Denaturants for sympathomimetic amine salts

Details Denaturants for sympathomimetic amine salts Denaturants for sympathomimetic amine salts

1999-09-08

2002-03-19

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C424S166100

Reexamination Certificate

active

06359011

ABSTRACT:

BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to pharmaceutical compositions comprising a sympathomimetic amine salt and at least one combination inhibitor, the combination inhibitor which acts both to interfere with the isolation of the sympathomimetic amine from the composition and to interfere with the conversion of the sympathomimetic amine to another pharmacologically active compound.
Sympathomimetic Amines and the Problem of Unconventional Use
The acid salts of sympathomimetic amines are widely used active agents in over-the-counter (OTC) pharmaceuticals. As their name suggests, this class of compounds produces pharmacological effects which mimic the activation of the sympathetic nervous system. For example, the hydrochloride salt of the sympathomimetic amine pseudoephedrine is a commonly used active ingredient in OTC decongestant products. It acts by causing adrenergic nerve endings to release norepinephrine, thereby stimulating alpha and beta norepinephrine receptors, particularly of the upper respiratory tract. This, in turn, results in vasoconstriction and shrinkage of swollen tissues in the sinuses and nasal passages. Its wide usage in numerous OTC products makes it readily available and easily accessible to the general public. When used in a recommended manner for approved indications, OTC pseudoephedrine hydrochloride pharmaceuticals are safe and effective. However, a problem arises when pseudoephedrine hydrochloride-containing OTC pharmaceuticals are used in an unconventional manner. Specifically, this active ingredient from OTC products is also a convenient starting material in the production of the pharmacologically active agent methamphetamine.
Methamphetamine is a powerful stimulant of the central nervous system (CNS). One of its principle pharmacological effects is the release of high levels of the neurotransmitter dopamine which stimulates brain cells. The approved therapeutic uses for methamphetamine are very limited, and such approved uses are commonly associated with the treatment of obesity. However, methamphetamine's pharmacological effects make it a popular candidate for illegal use as a recreational drug rather than as a legitimate therapeutic agent. Methamphetamine has various street names which include “speed”, “meth” and “crank”. In its hydrochloride salt form it appears as crystals and is referred to as “ice”, “crystal” and “glass”. When taken intravenously or by smoking, methamphetamine causes a burst of intense sensation which has been described as highly pleasurable. Oral or intranasal use causes a less intense euphoric high. Methamphetamine addiction can occur quickly and is characterized by increasing frequency and dosage of the drug. The CNS effects of the drug include irritability, insomnia, confusion, tremors, hyperthermia, convulsions, anxiety, paranoia and aggressiveness. In more extreme cases methamphetamine causes heart rate and blood pressure changes which can ultimately contribute to cardiovascular collapse and death.
As a natural progression, the illegal use of methamphetamine results in a demand for access to the drug through illicit routes. These illicit routes, in turn, are often supplied by the illegal production of the compound. One of the main methods used in the illegal synthesis of methamphetamine is known as the ephedrine reduction method. This procedure is relatively simple, requiring only a few steps and a small number of reagents to carry out the chemical process. The starting material used in this method is either ephedrine or pseudoephedrine. Previously, ephedrine, an enantiomer of pseudoephedrine, was the starting material of choice in the production of illegal methamphetamine. However, since regulatory efforts in the United States have significantly reduced the ease by which ephedrine can be obtained, pseudoephedrine or its corresponding salts from OTC products have become the preferred starting point for the production of illicit methamphetamine. The wide public availability of pseudoephedrine hydrochloride in OTC pharmaceuticals allows illicit drug manufacturers easy and abundant access to a suitable starting material for clandestine methamphetamine chemistry.
Methamphetamine abuse in the United States is expanding geographically as well as in numbers among the younger population. Traditionally the illegal use of this compound was predominantly localized in the west and southwest United States. However, trafficking patterns now have been detected in areas of the country previously not known to have problems with the illicit use of this drug, namely the midwest. Furthermore, among young adults the illegal use of methamphetamine is increasing. For example, in 1997 4.4% of high school seniors had used crystal methamphetamine at least once in their lifetime—up from 2.7% in 1990.
The increasing and broadening scope of illegal use of methamphetamine, combined with the decreased availability of ephedrine as a synthetic starting material for methamphetamine production, indicates the demand for OTC preparations of pseudoephedrine hydrochloride by illicit drug manufacturers will continue to escalate. The unconventional use of OTC pseudoephedrine can be combated by limiting the accessibility of such preparations to the general public. However, this restriction adversely impacts the consumer who seeks to use properly these safe and effective drugs and who has come to rely on ready access to them without the continuous authorization of a health care professional (e.g., physicians or pharmacists). The goal of the instant invention is to significantly deter the use of OTC products in illicit drug preparations without compromising the accessibility of these products to the general public.
Prior Attempts to Minimize Illicit Use of OTC Pharmaceuticals
Attempts to use the active ingredients in OTC pharmaceutical products to prepare illegal drugs is not uncommon. In response, various efforts have been made to modify pharmaceutical preparations in order to prevent this type of illicit use of these products. For example, codeine can be extracted from analgesic tablets and converted to morphine and heroin. Application WO 96/08252 disclosed codeine-containing solid dosage forms comprising components that interfere with the isolation of the active ingredient.
In the case of compositions containing sympathomimetic amines, WO 97/37689 which corresponds to U.S. Ser. No. 08/937,408 filed on Apr. 1, 1997, discloses modified pharmaceutical preparations which comprise denaturing components that complicate the use of these formulations in the illegal synthesis of drugs. The main mechanism by which such a denaturant system is effective involves creating an infeasible physical separation of the sympathomimetic amine from the formulation; this denaturant system is designed to combat widely known and used methods of preparing illegal drugs from OTC products. Comparatively, the sympathomimetic amine pharmaceutical composition of the instant invention offers the unique advantage in that it comprises a combination inhibitor which is a single component that remains with the amine when the composition is subjected to attempted separation. Such a component is not only effective against well known extraction methods commonly employed by illegal drug manufacturers, but it also deters alternate, and possibly more sophisticated means of sympathomimetic amine isolations.
The combination inhibitors in the instant invention offer a second, critical advantage over previously described denaturant systems used to inhibit methamphetamine synthesis from OTC pseudoephedrine preparations; in addition to hindering the isolation of the sympathomimetic amine, these combination inhibitors also chemically interfere with the conversion of the amine to other pharmacologically active compounds. This reaction interference occurs either when the chemical conversion is carried out on the original formulation or on a composition that has undergone an extraction; interference is effective on an extracted composition since at least a portion o

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