Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-23
2002-05-28
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S424000
Reexamination Certificate
active
06395757
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to methods for treating hot flashes as a consequence of declining estrogen levels or androgen levels in humans. Specifically, the methods of this invention involve the topical administration of a therapeutically effective amount of a glycopyrrolate analog to a human suffering from hot flashes.
2. References
The following publications, patent applications and patents are cited in this application as superscript numbers:
1. Loprinzi et al., “Megestrol acetate for the prevention of hot flashes”
N. Engl. J. Med.
331:347-351 (1994)
2. Goldberg et al., “Transdermal clonidine for ameliorating tamoxifen-induced hot flashes”
J. Clin. Onc.
12:155-158(1994)
3. Hays et al., “The Frey syndrome: a simple, effective treatment”
Otolaryngol Head Neck Surg.
90:419-425 (1982)
4. Atkin et al., “Treatment of diabetic gustatory sweating with topical glycopyrrolate cream”
Diabetic Medicine
13:493-494 (1996)
5. Shaw et al., “A randomized controlled trial of topical glycopyrrolate, the first specific treatment for diabetic gustatory sweating”
Diabetologia
40:299-301 (1997)
6. May et al., “Frey's Syndrome: Treatment with topical glycopyrrolate”
Head
&
Neck
(January/February 1989) p.85-89
7. Col. Leonard L. Hays, “The Frey syndrome: A review and double blind evaluation of the topical use of a new anticholinergic agent”
The Laryngoscope
88:1976 (1978)
8.
Remington's Pharmaceutical Sciences,
Mace Publishing Company Philadelphia Pa. 17
th
ed. (1985)
9. U.S. Pat. No. 5,525,347, Kellner et al.
10. U.S. Pat. No. 2,956,062, Lunsford et al.
All of the above publications, patent applications and patents are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent application or patent was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Hot flashes or flushing occur commonly in menopausal women. This is characterized by a sudden onset of warmth in the face and neck and often progressing to the chest. Such an episode generally lasts several minutes and is evidenced by a visible flushing of the skin. Often such episodes are accompanied by sweating, dizziness, nausea, palpitations and diaphoresis. Such symptoms can disrupt sleep and interfere with the quality of life. Although the cause of hot flashes is not completely understood, they are thought to be a disorder of thermoregulation within the hypothalamus that is a consequence of declining estrogen levels. Thus it is not surprising that hot flashes also occur in a high percentage of women taking the anti-estrogen drug tamoxifen.
Men may also have hot flashes following androgen-deprivation therapy (from bilateral orchiectomy or treatment with a gonadotrophin-releasing-hormone agonist) for metastatic prostate cancer.
Although estrogen replacement therapy is the most direct and effective treatment for hot flashes in women, there are women in whom such therapy is contraindicated, i.e. women with breast cancer or a strong family history of breast cancer, a history of clotting, severe migraine, or who are averse to taking the drug.
In these women, there are alternative medications to prevent or treat the serious consequences of menopause, such as osteoporosis and raised serum lipid levels. Included in this category are the selective estrogen-receptor modulators (SERMs), such as raloxifene, which selectively bind to and activate the estrogen receptors of some tissues such as bone, and block the receptors of others, i.e. breast and uterus. In so doing, they lack the negative impact that prolonged estrogen therapy may have on these organs. However, in contrast to estrogen, SERMs do not prevent hot flashes.
Other than estrogen-replacement therapy, there are no effective means to alleviate hot flashes. Low dose oral megestrol acetate, a progestational agent, was shown to reduce the frequency of hot flashes in both men and women in a short term study
1
. However, chronic adrenal insufficiency can be a side effect of low dose megestrol acetate when taken long term. Transdermal clonidine, a centrally active &agr;-agonist, had only a moderate effect on the frequency and severity of hot flashes in tamoxifen-treated women
2
. Accordingly, there is a need for a method of treating hot flashes.
Topical glycopyrrolate has been used previously to treat gustatory sweating associated with diabetic autonomic neuropathy
4,5
. In this disorder, sweating that often is profuse, begins soon after the patient ingests food, starting on the forehead and then involving the face, scalp and neck. A solution of glycopyrrolate was applied to the face of the patient which prevented the gustatory sweating.
Similarly, glycopyrrolate has also been used previously to treat gustatory sweating associated with Frey's syndrome which may develop after parotidectomy
3,6,7
. Frey's syndrome is believed to result from the aberrant reinnervation of the sweat glands of the face by the severed parotid parasympthetic nerve fibers.
In both diabetic gustatory sweating and Frey's syndrome, the profuse facial sweating is induced by the specific stimulus of eating. Moreover, the sweating in each is a consequence of a distinct neuropathological process. In contrast, the hot flashes of menopause occur spontaneously without a specific stimulus and are the consequence of a normal or physiological process, the natural decline in circulating levels of estrogen.
This invention is directed in part to the discovery that the transdermal application of a glycopyrrolate analog to a human overcomes many of the prior problems in treating hot flashes and the perspiration associated therewith. Additionally, it provides advantages heretofore not achieved by conventional treatments for the hot flashes associated with low levels of estrogen and/or androgen. For example, the glycopyrrolate analog to be applied does not have the side effects associated with estrogen replacement therapy. Secondly, the glycopyrrolate analogs can be applied to both males and females.
SUMMARY OF THE INVENTION
This invention is directed to methods for treating hot flashes by the topical application of a therapeutically effective amount of a glycopyrrolate analog of Formula (I):
wherein:
n is 1 or 2;
R
1
is alkyl or phenylalkyl;
R
2
is phenyl which is optionally substituted with alkyl, halo, alkoxy, hydroxy, or acyloxy, or -(alkylene)-CO
2
R
5
wherein R
5
is alkyl, alkenyl, cycloalkyl, or cycloalkenyl;
R
3
is cycloalkyl, cycloalkenyl, heteroaryl, phenyl which is optionally substituted with alkyl, halo, alkoxy, hydroxy, or acyloxy;
R
4
is hydrogen, hydroxy, or acyl; or
an acid addition, alkyl, or benzyl quaternary ammonium salt, individual isomer or a mixture of isomers thereof to a human such that the hot flashes are substantially reduced.
Preferably, the glycopyrrolate analog is a compound of Formula (II):
wherein:
n is 1 or 2;
R
1
is alkyl;
R
2
is phenyl which is optionally substituted with alkyl, halo, alkoxy, hydroxy, or acyloxy;
R
3
is cycloalkyl;
R
4
is hydroxy; or
an acid addition, alkyl, or benzyl quaternary ammonium salt, individual isomer or a mixture of isomers thereof to a human such that the hot flashes are substantially reduced.
Even more preferably, the glycopyrrolate analog of Formula (II) is a compound where:
n is 1;
R
1
is ethyl, propyl, or butyl;
R
2
is phenyl which is optionally substituted with methyl, ethyl, propyl, fluoro, chloro, methoxy, ethoxy, hydroxy, or acetyloxy;
R
3
is pentyl or hexyl;
R
4
is hydroxy; or
an acid addition, alkyl, or benzyl quaternary ammonium salt, individual isomer or a mixture of isomers thereof to a human such that the hot flashes are substantially reduced.
This invention is also directed to a method for alleviating the hot flashes in a human, which method comprises the steps of identifying a human susceptible to hot flashes; and administering to said human a therapeutically effective amount of a glycopyrrolate analog of Formula (I):
wherein:
n is 1 or 2;
R
1
is
Bobrove Arthur M.
Urman Jeffrey D.
Burns Doane , Swecker, Mathis LLP
Travers Russell
Wang Shengjun
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