Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-08-07
2004-01-27
Kim, Vickie (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S231200, C514S649000, C514S624000, C514S438000
Reexamination Certificate
active
06683114
ABSTRACT:
FIELD OF THE INVENTION
The invention belongs to the fields of pharmaceutical chemistry and dermatological medicine, and provides a method of treatment of the dermatological disorder known as psoriasis.
BACKGROUND OF THE INVENTION
Psoriasis is a chronic, painful skin disorder that affects more than 7 million Americans. With as many as 250,000 new cases occurring each year, psoriasis typically does not discriminate on the basis of the age or gender of its victims. The disorder occurs slightly more often in women than men, and it has been reported to present itself initially from birth to the age of 90 years. Psoriasis exacts a heavy societal burden in terms of both patient suffering and costs. Annual outpatient treatment of psoriasis was estimated in 1999 to be from $1.6 to $3.2 billion, with over 1.5 million patients seen annually for this disorder by U.S. physicians.
Treatment options currently available to patients suffering from psoriasis include a variety of topical medications, phototherapies, and internal medications. Topical treatments include steroids, coal tar, anthralin, vitamin D3 and analogs, retinoids, and sunshine. Side effects associated with the use of these topical treatments include skin thinning, stretch marks, burns, irritation, and photosensitivity. The use of steroids may also lead to resistance, rendering subsequent steroid treatment ineffective. Phototherapy encompasses the medically supervised administration of ultraviolet light B or psoralen in combination with ultraviolet light A. Long term use of phototherapies may prematurely age the skin and increase the incidence of skin cancers. Internal medications, typically reserved for the most serious cases of psoriasis, include the administration methotrexate, oral retinoids, and cyclosporine. The use of methotrexate requires careful monitoring to avoid liver damage. Use of oral retinoids must be carefully controlled in women because of the potential for severe birth defects. This risk extends for years after the use of the drug has been terminated. Cyclosporine, an immunosuppresant, is reserved for patients that have failed other internal treatments, or for whom the other internal treatments are contraindicated. Rotating between therapies, and combinations of topical medications with phototherapies, have also been found to be useful regimens in the treatment of psoriasis.
There is no cure for psoriasis, and not all patients respond to or tolerate currently available therapies. New treatment options for psoriasis, with improved efficacy, safety, and side effect profiles, are needed.
SUMMARY OF THE INVENTION
The present invention provides a method of treating psoriasis comprising the administration to a patient in need of such treatment of an effective amount of a norepinephrine reuptake inhibitor.
This invention also provides the use of a norepinephrine reuptake inhibitor for the manufacture of a medicament for the treatment of psoriasis. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of psoriasis containing a norepinephrine reuptake inhibitor.
DETAILED DESCRIPTION
Many compounds, including those discussed at length below, are norepinephrine reuptake inhibitors, and no doubt many more will be identified in the future. In the practice of the present invention, it is intended to include reuptake inhibitors which show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong et al.,
Drug Development Research
, 6, 397 (1985). The norepinephrine reuptake inhibitors useful for the method of the present invention are characterized in being selective for the inhibition of neurotransmitter reuptake relative to their ability to act as direct agonists or antagonists at other receptors. Norepinephrine reuptake inhibitors useful for the method of the present invention include, but are not limited to:
Tomoxetine, (R)-(−)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, is usually administered as the hydrochloride salt. Tomoxetine was first disclosed in U.S. Pat. No. 4,314,081. The word “tomoxetine” will be used here to refer to any acid addition salt or the free base of the molecule. See, for example, Gehlert, et al.,
Neuroscience Letters
, 157, 203-206 (1993), for a discussion of tomoxetine's activity as a norepinephrine reuptake inhibitor;
The compounds of formula I:
wherein X is C
1
-C
4
alkylthio, and Y is C
1
-C
2
alkyl or a pharmaceutically acceptable salt thereof. The compounds of formula I were described in U.S. Pat. No. 5,281,624, of Gehlert, Robertson, and Wong, and in Gehlert, et al.,
Life Sciences
, 55(22), 1915-1920, (1995). The compounds are there taught to be inhibitors of norepinephrine reuptake in the brain. It is also explained that the compounds exist as stereoisomers, and that they accordingly include not only the racemates, but also the isolated individual isomers as well as mixtures of the individual isomers. For example, the compounds of formula I include the following exemplary species:
N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propylamine benzoate;
(R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)-propylamine hydrochloride;
(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propylamine;
N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propylamine malonate;
(S)-N-methyl-3-phenyl-3-(2-tert-butylthiophenoxy)-propylamine naphthalene-2-sulfonate;
(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenyl-propylamine;
Reboxetine (Edronax™), 2-[&agr;-(2-ethoxy)phenoxybenzyl]morpholine, is usually administered as the racemate. It was first taught by U.S. Pat. No. 4,229,449, which describes its utility for the treatment of depression. Reboxetine is a selective norepinephrine reuptake inhibitor. The term “reboxetine” will be used here to refer to any acid addition salt or the free base of the molecule existing as the racemate or either enantiomer;
Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which shows its high potency. The word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule. A preferred duloxetine enteric formulation is a pellet formulation comprising a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer. This formulation is taught in U.S. Pat. No. 5,508,074;
Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compound A in that patent; and
Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as its Example 4. The patent describes its compounds as antidepressants. Moret et al.,
Neuropharmacology
24, 1211-19 (1985), describe its pharmacological activities as an inhibitor of serotonin and norepinephrine reuptake.
All of the U.S. patents mentioned above in connection with compounds and formulations used in the present invention are incorporated herein by reference.
While all compounds exhibiting norepinephrine reuptake inhibition are useful for the method of the present invention, certain are preferred. It is preferred that the norepinephrine reuptake inhibitor is selective for norepinephrine over other neurotransmitters. It is also preferred that the norepinephrine reuptake inhibitor is selected from tomoxetine, reboxetine, or a compound of formula I. It is especially preferred that the norepinephrine reuptake inhibitor be selected from tomoxetine, reboxetine, or (R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine. The use of tomoxetine hydrochloride for the treatment of psoriasis is the most preferred embodiment of the present invention.
It will be understood by the skilled r
Cohen Charles E.
Eli Lilly and Company
Kim Vickie
Titus Robert D.
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