known as T-helper cells, so named because of their role in the immune response. T-helper cells are characterized by the presence of a protein receptor on their surface called CD4. Accordingly, T-helper cells are said to be CD4+. [0003] The proliferation of T-helper cells results in the penetration, or infiltration, of these abnormal cells into the epidermal layer of the skin. The skin reacts with slightly scaling lesions_that itch, although the sites of greatest infiltration do not necessarily correspond to the sites of the lesions. The lesions are most often located on the trunk, but can be present on any part of the body. In the most common course of the disease, the patchy lesions progress to palpable plaques that are deeper red and have more defined edges. As the disease worsens, skin tumors develop that are often mushroom-shaped, hence the name mycosis fungoides. Finally, the cancer progresses to extracutanous involvement, often in the lymph nodes or the viscera. [0004] CTCL is a rare disease, with an annual incidence of about 0.29 cases per 100,000 persons in the United States. It is about half as common in Eastern Europe. However, this discrepancy may be attributed to a differing physician awareness of the disease rather than a true difference in occurrence. In the Unites States, there are about 500-600 new cases a year and about 100-200 deaths. CTCL is usually seen in older adults; the median age at diagnosis is 55-60 years. It strikes twice as many men as women. The average life expectancy at diagnosis is 7-10 years, even without treatment. [0005] The most common side effect for treatments applied to the skin is skin hypersensitivity to the drug. US 3,904,766 describes mechlorethamine in white mineral oil or vegetable oil for the treatment of psoriasis. However there is still a need for stable compositions comprising nitrogen mustards for the treatment of skin disorders. SUMMARY OF THE INVENTION

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[0006] A first aspect of the present invention provides a composition according to claim 1. [0007] Also disclosed herein is a nitrogen mustard composition for use in a method for treating a person with a skin disorder, the method comprising: topically applying to the affected skin a Nitrogen Mustard or an HX salt of the Nitrogen Mustard, wherein the Nitrogen Mustard or the HX salt of the Nitrogen Mustard is in a non-aqueous vehicle or carrier, wherein the non-aqueous vehicle or carrier does not include petrolatum or ethanol, wherein the Nitrogen Mustard is represented by the following structures:

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EP 1 858 864 B1

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wherein each R1, R2, R3 ... R34 (R1-R34) is independently selected from the group consisting of a hydrogen atom, a linear alkyl group having 1-6 carbon atoms, a branched alkyl group having 2-12 carbon atoms, a cycloalkyl group having 3-17 carbon atoms, a fluorinated linear alkyl group having 2-12 carbon atoms, a fluorinated branched alkyl group having 2-12 carbon atoms, a fluorinated cycloalkyl group having 3-17 carbon atoms, an aryl group, an aralkyl group, an alkaryl group, a cycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkalkenyl group, an alkenylalkyl group, an alkynyl group, an alkalkynyl group, an alkynylalkyl group, a trifluoropropyl group, a cyanopropyl group, an acryloyl group, an arylacryloyl group, an acryloylaryl group, an alkylacyl group, an arylacyl group, an alkylenylacyl group, and an alkynylacyl group, wherein n is 1, 2, or 3, wherein p is 0, 1 or 2, wherein n + p ≤ 3, and wherein any two R1 - R34 in the same molecule may be linked to form a three- to eight-membered cyclic group. [0008] Also disclosed herein is a method for stabilizing a volatile alkylating agent, comprising: providing a non-aqueous flowable ointment or cream, wherein the non-aqueous flowable ointment or cream does not include petrolatum or ethanol; reconsitituting an HX salt of the volatile alkylating agent in anhydrous solvent; combining with mixing the non-aqueous flowable ointment or cream and the HX salt of the volatile alkylating agent. [0009] Also disclosed herein is an apparatus having a wall around a compartment, wherein the wall is made of a material that is impervious to a mixture of a pharmaceutically acceptable nitrogen mustard • HCl and a non-aqueous vehicle or carrier that does not include petrolatum or ethanol. BRIEF DESCRIPTION OF THE DRAWINGS

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[0010] The features of the invention are set forth in the appended claims. The invention itself, however, will be best understood by reference to the following detailed description of an illustrative embodiment when read in conjunction with the accompanying drawings, wherein: comparative FIG. 1 illustrates use of compositions having stabilized alkylating agents for treating skin disease, Comparative FIG. 2 depicts a front cross-sectional view of an apparatus having a compartment partially enclosed by a wall, comparative FIG. 3 depicts the apparatus having plugs mechanically sealed to close an opening in the wall, and comparative FIG. 4 depicts the apparatus wherein the heat seals have been serrated to permit easy removal of the plugs.

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DETAILED DESCRIPTION OF THE INVENTION

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[0011] patients having MF topically treated with Nitrogen Mustard compounded into a polypropylene glycol (PPG, molecular weight from 300 to 2500), propylene glycol (PG,), polyethyleneglycol (PEG, molecular weight from 100 to 1000) or ethylene glycol ointment or cream showed no evidence of any systemic toxicities. [0012] Table 1 below provides a summary of topical treatment of patients having MF with nitrogen mustard in propylene glycol (PG), including response rates and toxicities. Table 1: Topical Nitrogen Mustard In Mycosis Fungoides (MF): Summary Of Clinical Outcomes & Toxicities.

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