TWO
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 .alpha.-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 bronchial 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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions of (-)-pseudoephedrine that are substantially free of (+)-pseudoephedrine. The present invention also provides methods of using such (-)-pseudoephedrine compositions for treating colds, treating nasal congestion, treating allergies, treating histamine-related inflammations, treating obesity, dilating the pupil, and treating other conditions typically treated with sympathomimetic drugs. According to the present invention, the structures of (+)-pseudoephedrine and (-)-pseudoephedrine are: ##STR1##
(+)-Pseudoephedrine is known as a decongestant, but it can readily be converted into the psychoactive drug, (S)-methamphetamine, by reduction of the hydroxyl group to hydrogen. Reduction of the hydroxyl in (-)-pseudoephedrine yields a compound with only one-tenth the psychoactivity of (S)-methamphetamine. Hence, the present compositions and methods avoid this problem.
The term "substantially free of (+)-pseudoephedrine" means that the composition contains at least 90% (-)-pseudoephedrine and 10% or less (+)-pseudoephedrine. In a more preferred embodiment, "substantially free of (+)-pseudoephedrine" means that the composition contains at least 95% (-)-pseudoephedrine and 5% or less (+)-pseudoephedrine. Still more preferred is an embodiment wherein the pharmaceutical composition contains 99% or more (-)-pseudoephedrine and 1% or less (+)-pseudoephedrine.
According to the present invention, compositions of (-)-pseudoephedrine which are substantially free of (+)-pseudoephedrine are also substantially free of the adverse side effects related to administration of (+)-pseudoephedrine. Such adverse side effects include but are not limited to interactions with other drugs such as antihistamines. Moreover, when similar amounts of (+)- and (-)-pseudoephedrine are administered, (-)-pseudoephedrine causes fewer cardiovascular side effects. In particular, (-)-pseudoephedrine does not adversely effect blood pressure at the doses of (+)-pseudoephedrine which are normally administered, whereas (+)-pseudoephedrine can adversely increase blood pressure. As a result, administration of the present compositions of (-)-pseudoephedrine produce reduced side effects relative to the administration of the (+)-stereoisomer of pseudoephedrine. It is also believed that administration of the present (-)-pseudoephedrine compositions has fewer side effects relative to the administration of a racemic mixture of (+)- and (-)-pseudoephedrine.
The (-)-pseudoephedrine of this invention may be prepared by known procedures. Methods for separating the stereoisomers in a racemic mixture are well-known to the skilled artisan.
The present invention also provides pharmaceutically acceptable salts of (-)-pseudoephedrine. For example, (-)-pseudoephedrine can be provided as a hydrochloride, bitartrate, tannate, sulfate, stearate, citrate or other pharmaceutically acceptable salt. Methods of making such pharmaceutical salts of (-)-pseudoephedrine are readily available to one of ordinary skill in the art.
The pharmaceutical compositions of the present invention contain (-)-pseudoephedrine with a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, sweeteners and the like. The pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and adsorbents that may be needed in order to prepare a particular therapeutic composition. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
According to the present invention, (-)-pseudoephedrine does not interact with other drugs, for example, with antihistamines. This is one advantage that the present compositions and methods of using (-)-pseudoephedrine have over compositions and methods of using (+)-pseudoephedrine: (-)-pseudoephedrine does interact with HI antihistamines such as triprolidine, whereas (+)-pseudoephedrine does interact with H.sub.1 antihistamines. Due to the lack of such drug interaction, supplementary active ingredients, such as additional antihistamines and decongestants, can be incorporated into the present (-)-pseudoephedrine compositions. The amount of the added antihistamine or decongestant present in the pharmaceutical composition will depend upon the particular drug used. Typical antihistamines include: diphenhydramine; chlorpheniramine; astemizole; terfenadine; terfenadine carboxylate; brompheniramine; triprolidine; acrivastine; and loratadine.
The present invention further contemplates a method of relieving nasal and/or bronchial congestion which comprises administering a therapeutically effective amount of (-)-pseudoephedrine which is substantially free of (+)-pseudoephedrine. Administration of (-)-pseudoephedrine avoids many of the side effects related to administering (+)-pseudoephedrine including drug interactions.
According to the present invention, (-)-pseudoephedrine is surprisingly effective as a physiological antagonist of histamine. This means (-)-pseudoephedrine counteracts the physiological effects of histamine. Histamine can cause nasal congestion, bronchial congestion, inflammation and the like. This present invention contemplates (-)-pseudoephedrine to counteract all of these histamine-related physiological responses. Moreover, according to the present invention (-)-pseudoephedrine can be combined with antihistamines, for example, antihistamines that bind to H.sub.1 antihistamine receptors.
The present invention also contemplates a method of treating inflammation and/or sinus congestion which comprises administering a therapeutically effective amount of (-)-pseudoephedrine. The pharmaceutical compositions of (-)-pseudoephedrine used for this method are substantially-free of (+)-pseudoephedrine and induce less side effects than does administration of a composition containing (+)-pseudoephedrine.
According to the present invention, a therapeutically effective amount of (-)-pseudoephedrine is an amount sufficient to relieve the symptoms of a condition which can be treated by a sympathomimetic drug. In one embodiment, an amount sufficient to reduce the symptoms of a condition which can be treated by a sympathomimetic drug is an amount of (-)-pseudoephedrine sufficient to bind or activate an adrenergic receptor, for example, and .alpha.- or a .beta.-adrenergic receptor. When the condition is nasal congestion the therapeutically effective amount is the amount needed to reduce nasal congestion. When bronchial congestion is the condition, the therapeutically effective amount is the amount needed to reduce bronchial congestion or provide bronchodilation. When inflammation and/or allergic reaction is the condition, the therapeutically effective amount is the amount needed to counteract the physiological effects of histamine. When eye pupil dilation is the desired, such as therapeutically effective amount of (-)-pseudoephedrine is an amount of (-)-pseudoephedrine sufficient to dilate the pupil. Preferably, such a pharmaceutically effective amount also produces less side effects than are observed upon administration of (+)-pseudoephedrine, or a racemic mixture of (+)- and (-)-pseudoephedrine. The skilled artisan can readily determine the necessary therapeutically effective amounts for treating these conditions, particularly in light of the teachings provided herein.
OK OK now find a bright side? You can now avoid that nasty (S)-methamphetamine
crap that has been keeping you awake and horny for lo these many years, and now make directly the stuff that Selegiline metabolizes into, l-methamphetamine,
and feel really good about yourself.
My test monkey notes that the MAOI-B action of Selegiline enhances the experience of the friendly and socially acceptable l-methamphetamine.
Get used to it.
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