Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-05-17
2001-09-25
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S534000, C514S540000, C514S826000, C424S449000
Reexamination Certificate
active
06294582
ABSTRACT:
BACKGROUND OF THE INVENTION
Asthma, bronchitis and emphysema are known as Chronic Obstructive Pulmonary Diseases (COPD). COPD is characterized as generalized airways obstruction, particularly of small airways, associated with varying degrees of symptoms of chronic bronchitis, asthma, and emphysema. The term COPD was introduced because these conditions often coexist, and it may be difficult in an individual case to decide which is the major condition producing the obstruction. Airways obstruction is defined as an increased resistance to airflow during forced expiration. It may result from narrowing or obliteration of airways secondary to intrinsic airways disease, from excessive collapse of airways during a forced expiration secondary to pulmonary emphysema, from bronchospasm as in asthma, or may be due to a combination of these factors. Although obstruction of large airways may occur in all these disorders, particularly in asthma, patients with severe COPD characteristically have major abnormalities in their small airways, namely those less than 2 mm internal diameter, and much of their airways obstruction is situated in this zone. The airways obstruction is irreversible except for that which can be ascribed to asthma.
Asthma is a reversible obstructive pulmonary disorder (ROPD) characterized by increased responsiveness of the airway, resulting in airway obstruction. Airway obstruction is defined as an increased resistance to air flow during forced expiration. In asthma, airway obstruction typically results from bronchospasm. The underlying mechanisms causing asthma are unknown, but inherited or acquired imbalance of adrenergic and cholinergic control of airway diameter has been implicated. Asthmatics manifesting such imbalance have hyperactive bronchi and, even without symptoms, bronchoconstriction may be present. Overt asthma attacks may occur when such individuals are subjected to various stresses, such as viral respiratory infection, exercise, emotional upset, nonspecific factors (e.g., changes in barometric pressure or temperature), inhalation of cold air or irritants (e.g., gasoline fumes, fresh paint and noxious odors, or cigarette smoke), exposure to specific allergens, and ingestion of aspirin or sulfites in sensitive individuals. Those whose asthma is precipitated by allergens (most commonly airborne pollens and molds, house dust, animal danders) and whose symptoms are IgE-mediated are said to have allergic or “extrinsic” asthma. They account for about 10 to 20% of adult asthmatics; in another 30 to 50%, symptomatic episodes seem to be triggered by non-allergenic factors (e.g., infection, irritants, emotional factors), and these patients are said to have non-allergic or “intrinsic” asthma. In many persons, both allergenic and non-allergenic factors are significant.
Oxybutynin is used therapeutically in the treatment of intestinal hypermotility and in the treatment of urinary incontinence due to detrusor instability. Oxybutynin is sold for this purpose under the trade name of Ditropan®. Chemical names for oxybutynin are 4-(diethylamino)-2-butynyl-&agr;-cyclohexyl-&agr;-hydroxy benzeneacetate, and 4-(diethylamino)-2-butynylphenylcyclohexyl-glycolate. It is a racemic mixture of the R-enantiomer, R-oxybutynin, and the S-enantiomer, S-oxybutynin.
Use of the S-enantiomer of oxybutynin, S-oxybutynin, for the treatment of urinary incontinence has been described in U.S. Pat. No. 5,532,278, and 5,736,577. The structure of S-oxybutynin (Registry Number 119618-22-3) is shown in formula I. S-oxybutynin is not commercially available at the present time.
Administration of racemic oxybutynin may result in a number of adverse effects. These adverse effects include, but are not limited to, xerostomia, mydriasis, drowsiness, nausea, constipation, palpitations and tachycardia. The amelioration of cardiovascular side effects of racemic oxybutynin, such as tachycardia and palpitations, is of particular therapeutic value.
There is a continuing need for treatments for asthma, particularly those that minimize side effects.
SUMMARY OF INVENTION
It has now been found unexpectedly that S-oxybutynin provides a superior therapy for the treatment of reversible obstructive pulmonary disorders, including asthma, and provides this treatment while substantially reducing the adverse effects that are associated with the administration of racemic oxybutynin for other indications.
In one aspect, the present invention relates to a method of treating ROPD comprising administering to an individual in need of such therapy a therapeutically effective quantity of substantially optically pure S-oxybutynin, or a pharmaceutically acceptable salt thereof. In another aspect, such treatment is provided while reducing the adverse effects associated with the administration of racemic oxybutynin. Preferably, the treatment comprises inducing bronchodilation or relieving or preventing bronchoconstriction. The therapeutically effective quantity is preferably a quantity sufficient to reverse or prevent bronchospasms and the substantially optically pure S-oxybutynin preferably comprises at least 98% by weight of the S-isomer and 2% or less by weight of the R-isomer.
The S-oxybutynin may be administered orally, rectally, or by subcutaneous injection, intravenous infusion, inhalation or transdermal delivery. Preferably, the S-oxybutynin is administered orally, by inhalation or in the form of a transdermal patch. Where administration is by mouth, preferred forms are syrups, tablets or capsules. The amount administered orally is preferably from about 1 mg to about 1 g per day, more preferably from about 25 mg to about 700 mg per day. The amount administered by inhalation is preferably from about 0.1 mg to about 100 mg per day.
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Howell et al., “Pulmonary Pharmacology of a Novel, Smooth Muscle-Selective Muscarinic Antagonist In Vivo”, The Journal of Pharmacology and Experimental Therapeutics, 1994, Vo. 270, No. 2, pp. 546-553.
Characterization of the airway smooth muscle muscarinic receptor in vivo, Howell et al., European Journal of Pharmacology, 197 (1991) 109-112.
Heslin Rothenberg Farley & & Mesiti P.C.
Krass Frederick
Sepracor Inc.
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