Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2001-08-09
2003-07-08
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S489000, C424S400000, C424S443000, C424S451000, C424S464000, C514S826000
Reexamination Certificate
active
06589508
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel compositions of matter containing optically pure (R,R) formoterol. These compositions possess potent, long-lasting bronchodilating activity as &bgr;-adrenergic agonists while avoiding or reducing adverse effects including but not limited to muscle tremor and tachycardia as well as avoiding or reducing the development of tolerance or hypersensitivity on repeated administration. The compositions also provide an improved duration of action. This invention also relates to methods of treating asthma, bronchitis, emphysema, bronchospasms, and other ailments in patients with obstructive airway or allergic disorders while avoiding adverse effects, development of tolerance or hypersensitivity on repeated administration or a limited pattern of bronchial distribution when administered by inhalation.
The active compound of these compositions and methods is an optical isomer of formoterol, which is described by Ida in Arzneim, Forsch. 26, 839-842 and 1337-1340 (1976) and in U.S. Pat. No. 3,994,974. Chemically, the active compound is N-hydroxy-5-(1-hydroxy-2-[(2-(4-methoxyphenyl)methylethyl]amino]ethyl]phenylformamide, which exists as two enantiomeric pairs of diastereomers. Of these, the R,R diastereomer is the most active and, when substantially optically pure, will be hereinafter referred to as (R,R) formoterol. Formoterol is available commercially only as a racemic diastereomer, (R,R) plus (S,S) in a 1:1 ratio, and the generic name formoterol refers to this enantiomeric mixture. The racemic mixture of (±) formoterol that is commercially available for administration is a dihydrate of the fumarate salt.
When two chiral centers occur in the same molecule each of them can exist in two possible configurations. This gives rise to four combinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirror images of each other and are therefore enantiomers which share chemical properties and melting points just like any other enantiomeric pair. (R,S) and (S,R) are similarly an enantiomeric pair. The mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R). This relationship is called diastereomeric, and (R,R) is a diastereomer of (R,S). Formoterol, having two chiral centers, falls into this category.
Adrenergic or sympathomimetic drugs are so called because they are understood to exert their effect through their action on the body's adrenergic receptors of which there are three functionally divided types, the &agr;, &bgr;
1
and &bgr;
2
receptors. On the basis of their interaction with these three receptor types, the adrenergic or sympathomimetic drugs are in turn classifiable into three groups:
1.1 Non-selective sympathomimetic drugs;
1.2 Non-selective &bgr; sympathomimetic drugs; and
1.3 Selective &bgr;
2
sympathomimetic bronchodilator drugs.
Drugs of group 1.1 exert both &agr; and &bgr; sympathomimetic effects. They include the drug substances adrenaline and ephedrine. Both adrenaline and ephedrine are known clinically as bronchodilators. Though adrenaline, despite side effect induced via its &agr;-sympathomimetic properties, is still used by some practitioners for the treatment of acute asthma, both adrenaline and ephedrine have been largely superseded in asthma therapy.
The drugs of group 1.2 have both &bgr;
1
and &bgr;
3
sympathomimetic activity but no, or only limited, &agr;-sympathomimetic activity. Of the group 1.2 drugs, isoprenaline is the best known representative. Isoprenaline differs from the drugs of group 1.3 in its faster onset but shorter duration of action and its cardiac stimulating effects which result largely from its &bgr;
1
activity. Though isoprenaline has previously been extensively used as bronchodilator therapy in asthma, its use has today become clinically restricted. Thus, in the UK, a rise in the rate of asthma death in the 1960's believed to have been specifically associated with isoprenaline usage has resulted in discontinuation of its clinical application.
The selective &bgr;
2
sympathomimetic bronchodilator drugs of group 1.3 (herein referred to for convenience collectively as “Group 1.3 drugs”) act, as their name implies, selectively on the &bgr;
2
adrenergic receptors. The Group 1.3 drugs include for example, the drug substances terbutaline, albuterol, fenoterol, isoetharine, metaproterenol and, more recently, the so-called “long acting selective &bgr;
2
sympathomimetic bronchodilator drug substances” formoterol, bambuterol and salmeterol. All of the above recited Group 1.3 drugs are commercially available and clinically used, generally in pharmaceutically acceptable salt form, e.,g. as the sulphate, hydrobromide, hydrochloride, fumarate or methanesulfonate or, where appropriate, one or other of the hydrate forms thereof.
Group 1.3 drugs characteristically contain as part of their structure an ethanolamine or 2-amino-ethanol moiety of formula I
in which R
1
is an aromatic group. Commonly R
1
is 3,4-or 3,5-dihydroxyphenyl or 4-hydroxy-3-hydroxymethylphenyl. R
1
may also be 3-formylamino-4-hydroxyphenyl, as in the case of formoterol. R
2
and R
3
in formula I are commonly H. Since the formula I moiety comprises at least 1 asymmetric carbon atom (Cl in formula I), all of the Group 1.3 drugs exist in optically active isomeric form, with the chiral carbon atom having the (R) or (S) configuration [as designated using the Cahn-Ingold-Prelog system (Angew. Chem. Intern. Ed. 5, 385-415 (1966)]. When the Cl carbon atom is the sole asymmetric carbon atom present, Group 1.3 drugs thus exist as individual (R) or (S) enantiomers or in racemic [(RS)] form, i.e. as a 50:50 mixture of the (R) and (S) enantiomers.
Individual Group 1.3 drugs in which R
2
in the formula I moiety is other than H, or in which the remainder of the molecule includes an asymmetric carbon atom (e.g. formoterol) exist in a variety of isomeric forms, i.e. in individual (R,R), (S,S) (R,S) and (S,R) isomeric form, as racemic [(RS,RS) and (RS,SR)] mixtures comprising the (R,R) plus (S,S) and (R,S) plus (S,R) enantiomeric pairs, as well as in the form of diastereomeric mixtures comprising all four isomeric forms.
The Group 1.3 drugs can be administered orally, parenterally or (most commonly) by inhalation, e.g. using nebulizers or metered aerosol devices or as inhaled powders. Inhalation of Group 1.3 drugs presently represents the mainstay of bronchodilator therapy for the treatment of asthma of all grades of severity. The duration of bronchodilatation induced by the majority of Group 1.3 drugs is relatively short and they are employed to relieve asthma attack as and when it occurs. As indicated above, the more recently introduced Group 1.3 drugs, such as formoterol, are characterized by their longer duration of action and hence apparent reduced frequency of dosaging required.
Although the Group 1.3 drugs are effective and generally seem to be well tolerated, their safety, especially at high dosages, has been questioned over many years and numerous reports have appeared on the adverse effects of Group 1.3 drug therapy (see e.g. Paterson et al:
American Review of Respiratory Disease
120, 844-1187 (1979) especially at page 1165 et seq.). More recently, from New Zealand, where a continuing increase in asthma death has been recorded, two case control studies reported in
The Lancet
have linked increase in asthma mortality to use of the Group 1.3 drug, fenoterol—see in particular: Editorial “&bgr;
2
agonists in asthma: relief, prevention, morbidity”,
Lancet
336, 1411-1412 (1990). A subsequently reported Canadian study finds that the use of inhaled Group 1.3 drugs, principally fenoterol and albuterol, is associated with “an increased risk of the combined outcome of fatal and near-fatal asthma, as well as of death from asthma alone”—see Spitzer et al.,
New England J. Med
. 326 (8), 501-506 (1992) and the Editorial to the same issue at page 560.
Various possible explanations for observed episodes of increased airway obstruction, arterial hy
Aberg Gunnar
Morley John
Clement, Esq. Candice J.
Haghighatian M.
Hartley Michael G.
Heslin Rothenberg Farley & & Mesiti P.C.
Sepracor Inc.
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