Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-04-16
2002-12-17
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S648000, C514S649000, C514S912000
Reexamination Certificate
active
06495529
ABSTRACT:
FIELD OF THE INVENTION
The present application provides pharmaceutical compositions and methods of using the sympathomimetic composition of (−)-pseudoephedrine as a decongestant, bronchodilator, and the like. The present compositions of (−)-pseudoephedrine are substantially-free of (+)-pseudoephedrine. According to the present invention, at similar doses, (−)-pseudoephedrine binds &agr;
1
- and &agr;
2
adrenergic receptors better than (+)-pseudoephedrine and yet has less adverse effects upon blood pressure and fewer drug interactions.
BACKGROUND OF THE INVENTION
Sympathomimetic drugs are structurally and pharmacologically related to amphetamine. They generally act by binding to or activating &agr;- and &bgr;-adrenergic receptors, resulting in vascular constriction, reduced blood flow and/or reduced secretion of fluids into the surrounding tissues. Such receptor binding generally decreases swelling of nasal membranes and the amount of mucous secreted into nasal passages. Sympathomimetic drugs are therefore used to treat nasal congestion, allergies and colds. In addition, they are used as appetite suppressants and mydriatic agents.
At the present time, some drugs are sold as racemic mixtures. Alternatively, the most easily isolated stereoisomer is sold, even though another stereoisomer may have greater activity or fewer side effects because that stereoisomer interacts more selectively with the receptors involved in sympathomimetic action. Isolation and use of the more selective stereoisomer may therefore reduce not only the required dosage, but many unwanted side effects.
Many organic compounds exist in optically active forms. This means that they have the ability to rotate the plane of plane-polarized light. An optically active compound is often described as a chiral compound. Such a chiral compound has at least one asymmetric carbon which can exist in two different, mirror image configurations. Compounds which have the same composition but are mirror images of each other are called enantiomer. The prefixes d and l, or (+) and (−), identify the direction in which an enantiomer rotates light. The d or (+) steroisomer, or enantiomer, is dextrorotatory. In contrast, the l or (−) enantiomer is levorotatory. A mixture of (+) and (−) enantiomers is called a racemic mixture.
An alternative classification system for stereoisomers exists where prefixes (S) and (R) are used. This classification system is based on the structure of the compound.
(+)-Pseudoephedrine is known to be sympathomimetic amine which binds to &agr;-adrenergic receptors. It is sold under the tradename SUDAFED®. However, (+)-pseudoephedrine has undesirable side effects, including central nervous system stimulation, lightheadedness, nervousness, anxiety, paranoia, heart arrhythmia, atrial fibrillations and premature ventricular contractions. 95 American Hospital Formulatory Service 847-48. Moreover, (+)-pseudoephedrine can easily be converted into the controlled drug, (S)-methamphetamine, by simply converting the hydroxyl in (+)-pseudoephedrine to a hydrogen.
Hence, a need exsists for a compsition having the beneficial decongestant activities of (+)-pseudoephedrine, without its adverse side effects, and without its (S)-methamphetamine-conversion problem.
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition containing (−)-pseudoephedrine and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is substantially-free of (+)-pseudoephedrine. Suprisingly, the present (−)-pseudoephedrine compositions bind to &agr;-adrenergic receptors with greater affinity than do (+)-pseudoephedrine compositions while causing less adverse effects on blood pressure. Moreover, (−)-pseudoephedrine has decongestant activity which is similar to several known decongestants. The pharmaceutical composition has (−)-pseudoephedrine in a therapeutic dosage suitable for treating nasal or broncial congestion, counteracting the physiological effects of histamine, dilating the pupil, suppressing the appetite, treating attention deficit hyperactivity disorder and treating other conditions typically treated with sympathomimetic drugs. Upon administration to a mammal in a therapeutically effect amount, the present compositions may have reduced side effects relative to administration of (+)-pseudoephedrine, for example, interactions with drugs such as antihistamines. Moreover, (−)-pseudoephedrine reduces the (S)-methamphetamine conversion problem of (+)-pseudoephedrine, because reduction of the hydroxyl in (−)-pseudoephedrine results in (R)-methamphetamine with substantially less psychoactivity than (S)-methamphetamine.
The present invention is also directed to a method of relieving nasal and bronchial congestion which includes administering a therapeutically effective amount of (−)-pseudoephedrine to a mammal, wherein such (−)-pseudoephedrine is substantially-free of (+)-pseudoephedrine. This method has less side effects than a method which includes administration of a racemic pseudoephedrine mixture or a composition of (+)-pseudoephedrine. In this embodiment, a therapeutically effective amount of (−)-pseudoephedrine is a dosage suitable for treating nasal and/or bronchial congestion.
The present invention is also directed to a method of antagonizing the physiological effects of histamine which includes administering a therapeutically effective amount of (−)-pseudoephedrine to a mammal, wherein such (−)-pseudoephedrine is substantially-free of (+)-pseudoephedrine. According to the present invention, (−)-pseudoephedrine surprisingly is a physiological antagonist of histamine. This method has fewer side effects than a method which includes administration of a composition including (+)-pseudoephedrine. It is also believed that this method has less side effects than administration of a racemic mixture of (+)- and (−)-pseudoephedrine. In this embodiment, a therapeutically effective amount of (−)-pseudoephedrine is a dosage suitable for relieving the physiological effects of histamine, for example, nasal congestion, inflammation, and other allergic responses.
The present invention is also directed to a method of treating conditions typically treated with sympathomimetic drugs, which includes administering a therapeutically effective amount of (−)-pseudoephedrine to a mammal, wherein such (−)-pseudoephedrine is substantially-free of (+)-pseudoephedrine. This method may have fewer side effects than a method which includes administration of a composition of (+)-pseudoephedrine alone. It is also believed to have fewer side effects than administration of a racemic mixture of (+)- and (−)-pseudoephedrine. In this embodiment, a therapeutically effective amount of (+)-phenylephrine is a dosage suitable for treating the condition typically treated with a sympathomimetic drug.
REFERENCES:
patent: 4801461 (1989-01-01), Hamel et al.
patent: 5354693 (1994-10-01), Brynes et al.
patent: 9217171 (1992-10-01), None
Kier; “The Preferred Conformations of Ephedrine Isomers and the Nature of the Alpha Adrenergic Receptor”; J. Pharmacol. Exp. Ther.; vol. 164; No. 1; 164: 75-81; 1968.
Fauley et al.; “The Stereoselective Inhibition of Lipolysis by Nonphenolic Phenethylamines”; Eur. J. Pharmacol. vol. 27; No. 1, 136-140; 1974.
Patil et al.; “Steric Aspects of Adrenergic Drugs. I. Comparative Efects of DL Isomers and Desoxy Derivatives”; J. Pharmacol. Exp. Ther. vol. 155; No. 1; 1-12; 1967.
Lapdius et al.; Steric Aspects of Adrenergic Drugs VII Certain Pharmacological Actions of D(−)-Pseudoephedrine; J. Pharm. Sci., vol. 56, No. 9; 1125-1130; 1967.
Bukowiecki et al.; ephedrine, a potential slimming drug, directly stimulates thermogenesis in brown adipocyctes via &bgr;-andrenoreceptors; Int J. Obes; vol. 6, No. 4; 343-350; 1982.
Booth Anthony
Caffrey James L.
Forster Michael
Gwirtz Patricia
Raven Peter
Fay Zohreh
Federman Evan J.
Jacobsen Barry H.
Warner-Lambert & Company
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