Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-26
2002-09-17
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...
Reexamination Certificate
active
06451807
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to highly selective phosphodiesterase (PDE) enzyme inhibitors and to their use in pharmaceutical articles of manufacture. In particular, the present invention relates to potent inhibitors of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase type 5 (PDE5) that when incorporated into a pharmaceutical product are useful for the treatment of sexual dysfunction. The articles of manufacture described herein are characterized by selective PDE5 inhibition, and accordingly, provide a benefit in therapeutic areas where inhibition of PDE5 is desired, with minimization or elimination of adverse side effects resulting from inhibition of other phosphodiesterase enzymes.
BACKGROUND OF THE INVENTION
The biochemical, physiological, and clinical effects of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase (cGMP-specific PDE) inhibitors suggest their utility in a variety of disease states in which modulation of smooth muscle, renal, hemostatic, inflammatory, and/or endocrine function is desired. Type 5 cGMP-specific phosphodiesterase (PDE5) is the major cGMP hydrolyzing enzyme in vascular smooth muscle, and its expression in penile corpus cavernosum has been reported (Taher et al.,
J. Urol.,
149:285A (1993)). Thus, PDE5 is an attractive target in the treatment of sexual dysfunction (Murray,
DN
&
P
6(3):150-56 (1993)).
A pharmaceutical product, which provides a PDE5 inhibitor, is currently available and marketed under the trademark VIAGRA®. The active ingredient in VIAGRA® is sildenafil. The product is sold as an article of manufacture including 25, 50, and 100 mg tablets of sildenafil and a package insert. The package insert provides that sildenafil is a more potent inhibitor of PDE5 than other known phosphodiesterases (greater than 80 fold for PDE1 inhibition, greater than 1,000 fold for PDE2, PDE3, and PDE4 inhibition). The IC
50
for sildenafil against PDE5 has been reported as 3 nM (
Drugs of the Future,
22(2), pp. 128-143 (1997)), and as 3.9 nM (Boolell et al.,
Int. J. of Impotence Res.,
8 p. 47-52 (1996)). N.C. Sildenafil is described as having a 4,000-fold selectivity for PDE5 versus PDE3, and only a 10-fold selectivity for PDE5 versus PDE6. Its relative lack of selectivity for PDE6 is theorized to be the basis for abnormalities related to color vision.
While sildenafil has obtained significant commercial success, it has fallen short due to its significant adverse side effects, including facial flushing (10% incidence rate). Adverse side effects limit the use of sildenafil in patients suffering from visual abnormalities, hypertension, and, most significantly, by individuals who use organic nitrates (Welds et al.,
Amer. J. of Cardiology,
83 (5A), pp. 21(C)-28(C) (1999)).
The use of sildenafil in patients taking organic nitrates is believed to cause a clinically significant drop in blood pressure which could place the patient in danger. Accordingly, the package label for sildenafil provides strict contraindications against its use in combination with organic nitrates (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, erythrityl tetranitrate) and other nitric oxide donors in any form, either regularly or intermittently, because sildenafil potentiates the hypotensive effects of nitrates. See C. R. Conti et al.,
Amer. J. of Cardiology,
83(5A), pp. 29C-34C (1999). Thus, even with the availability of sildenafil, there remains a need to identify improved pharmaceutical products that are useful in treating sexual dysfunction.
The present invention provides an article of manufacture for human pharmaceutical use, comprising a package insert, a container, and an oral dosage form comprising a selective PDE5 inhibitor at unit dosages between about 1 and about 20 mg/dosage form. The beneficial effects of the present invention were observed in clinical studies and through the discovery that a selective PDE5 inhibitor meeting the following criteria allows for the effective oral administration of about 1 to about 20 mg/dosage form without contraindications generally required for PDE5 inhibitor products, such as warnings directed to vision abnormalities. A selective PDE5 inhibitor of the present invention exhibits:
1) at least a 100 fold differential in the IC
50
values for the inhibition of PDE5 versus PDE6 for a particular PDE5 inhibitor (i.e., the IC
50
value versus PDE5 is at least 100 times less than the IC
50
value versus PDE6);
2) at least a 1000 fold differential in the IC
50
values for the inhibition of PDE5 versus PDE1c; and
3) an IC
50
value less than 10 nM.
Significantly, clinical studies also revealed that an effective product having a reduced tendency to cause flushing in susceptible individuals can be provided. Most unexpectedly, the product also can be administered with clinically insignificant side effects associated with the combined effects of a PDE5 inhibitor and an organic nitrate. Thus, the contraindication once believed necessary for a product containing a PDE5 inhibitor is unnecessary when a selective PDE5 inhibitor, as defined above, is used as disclosed herein. Thus, the present invention provides an effective therapy for sexual dysfunction in individuals who previously were untreatable or suffered from unacceptable side effects, including individuals having cardiovascular disease, such as in individuals requiring nitrate therapy, having suffered a myocardial infarction more than three months before the onset of sexual dysfunction therapy, and suffering from class 1 congestive heart failure as defined by the New York Heart Association (NYHA), or individuals suffering from vision abnormalities.
SUMMARY OF THE INVENTION
The present invention provides an article of manufacture for human pharmaceutical use, comprising a package insert, a container, and an oral dosage form comprising about 1 to about 20 mg of a selective PDE5 inhibitor per dosage form.
The present invention further provides a method of treating conditions where inhibition of PDE5 is desired, which comprises administering to a patient in need thereof an oral dosage form containing about 1 to about 20 mg of a selective PDE5 inhibitor, as needed, up to a total dose of 20 mg/-day. The invention further provides the use of an oral dosage form comprising a selective PDE5 inhibitor at a dosage of about 1 to about 20 mg for the treatment of sexual dysfunction.
Specific conditions that can be treated by the method and article of the present invention, include, but are not limited to, male erectile dysfunction and female sexual dysfunction, particularly female arousal disorder, also known as female sexual arousal disorder.
In particular, the present invention provides an article of manufacture for human pharmaceutical use comprising:
(a) an oral dosage form comprising about 1 to about 20 mg of a selective PDE5 inhibitor having
(i) at least a 100 fold differential in IC
50
values for the inhibition of PDE5 versus PDE6,
(ii) at least a 1000 fold differential in IC
50
values for the inhibition of PDE5 versus PDE1c,
(iii) an IC
50
less than 10 nM, and
(iv) sufficient bioavailability to be effective in about 1 to about 20 mg unit oral dosages;
(b) a package insert providing that the PDE5 inhibitor is useful to treat sexual dysfunction in a patient in need thereof, and that is free of contradictions associated with administration of organic nitrates; and
(c) a container.
The present invention further provides an article of manufacture for human pharmaceutical use comprising:
(a) an oral dosage form comprising about 1 to about 20 mg of selective PDE5 inhibitor having
(i) at least a 100 fold differential in IC
50
values for the inhibition of PDE5 versus PDE6,
(ii) at least a 1000 fold differential in IC
50
values for the inhibition of PDE5 versus PDE1c,
(iii) an IC
50
less than 10 nM, and
(iv) a sufficient bioavailability to be effective in about 1 to about 20 mg unit oral dosages;
(b) a package insert providing that the PDE5 inhibitor is useful to treat sexual dysfunction in a patient in need t
Emmick Jeffrey T.
Ferguson Kenneth M.
Pullman William E.
Whitaker John S.
Bahar Mojdeh
Lilly Icos LLC.
Marshall Gerstein & Borun.
Travers Russell
LandOfFree
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