U.S. patent application number 09/996438 was filed with the patent office on 2002-06-27 for denaturants for sympathomimetic amine salts.
Invention is credited to Bess, William Stefan, Nichols, William Michael.
Application Number | 20020082304 09/996438 |
Document ID | / |
Family ID | 22276270 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082304 |
Kind Code |
A1 |
Bess, William Stefan ; et
al. |
June 27, 2002 |
Denaturants for sympathomimetic amine salts
Abstract
The instant invention makes impractical the use of
sympathomimetic amine compositions in illicit drug production. More
specifically, the preparation of methamphetamine from the disclosed
pseudoephedrine hydrochloride formulations is inhibited. The
present invention defines 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. The contemplated
compositions may also include reaction and separation inhibitors in
any mixture to assure maximum protection against the use of the
sympathomimetic amine-containing compositions for illegal drug
manufacture. The presence of the combination, reaction and
separation inhibitors does not significantly alter the release of
the sympathomimetic amine from the composition.
Inventors: |
Bess, William Stefan;
(Edison, NJ) ; Nichols, William Michael; (Fanwood,
NJ) |
Correspondence
Address: |
Evan J. Federman
Legal Division, Warner-Lambert Company
201 Tabor Road
Morris Plains
NJ
07950
US
|
Family ID: |
22276270 |
Appl. No.: |
09/996438 |
Filed: |
November 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09996438 |
Nov 20, 2001 |
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09391739 |
Sep 8, 1999 |
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60099712 |
Sep 10, 1998 |
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Current U.S.
Class: |
514/646 ;
424/487 |
Current CPC
Class: |
A61K 9/1652 20130101;
A61K 31/765 20130101; A61P 25/02 20180101; A61K 9/2081 20130101;
A61P 25/18 20180101; A61K 31/137 20130101; A61P 9/00 20180101; A61K
31/205 20130101; A61K 45/06 20130101; A61K 9/146 20130101; A61K
31/205 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/646 ;
424/487 |
International
Class: |
A61K 031/137; A61K
009/14 |
Claims
What is claimed is:
1. A pharmaceutical composition comprising: an acid salt of a
sympathomimetic amine; and at least one combination inhibitor,
wherein said combination inhibitor is present in amounts sufficient
to interfere with the isolation of said sympathomimetic amine and
to interfere with the conversion of said sympathomimetic amine to
other pharmacologically active compounds without significantly
altering the release of said sympathomimetic amine from said
pharmaceutical composition as compared to the undenatured
composition.
2. The pharmaceutical composition according to claim 1 further
comprising at least one reaction inhibitor, wherein said reaction
inhibitor is present in amounts sufficient to interfere with the
conversion of said sympathomimetic amine to other pharmacologically
active compounds without significantly altering the release of said
sympathomimetic amine from said pharmaceutical composition as
compared to the undenatured composition.
3. The pharmaceutical composition according to claim 1 further
comprising at least one separation inhibitor, wherein said
separation inhibitor is present in amounts sufficient to interfere
with the isolation of said sympathomimetic amine without
significantly altering the release of said sympathomimetic amine
from said pharmaceutical composition as compared to the undenatured
composition.
4. The pharmaceutical composition according to claim 2 further
comprising at least one separation inhibitor, wherein said
separation inhibitor is present in amounts sufficient to interfere
with the isolation of said sympathomimetic amine without
significantly altering the release of said sympathomimetic amine
from said pharmaceutical composition as compared to the undenatured
composition.
5. The pharmaceutical composition according to claim 1 wherein said
sympathomimetic amine is selected from the group consisting of
pseudoephedrine hydrochloride, pseudoephedrine sulfate, ephedrine
hydrochloride and phenylpropanolamine hydrochloride.
6. The pharmaceutical composition according to claim 5 wherein said
sympathomimetic amine is pseudoephedrine hydrochloride.
7. The pharmaceutical composition according to claim 1 wherein said
other pharmacologically active compound is selected from the group
consisting of methamphetamine, amphetamine, methacathinone and
cathinone.
8. The pharmaceutical composition according to claim 7 wherein said
other pharmacologically active compound is methamphetamine.
9. The pharmaceutical composition according to claim 1 wherein said
combination inhibitor is selected from the group consisting of
transition metal salts and amino polymers.
10. The pharmaceutical composition according to claim 9 wherein
said amino polymer is in a neutralized salt form.
11. The pharmaceutical composition according to claim 10 wherein
said amino polymer is from about 1% to about 100% in the
neutralized salt form.
12. The pharmaceutical composition according to claim 10 wherein
said amino polymer is from about 50% to about 100% in the
neutralized salt form.
13. The pharmaceutical composition according to claim 10 wherein
said amino polymer is from about 70% to about 100% in the
neutralized salt form.
14. The pharmaceutical composition according to claim 10 wherein
said amino polymer is from about 85% to about 98% in the
neutralized salt form.
15. The pharmaceutical composition according to claim 9 wherein
said amino polymer is a copolymer of methyl methacrylate, butyl
methacrylate and dimethylaminoethyl methacrylate.
16. The pharmaceutical composition according to claim 15 wherein
said amino polymer is the neutralized hydrochloride salt form of
the copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate.
17. The pharmaceutical composition according to claim 16 wherein
said copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate is from about 1% to about 100% in
the neutralized hydrochloride salt form.
18. The pharmaceutical composition according to claim 16 wherein
said copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate is from about 50% to about 100% in
the neutralized hydrochloride salt form.
19. The pharmaceutical composition according to claim 16 wherein
said copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate is from about 70% to about 100% in
the neutralized hydrochloride salt form.
20. The pharmaceutical composition according to claim 16 wherein
said copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate is from about 85% to about 98% in
the neutralized hydrochloride salt form.
21. The pharmaceutical composition according to claim 15 wherein
said copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate is homogeneously mixed together
with said sympathomimetic amine and all other components of said
pharmaceutical composition.
22. The pharmaceutical composition according to claim 15 wherein
said copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate coats said sympathomimetic amine
prior to mixing with all other components of said pharmaceutical
composition.
23. The transition metal salt according to claim 9 wherein said
transition metal is selected from the group consisting of iron,
cobalt, copper, chromium, manganese, nickel and zinc.
24. The transition metal salt according to claim 9 wherein the
anion of said transition metal salt is selected from the group
consisting of chloride, oxide, sulfate and gluconate.
25. The pharmaceutical composition according to claim 9 wherein
said transition metal salt is selected from the group consisting of
ferric chloride, ferric oxide, ferrous sulfate, ferrous chloride,
ferrous gluconate ferrous oxide, zinc gluconate and copper
gluconate.
26. The pharmaceutical composition according to claim 25 wherein
said transition metal salt is selected from the group consisting of
ferrous gluconate, zinc gluconate and copper gluconate.
27. The pharmaceutical composition according to claims 2 or 4
wherein said reaction inhibitor is selected from the group
consisting of water insoluble polyhydroxy compounds, non-polymeric
water soluble polyhydroxy compounds and solvent soluble ester
compounds.
28. The pharmaceutical composition according to claim 27 wherein
said water insoluble polyhydroxy compound is selected from the
group consisting of ethylcellulose and cellulose.
29. The pharmaceutical composition according to claim 27 wherein
said non-polymeric water soluble polyhydroxy compound is selected
from the group consisting of glycerin, sorbitol, lactitol,
mannitol, xylitol, maltitol and galactose.
30. The pharmaceutical composition according to claim 27 wherein
said solvent soluble ester is selected from the group consisting of
glycerin esters, esters of glycerin polymers, sorbitol esters,
propylene glycol esters, polyethylene glycol esters, sucrose esters
and esters of ethoxylated fatty alcohols.
31. The pharmaceutical composition according to claims 3 or 4
wherein said separation inhibitor is selected from the group
consisting of water soluble cellulose compounds, polysaccharide
gums, polyethylene oxide polymers, acrylic acid polymers, starches,
magnesium aluminum silicates, polyvinylpyrrolidones and clays.
Description
[0001] This application claims priority to U. S. provisional
application no. 60/099,712, filed Sep. 10, 1998.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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.
[0004] 2. Sympathomimetic Amines and the Problem of Unconventional
Use
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] Prior Attempts to Minimize Illicit Use of OTC
Pharmaceuticals
[0011] 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.
[0012] 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.
[0013] 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 of the combination inhibitor
remains with the sympathomimetic amine under a broad range of
extraction conditions. Theoretically, a combination inhibitor
chemically reacts in multiple ways to prevent the conversion of the
sympathomimetic amine to another compound. A combination inhibitor
may react not only with itself and other reagents directed to the
sympathomimetic amine, but it also may react with the amine. Since
the combination inhibitor reacts with the principle starting
material such as pseudoephedrine, addition of increased amounts of
reactants will not likely overcome to any significant extent the
reaction of the inhibitor with the sympathomimetic amine.
Furthermore, the generation of multiple side products requires
sophisticated separation techniques to isolate any minimal amount
of methamphetamine that may be generated.
[0014] The present invention addresses the problem of the use of
widely available OTC sympathomimetic amine formulations in the
preparation of illegal drugs by disclosing novel pharmaceutical
compositions that are impractical as starting material in illegal
drug synthesis. These compositions are effective in deterring both
well known extraction methods as well as different and possibly
more sophisticated illegal drug production methods. Furthermore,
the compositions of the present invention are not compromised in
their release, bioavailability or dosing frequency relative to
corresponding, undenatured sympathomimetic amine preparations
presently available to the consumer.
SUMMARY OF THE INVENTION
[0015] The incorporation of at least one combination inhibitor in
pharmaceutical compositions of sympathomimetic amines, the subject
of this invention, represents a unique discovery in the area of
drug formulations involving this class of active agents. The
purpose of the combination inhibitor is to prevent the use of OTC
sympathomimetic amine pharmaceuticals in the production of illegal
drugs, particularly the synthesis of methamphetamine from
pseudoephedrine. It achieves this purpose by interfering with both
the isolation of the sympathomimetic amine from the composition and
the conversion of the sympathomimetic amine to other
pharmacologically active compounds. The combination inhibitor is
present in an amount sufficient to accomplish the goal without
significantly altering the release, bioavailability or dosage of
the active ingredient. The advantage of the present invention is
that a single component deters both traditional extraction
conditions used in illegal drug synthesis as well as alternate,
more sophisticated separation techniques.
DETAILED DESCRIPTION OF THE INVENTION
[0016] General Terms and Definitions
[0017] The term "inhibitor" as used in the instant invention is any
component, added to a composition containing a sympathomimetic
amine, that interferes with the isolation of that sympathomimetic
amine and/or interferes with the conversion of that sympathomimetic
amine to another pharmacologically active compound. A single
inhibitor of any class (i.e., combination, reaction or separation)
or any mixture of more than one inhibitor of the same or of
multiple classes of inhibitors will not significantly effect the
release of the sympathomimetic amine from the formulation as
compared to the undenatured composition. The term inhibitor is
interchangeable with the term "denaturant". A "pharmacologically
active compound" is any chemical substance that affects living
tissue, producing a biological effect in a living organism.
[0018] The terms "immediate release" and "modified release" are
used in the instant invention as they are commonly understood in
the pharmaceutical industry. For immediate release products in
solid dosage form (such solid dosage forms including but not
limited to tablets, capsules, powders and films), release is
defined as the amount of sympathomimetic amine measured using an
appropriate USP dissolution test procedure with distilled water as
the medium. If no official USP dissolution test procedure has been
established, (e.g., as in the case of chewable tablets), then the
most appropriate USP dissolution test will apply, utilizing
distilled water as the medium and taking measurements at
appropriate time points up to and including the final dosing
interval. For immediate release products in non-solid dosage form
(such non-solid dosage forms including but not limited to liquids,
syrups, elixers, liquid center oral products, creams, pastes and
gels), release is defined as the amount of sympathomimetic amine
measured after mixing a 1% solution of the product in distilled
water at 37.degree. C. for 30 minutes. For modified release
products in solid dosage form (such solid dosage forms including
but not limited to tablets, capsules, powders and films), release
is defined as the amount of sympathomimetic amine measured using an
appropriate USP dissolution test procedure with distilled water as
the medium. If no official USP dissolution test procedure has been
established, (e.g., as in the case of chewable tablets), then the
most appropriate USP dissolution test will apply, utilizing
distilled water as the medium and taking measurements at
appropriate time points up to and including the final dosing
interval. For modified release products in non-solid dosage form
(such non-solid dosage forms including but not limited to liquids,
syrups, elixers, liquid center oral products, creams, pastes and
gels), release is defined as the amount of sympathomimetic amine
measured after mixing a 1% solution of the product in distilled
water at 37.degree. C. for 1 hour and taking at least one
additional measurement up to and including the final dosing
interval.
[0019] For the purposes of this invention, the term "combination
inhibitor" refers to a component of a composition which both
interferes with the isolation of a sympathomimetic amine from the
composition and interferes with the conversion of the
sympathomimetic amine to another pharmacologically active compound.
The combination inhibitor interferes with such a conversion either
directly from the original formulation or after attempts have been
made to isolate the sympathomimetic amine. It is both the physical
and chemical properties of the combination inhibitors which allow
them to act as multifaceted deterrents to the use of these
compositions in the preparation of other pharmacologically active
compounds. Combination inhibitors of the instant invention
demonstrate all of the following characteristics: (1) they
significantly interfere with chemical reactions which convert the
sympathomimetic amine to another pharmacologically active compound;
(2) they are not readily separable from the sympathomimetic amine
to an extent that they would no longer be able to significantly
interfere with chemical reactions which convert the sympathomimetic
amine to another pharmacologically active compound; and, (3) they
may also interfere with the separation of the sympathomimetic amine
from the other components of the composition. A single combination
inhibitor may be used or multiple combination inhibitors may be
included in the composition of the instant invention.
[0020] In the present invention "reaction inhibitors" are
components of a composition that mainly .interfere with the
conversion of sympathomimetic amines to other pharmacologically
active compounds. Unlike combination inhibitors, under certain
conditions a reaction inhibitor may be readily separable from the
sympathomimetic amine to the extent that it no longer can
significantly effect the chemical reactions which convert the
sympathomimetic amine to another pharmacologically active compound.
A single reaction inhibitor may be used or multiple reaction
inhibitors may be included in the composition of the instant
invention.
[0021] A "separation inhibitor" in the instant invention is a
component of a composition that primarily interferes with the
separation of the sympathomimetic amine from the composition. The
interference with the separation is predominately due to the
inability of the sympathomimetic amine to be physically isolated
from the composition. Separation inhibitors are of two main types:
water soluble and solvent soluble. An example of a typical
separation technique which may be affected by the properties of a
separation inhibitor involves the use of filtration as a means of
separating the sympathomimetic amine from the composition. In the
case of filtration, the separation inhibitor interferes with the
filtration and results in a reduced yield of separated
sympathomimetic amine. Water soluble inhibitors interfere with
water based separations and solvent soluble inhibitors interfere
with solvent based separations. A third class of separation
inhibitors can also be used in the present invention. This class
includes compounds that are soluble in both aqueous and organic
solvents. A single separation inhibitor may be used or multiple
separation inhibitors may be included in the composition of the
instant invention.
[0022] Sympathomimetic Amines in OTC Pharmaceuticals and the
Corresponding Pharmacologically Active Compounds Produced From The
Sympathomimetic Amines
[0023] Sympathomimetic amines are compounds that cause
vasoconstriction in the vascular bed of the nasal mucosa resulting
in a shrinking of the engorged mucous membranes. The ultimate
physiological response is increased drainage and improved nasal air
flow. As a result of these effects, sympathomimetic amines are
highly effective as nasal decongestants. Unless otherwise stated,
as used herein the term "sympathomimetic amine" can be used
interchangeably with and may refer to a corresponding
pharmaceutically acceptable acid salt form of the amine. The amine
and its acid salt form may have asymmetric centers and occur as
racemates, racemic mixtures, individual diastereomers, or
enantiomers, with all isomeric forms being included in the present
invention.
[0024] In a preferred embodiment of the present invention, the
sympathomimetic amines are those with the structural formula I:
1
[0025] wherein R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11,
R.sub.12 and R.sub.13 are selected from the following: hydrogen;
substituted or unsubstituted C.sub.1-12 alkyl; substituted or
unsubstituted C.sub.1-12 alkoxy; hydroxy; and halogen.
Notwithstanding the foregoing, R.sub.11 and R.sub.12 are not
halogens.
[0026] Those sympathomimetic amines widely available as OTC nasal
decongestants are particularly contemplated for use in the instant
invention; specific preferred examples include: pseudoephedrine
hydrochloride, pseudoephedrine sulfate, ephedrine hydrochloride and
phenylpropanolamine hydrochloride. The sympathomimetic amine
phenylephrine hydrochloride is also contemplated in the instant
invention. While the descriptions and examples of the compositions
comprising combination inhibitors, reaction inhibitors and
separation inhibitors may use a specific sympathomimetic amine such
as pseudoephedrine hydrochloride, it is understood that the
inhibitors are applicable to any composition comprising
sympathomimetic amines and their corresponding acid salt forms.
[0027] Sympathomimetic amines in OTC preparations can be converted
to a wide variety of other pharmacologically active compounds. In
the instant invention the pharmacologically active compounds
contemplated are ones that are used for recreational purposes in an
illicit manner. Examples of such pharmacologically active compounds
produced from sympathomimetic amines include, but are not limited
to: methamphetamine, amphetamine, methcathinone and cathinone. The
production of these illegal drugs occurs by various reductive or
oxidative reactions widely known to those skilled in the art.
[0028] The Amount of Sympathomimetic Amine Relative to the Amount
of inhibitors in the Invention
[0029] The ratio of sympathomimetic amine salts to the inhibitor
components in any composition of the instant invention is from
about 1:100 to about 100:1, preferably from about 1:10 to about
10:1. Even more preferably, the amount of sympathomimetic amine
salts and inhibitor mixture in any composition of the present
invention is in a ratio of about 1:5 to about 5:1.
[0030] The amount of inhibitor needed to effectively interfere with
the isolation of the sympathomimetic amine and the conversion of
the sympathomimetic amine to another pharmacologically active
compound from a composition is dependent upon the size of the unit
dose. For immediate release products, typical dosages (milligrams,
mg) for commonly used sympathomimetic amine decongestants are 60 mg
for pseudoephedrine hydrochloride, 10 mg for phenylephrine
hydrochloride, 25 mg for phenylpropanolamine hydrochloride and 24
mg for ephedrine hydrochloride. Generally, the total quantity of
the inhibitors per unit dose preparation may be varied or adjusted
from about 0.1 mg to about 750 mg according to the particular
application and the potency of the sympathomimetic amine salt. For
example, when a 30 mg pseudoephedrine hydrochloride tablet is being
prepared, the amount of the inhibitor components is in a range from
about 0.3 mg to about 3000 mg, more preferably in a range from
about 3 mg to about 300 mg and most preferably in a range from
about 6 mg to about 150 mg. The specific amounts used in the
compositions can be readily determined by one of ordinary skill in
the art of pharmaceutical formulations.
[0031] The goal of the instant invention is an OTC pharmaceutical
composition of a sympathomimetic amine which is not usable in
illicit drug preparation. The pharmaceutical composition of the
present invention comprises amounts of inhibitors sufficient to
interfere with both the isolation of the sympathomimetic amine and
the use of the sympathomimetic amine in chemical reactions without
compromising the release, bioavailability or dosing frequency
associated with the undenatured composition.
[0032] Combination Inhibitors
[0033] Combination inhibitors are components which interfere with
the use of compositions of sympathomimetic amines in the production
of other pharmacologically active compounds by both interfering
with the isolation of the sympathomimetic amine from the
composition and interfering with the conversion of the
sympathomimetic amine to other pharmacologically active compounds.
The presence of the combination inhibitor does not significantly
alter the release of the sympathomimetic amine from the composition
as compared to the undenatured composition.
[0034] In the instant invention a preferred combination inhibitor
may be an amino polymer or the corresponding neutralized salt form
of the amino polymer. The amino polymer, in both the amine and
neutralized salt forms, has a similar solubility profile to the
corresponding form of many sympathomimetic amines, making it very
difficult to separate the amine from a composition containing an
amino polymer. Additionally, the amino polymer inhibits the
chemical conversion of sympathomimetic amines to other
pharmacologically active compounds. The prior art teaches the use
of unneutralized amino polymers as coating agents for
sympathomimetic amines (or other pharmacologically active agents).
In such references the purpose of the uneutralized amino polymer in
the composition is to prevent the active ingredient (e.g., a
sympathetic amine) from dissolving in the mouth and creating an
undesirable taste. Thus, the unneutralized amino polymer is used in
a manner specifically intended to modify the release of the coated
active agent in water as compared to the uncoated active
ingredient. In the instant invention the use of the unneutralized
(and/or neutralized) amino polymer is specifically designed to have
no significant effect on the release of the active ingredient in
water as compared to the same formulation without the amino
polymer.
[0035] One example of an amino polymer contemplated in this
invention is a copolymer of methyl methacrylate, butyl methacrylate
and dimethylaminoethyl methacrylate, also known as aminoalkyl
methacrylate copolymer E, JP. A preferred copolymer of methyl
methacrylate, butyl methacrylate and dimethylaminoethyl
methacrylate is Eudragit-E.RTM. which is available from Rohm
America, Somerset, N.J. In the instant invention the amino polymer
can be from about 0% to about 100% in the neutralized salt form. In
a preferred embodiment the amino polymer is from about 50% to about
100% in the neutralized salt form. More preferably, the amino
polymer is from about 70% to about 100% in the neutralized salt
form and most preferably it is from about 85% to about 98% in the
neutralized salt form. The neutralized form of the amino polymer in
the instant invention can be a salt of a strong or a weak acid.
Examples of strong acids used in the preparation of a neutralized
amino polymer are hydrochloric, sulfuric, nitric and phosphoric
acids. Weak acids contemplated in the preparation of the
neutralized amino polymer include citric, ascorbic and acetic
acids. An example of a preferred form of a neutralized amino
polymer is the hydrochloric acid salt form of the amino polymer.
The hydrochloride salt of the amino polymer is prepared by
suspending the free base in distilled water and adding hydrochloric
acid. The suspension may be warmed and mixed until the solution is
complete. The resultant thick, viscous solution is then dried to
produce a clear, brittle film. The film is milled to produce a
powder suitable for incorporation into a tablet powder blend.
[0036] In one preferred embodiment of the instant invention the
amino polymer is the neutralized hydrochloride salt form of the
copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate. The copolymer of methyl
methacrylate, butyl methacrylate and dimethylaminoethyl
methacrylate can be from about 0% to about 100% in the neutralized
hydrochloride salt form. In a preferred embodiment the copolymer of
methyl methacrylate, butyl methacrylate, and dimethylaminoethyl
methacrylate is from about 50% to about 100% in the neutralized
hydrochloride salt form. More preferably, the copolymer of methyl
methacrylate, butyl methacrylate and dimethylaminoethyl
methacrylate is from about 70% to about 100% in the neutralized
hydrochloride salt form and most preferably it is from about 85% to
about 98% in the neutralized hydrochloride salt form. As an
example, in an immediate release product the amino polymers and the
corresponding acid salts of the amino polymers can be used in
amounts (milligrams, mg) per unit dose from about 10 to about 100
mg, more preferably from about 20 to about 50 mg and even more
preferably from about 30 to about 40 mg.
[0037] In one embodiment of the instant invention it is
contemplated that the amino polymer is homogeneously mixed together
with the sympathomimetic amine and any other components necessary
to prepare the final composition. In a preferred embodiment the
sympathomimetic amine is first coated with the amino polymer prior
to combining these two components with any additional components
required in the formulation.
[0038] In another embodiment of the instant invention, the
combination inhibitor may be one or more transition metal salts.
Preferably, the transition metal of the transition metal salt is
chosen from the group consisting of iron, copper, zinc, cobalt,
chromium, manganese and nickel. In a more preferred embodiment of
the instant invention the transition metal is selected from the
group consisting of iron, copper and zinc and the anion of the
transition metal salt is selected from the group consisting of
oxide, chloride, sulfate and gluconate. An even more preferred
embodiment of the instant invention utilizes ferrous gluconate as
the transition metal salt. As an example, in an immediate release
product the transition metal salts can be used in amounts
(milligrams, mg) per unit dose from about 0.1 mg to about 25 mg,
more preferably 0.25 mg to about 15 mg and most preferably from
about 0.5 mg to about 10 mg. The most preferred embodiment of a
combination inhibitor in the instant invention encompasses a
formulation comprising an acid salt of an amino polymer, an iron
salt, a copper salt and a zinc salt. The most preferred embodiment
of the instant invention comprises at least one combination
inhibitor, at least one reaction inhibitor and at least one
separation inhibitor.
[0039] Reaction Inhibitors
[0040] A preferred embodiment of the instant invention is a
pharmaceutical composition comprising an acid salt of a
sympathomimetic amine, at least one combination inhibitor and at
least one reaction inhibitor. The combination inhibitor is present
in amounts sufficient to interfere with both the isolation of the
amine and the conversion of the amine to another pharmacologically
active compound; the reaction inhibitor is present in amounts
sufficient to interfere with the conversion of the amine to another
pharmacologically active compound. The presence of the combination
and reaction inhibitors does not significantly alter the release of
the sympathomimetic amine from the composition as compared to the
undenatured composition.
[0041] Reaction inhibitors useful in the instant invention include
the following classes of agents of which examples of preferred
compounds are listed: (1) water insoluble polyhydroxy compounds
such as cellulose, ethylcellulose and microcrystalline cellulose;
(2) non-polymeric (three or fewer repeating units) water soluble
polyhydroxy compounds such as glycerin, sucrose, lactose, fructose,
sorbitol, lactitol, maltose, other mono- and disaccharides and
other sugar alcohols; and, (3) solvent soluble esters such as
glycerin esters, esters of glycerin polymers, sorbitol esters,
propylene glycol esters, polyethylene glycol esters, sucrose esters
and esters of ethoxylated fatty acids.
[0042] The compositions according to this invention can include a
single reaction inhibitor that is soluble in water, methanol,
chloroform and/or other organic solvents; alternatively, the
reaction inhibitor can be a mixture consisting of a group of
reaction inhibitors that individually are soluble in one or more
solvents but have a combined solubility profile such that they
cover a range of aqueous and organic solubilities. The use of such
a reaction inhibitor mixture provides a high likelihood that at
least one reaction inhibitor remains with the sympathomimetic amine
to interfere with subsequent chemical reactions if a separation
step is successful. An example of a reaction inhibitor mixture that
has combined solubility in water, methanol and chloroform could
contain lactose and ethylcellulose. In one embodiment of the
instant invention, at least one combination inhibitor and one
reaction inhibitor are utilized.
[0043] Separation Inhibitors
[0044] One embodiment of the instant invention is a pharmaceutical
composition comprising an acid salt of a sympathomimetic amine, at
least one combination inhibitor and at least one separation
inhibitor. In a more preferred embodiment at least one reaction
inhibitor is included in the formulation. Separation inhibitors
useful in the instant invention include the following classes of
agents of which examples of the preferred compounds are listed: (1)
water soluble celluloses such as hydroxypropyl cellulose,
methylcellulose and hydroxyethycellulose; (2) polysaccharide gums
such as guar and xanthan; (3) polyethylene oxide polymers such as
polyethylene oxide, poly(oxypropylene)-poly(oxyethylene) block
polymers and polyethylene glycols; (4) acrylic acid polymers such
as carbomers; (5) starches such as pre-gellatinized starch, corn
starch and potato starch; (6) magnesium aluminum silicates such as
Veegum; (7) polyvinylpyrrolidones; and (8) clays such as Kaolin and
Bentonite. As an example, in an immediate release product
separation inhibitors may be used in amounts (milligrams, mg) per
unit dose from about 0.1 mg to about 100 mg, more preferably from
about 0.5 mg to about 75 mg and most preferably from about 1 mg to
about 50 mg. The most preferred embodiment of a separation
inhibitor in the instant invention comprises a separation inhibitor
mixture comprising hydroxypropyl cellulose, hydroxyethylcellulose,
hydroxypropyl methylcellulose, polyethylene oxide and
poly(oxypropylene)-poly(oxyethylene) block polymer.
[0045] Pharmaceutical Forms of the Invention
[0046] The compositions of the instant invention may take a wide
variety of forms depending upon the desired route of
administration. For example, the compositions according to this
invention may take the form of tablets, capsules, granules,
powders, lozenges, or liquid preparations such as solutions and
suspensions. Also, pharmaceutical compositions of the instant
invention may be sustained release products in all the
above-mentioned forms. Any combinations, compositions or products
described herein are used for known indications treated by
sympathomimetic amines.
[0047] The compositions of the instant invention may optionally be
formulated with conventional carriers or excipients using well
established techniques. Without being limited thereto, such
conventional carriers or excipients include diluents, binders and
adhesives (e.g., cellulose derivatives and acrylic derivatives),
lubricants (e.g., magnesium stearate, calcium stearate, vegetable
oils, polyethylene glycols, talc, sodium lauryl sulfate, polyoxyl
ethylene monostearate), disintegrants, colorants, flavorings,
preservatives, sweeteners and miscellaneous materials such as
buffers and adsorbents. The compositions of the present invention
in tablet form may be coated, the coating which may include one or
more of the inhibitors contemplated in the instant invention. For
example, Eudragit-E.RTM., ethylcellulose, hydroxypropyl cellulose
and hydroxyethyl cellulose all have been used in amounts effective
to form a film coating on tablets. The purposes of these film
coatings are to minimize oxidation of the tablet, prevent the user
from tasting the drug, facilitate the use of high-speed packaging
equipment or provide "selective release" of the active ingredient.
Selective release means to prevent dissolution of the active in one
part of the gastrointestinal system so that the active ingredient
can be released in the desired portion of the gastrointestinal
system. Also, selective release formulations may prevent release of
the active ingredient in the mouth, thus masking the taste of the
active ingredient. Selective release formulations are to be
contrasted with "extended release" formulations which release the
active over time to provide a prolonged efficacy, thereby reducing
the number of dosages needed. The amount of film forming ingredient
required to achieve the purposes of coating is from about 0.5% to
about 10%. The film forming use of these components is
distinguished from the use of these same components in the instant
invention in that the amounts, purposes and tablet portion of the
components are distinct. Additionally, a sugar coating on the
tablet is contemplated in the instant invention.
[0048] The compositions of the instant invention may be in the form
of non-aqueous formulations which can be obtained by dispersing the
sympathomimetic amine and inhibitors in a suitable non-aqueous
based vehicle or in non-aqueous solutions such as those used in
soft gelatin capsule formulations. Non-aqueous vehicles appropriate
for these formulations include, for example, almond oil, arachis
oil, soybean oil or fractionated vegetable oils such as
fractionated coconut oil. These non-aqueous formulations may
optionally include suitable viscosity enhancing agent(s) (e.g.,
hydrogenated edible fats, aluminum stearate) and preservative(s)
(e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, sodium
benzoate, or sorbic acid). Solvents used in non-aqueous solutions
can include glycols, polyols and glycerin.
[0049] A large collection of additional active ingredients may
optionally be present in the sympathomimetic amine and inhibitor
composition of the instant invention. The suitable categories of
optional active ingredients that may be employed varies widely; the
individual compounds within a category may include their acid
addition salts. Illustrative categories and specific examples of
these optional active ingredients include but are not limited to:
(a) antitussives such as dextromethorphan, dextromethorphan
hydrobromide, noscapine, carbetapentane citrate, and chlophedianol
hydrochloride; (b) antihistamines such as chlorpheniramine maleate,
phenindamine tartrate, pyrilamine maleate, brompheniramine maleate,
dexchlorpheniramine maleate, dexbromphenitamine maleate,
doxylamione succinate, phenyltoloxamine citrate, diphenhydramine
hydrochloride, promethazine and triprolidine hydrochloride; (c)
antiasthmatic drugs such as alpha2-adrenergics (e.g., salbutamol
[albuterol], terbutaline, carbuterol, broxaterol, aminophylline and
theophylline; (d) analgesics such as acetaminophen; (e)
non-steroidal anti-inflammatory drugs (NSAIDs) such as
acetylsalicylic acid, indomethacin, acemethacin, sulindac,
piroxicam, ibuprofen, naproxen, ketoprofen; and (f) expectorants
such as glyceryl guaiacolate and carbocysteine.
EXAMPLES
[0050] The present invention is directed to compositions comprising
an acid salt of a sympathomimetic amine and at least one
combination inhibitor. The compositions may also include reaction
and separation inhibitors in any mixture to assure maximum
protection against the use of the sympathomimetic amine-containing
compositions for illegal drug manufacture.
[0051] Compositions of the Instant Invention: Examples A-H
[0052] The following non-limiting examples are for core tablets of
pseudoephedrine-containing compositions. All of the ingredients are
in mg per tablet. All of the tablets can be uncoated or coated
using ingredients and processes known to those skilled in the
art.
Example A
[0053] A. Combine 30 mg pseudoephedrine HCl USP/EP, 5 mg poloxamer
407 NF, 5 mg glyceryl monostearate NF, 3 mg polyethylene oxide
N-60K NF, 5 mg hydroxypropyl cellulose NF and 30 mg ethylcellulose
NF and mix well. This mixture is then thermally extruded to produce
a granulation.
[0054] B. Add 30 mg of aminoalkyl methacrylate copolymer E, JP with
99 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0055] C. Delump 2 mg of silicon dioxide NF/EP, 30 mg lactose NF,
30 mg fructose NF and 5 mg crospovidone NF.
[0056] D. Combine the material produced from step B with the
granulation of step A and size through an appropriate mill.
[0057] E. Add the delumped material to the sized material and blend
until uniform.
[0058] F. Sift 2.5 mg stearic acid NF and 0.5 mg magnesium stearate
NF into the blend produced in step E.
[0059] G. Compress the resultant blend on a standard press to the
desired weight and thickness.
Example B
[0060] A. Combine 60 mg pseudoephedrine HCl USP/EP, 10 mg poloxamer
407 NF, 10 mg glyceryl monostearate NF, 6 mg polyethylene oxide
N-60K NF, 10 mg hydroxypropyl cellulose NF and 60 mg ethylcellulose
NF and mix well. This mixture is then thermally extruded to produce
a granulation.
[0061] B. Add 60 mg of aminoalkyl methacrylate copolymer E, JP with
100 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0062] C. Delump 4 mg of silicon dioxide NF/EP, 60 mg lactose NF,
60 mg fructose NF, 4 mg ferrous sulfate USP 0.5 mg cobalt chloride,
2.5 mg crospovidone NF, 1 mg hydroxyethylcellulose NF, 1 mg
hydroxypropyl methylcellulose USP, 1 mg sodium
carboxymethylcellulose USP, 1 mg xanthan gum NF, 2 mg
microcrystalline cellulose NF, 1 mg carrageenan NF, 1 mg guar gum
NF, 1 mg sodium alginate NF, 1 mg Carbomer NF, 1 mg tragacanth gum
NF, 1 mg acacia gum NF and 1 mg methylcellulose USP.
[0063] D. Combine the material produced from step B with the
granulation of step A and size through an appropriate mill.
[0064] E. Add the delumped material to the sized material and blend
until uniform.
[0065] F. Sift 2.5 mg stearic acid NF and 1 mg magnesium stearate
NF into the blend produced in step E.
[0066] G. Compress the resultant blend on a standard press to the
desired weight and thickness.
Example C
[0067] A. Combine 30 mg pseudoephedrine HCl USP/EP, 5 mg poloxamer
407 NF, 5 mg glyceryl monostearate NF, 3 mg polyethylene oxide
N-60K NF, 5 mg hydroxypropyl cellulose NF and 5 mg ethylcellulose
NF and mix well. This mixture is then thermally extruded to produce
a granulation.
[0068] B. Add 5 mg of aminoalkyl methacrylate copolymer E, JP with
15 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0069] C. Delump 2 mg of silicon dioxide NF/EP, 20 mg lactose NF,
30 mg fructose NF, 1 mg copper sulfate, 1 mg zinc gluconate, 5 mg
crospovidone NF, 5 mg hydroxyethylcellulose NF and 5 mg
microcrystalline cellulose NF.
[0070] D. Combine the material produced from step B with the
granulation of step A and size through an appropriate mill.
[0071] E. Add the delumped material to the sized material and blend
until uniform.
[0072] F. Sift 3.5 mg stearic acid NF and 0.5 mg magnesium stearate
NF into the blend produced in step E.
[0073] G. Compress the resultant blend on a standard press to the
desired weight and thickness.
Example D
[0074] A. Combine 30 mg pseudoephedrine HCl USP/EP, 20 mg
ethylcellulose NF, 20 mg fructose USP and 5 mg crospovidone NF and
mix well.
[0075] B. Dissolve 5 mg hydroxypropyl cellulose NF in water and
granulate with the materials in step A. Dry this granulation.
[0076] C. Add 50 mg of aminoalkyl methacrylate copolymer E, JP with
100 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0077] D. Delump 2 mg of silicon dioxide NF/EP, 1 mg chromium
chloride, 0.5 mg nickelous sulfate, 5 mg poloxamer 407 NF, 3 mg
polyethylene oxide N-60K NF, and 5 mg hydroxyethylcellulose NF.
[0078] E. Combine the materials produced from steps C and D and
size through an appropriate mill.
[0079] F. Add the delumped material to the sized material and blend
until uniform.
[0080] G. Sift 3.5 mg stearic acid NF and 0.5 mg magnesium stearate
NF into the blend produced in step F.
[0081] H. Compress the resultant blend on a standard press to the
desired weight and thickness.
Example E
[0082] A. Mix 20 mg ethylcellulose NF, 10 mg crospovidone NF and 30
mg fructose USP.
[0083] B. Mill 60 mg pseudoephedrine HCl USP/EP and 10 mg poloxamer
407 NF. Then mill together with the mixture from step A.
[0084] C. Add 40 mg of aminoalkyl methacrylate copolymer E, JP with
106 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0085] D. Delump 4 mg of silicon dioxide NF/EP, 20 mg lactose NF, 5
mg glyceryl monostearate NF, 4 mg ferric chloride USP, 0.5 mg
nickelous sulfate, 1 mg zinc sulfate, 6 mg polyethylene oxide N-60K
NF, 10 mg hydroxyethylcellulose NF, 10 mg hydroxypropyl cellulose
NF, 1 mg hydroxypropyl methylcellulose USP, 1 mg sodium
carboxymethylcellulose USP, 1 mg xanthan gum NF, 1 mg
microcrystalline cellulose NF, 1 mg carrageenan NF, 1 mg guar gum
NF, 1 mg sodium alginate NF, 1 mg Carbomer NF, 1 mg tragacanth gum
NF, 1 mg acacia gum NF and 1 mg methylcellulose USP.
[0086] E. Combine the materials produced from steps C and D and
size through an appropriate mill.
[0087] F. Add the delumped material to the sized material and blend
until uniform.
[0088] G. Sift 7 mg stearic acid NF and 1 mg magnesium stearate NF
into the blend produced in step F and mix well.
[0089] H. Compress the resultant blend on a standard press to the
desired weight and thickness.
Example F
[0090] A. Mix 20 mg ethylcellulose NF, 10 mg crospovidone NF and 40
mg fructose USP.
[0091] B. Mill 60 mg pseudoephedrine HCl USP/EP and 10 mg poloxamer
407 NF. Then mill together with the mixture from step A.
[0092] C. Add 40 mg of aminoalkyl methacrylate copolymer E, JP with
119 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0093] D. Delump 4 mg of silicon dioxide NF/EP, 2 mg ferrous
gluconate, 1 mg copper gluconate, 1 mg zinc gluconate, 6 mg
polyethylene oxide N-60K NF, 10 mg hydroxyethylcellulose NF, 4 mg
microcrystalline cellulose and 10 mg hydroxypropyl cellulose
NF.
[0094] E. Combine the materials produced from steps C and D and
size through an appropriate mill.
[0095] F. Add the delumped material to the sized material and blend
until uniform.
[0096] G. Sift 7 mg stearic acid NF and 1 mg magnesium stearate NF
into the blend produced in step F and mix well.
[0097] H. Compress the resultant blend on a standard press to the
desired weight and thickness.
Example G
[0098] A. Mix 30 mg pseudoephedrine HCl USP/EP, 5 mg poloxamer 407
NF, 10 mg ethylcellulose NF, 20 mg fructose USP and 10 mg xanthan
gum.
[0099] B. Add 20 mg of aminoalkyl methacrylate copolymer E, JP with
50 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0100] C. Combine the mixtures produced in steps A and B, mix well
and size through an appropriate mill.
[0101] D. Delump 2 mg of silicon dioxide NF/EP, 2 mg manganese
sulfate, 2 mg zinc oxide, 3 mg polyethylene oxide N-60K NF, 5 mg
hydroxyethylcellulose NF, 1 mg hydroxypropyl methylcellulose USP, 1
mg sodium carboxymethylcellulose USP, 1 mg carrageenan NF, 1 mg
guar gum NF, 1 mg Carbomer NF, 1 mg acacia gum NF, 5 mg
hydroxypropyl cellulose NF and 5 mg crospovidone.
[0102] E. Combine the materials produced from steps C and D and
size through an appropriate mill.
[0103] F. Add the delumped material to the sized material and blend
until uniform.
[0104] G. Sift 3.5 mg stearic acid NF and .5 mg magnesium stearate
NF into the blend produced in step F and mix well.
[0105] H. Compress the resultant blend on a standard press to the
desired weight and thickness.
Example H
[0106] A. Mix 60 mg pseudoephedrine HCl USP/EP, 10 mg poloxamer 407
NF, 15 mg ethylcellulose NF, 45 mg fructose USP and 1 mg xanthan
gum.
[0107] B. Add 45 mg of aminoalkyl methacrylate copolymer E, JP with
100 mg of hydrochloric acid, Normal USP. Mix these ingredients and
dry.
[0108] C. Combine the mixtures produced in steps A and B, mix well
and size through an appropriate mill.
[0109] D. Delump 3 mg of silicon dioxide NF/EP, 2 mg copper
sulfate, 4 mg polyethylene oxide N-60K NF, 5 mg
hydroxyethylcellulose NF, 5 mg hydroxypropyl methylcellulose USP, 2
mg sodium carboxymethylcellulose USP, 2.5 glyceryl monostearate NF,
10 mg hydroxypropyl cellulose NF, 15 mg lactose NF, 3 mg ferrous
sulfate USP, 7.5 mg crospovidone NF, 5 mg microcrystalline
cellulose NF, 5 mg Carbomer NF and 5 mg methylcellulose USP.
[0110] E. Combine the materials produced from steps C and D and
size through an appropriate mill.
[0111] F. Add the delumped material to the sized material and blend
until uniform.
[0112] G. Sift 5 mg stearic acid NF and 1 mg magnesium stearate NF
into the blend produced in step F and mix well.
[0113] H. Compress the resultant blend on a standard press to the
desired weight and thickness.
[0114] Dissolution Tests
[0115] Several of the ingredients used in the present invention as
inhibitors previously have been used in pharmaceutical compositions
as controlled release agents. For example, polyethylene oxide,
hydroxyethyl cellulose and hydroxypropyl cellulose have been used
in tablets to provide a controlled or extended release of the
active. In contrast, the present invention uses such ingredients in
immediate release compositions as inhibitors of the use of the
composition in the illegal production of pharmacologically active
agents. Tables 1 and 2 show two examples within the scope of the
present invention which release, on average, 88.5% to 91.7% of the
pseudoephedrine within 45 minutes.
1 TABLE 1 5 MIN 15 MIN 30 MIN 45 MIN Vessel mg/tab % Release mg/tab
% Release mg/tab % Release mg/tab % Release 1 1.5 5.0 9.8 32.7 20.9
70.1 27.2 91.9 2 1.5 5.0 11.6 38.7 25.9 86.8 26.3 89.1 3 1.9 6.3
11.2 37.4 24.8 83.2 28.9 97.8 4 1.6 5.3 11.4 38.1 26.9 90.2 27.4
92.8 5 2.0 6.7 12.1 40.4 24.8 83.2 25.7 87.1 6 2.2 7.3 13.5 45.1
26.5 88.9 26.9 91.3 Average 5.9 38.7 83.7 91.7
[0116]
2 TABLE 2 5 MIN 15 MIN 30 MIN 45 MIN Vessel mg/tab % Release mg/tab
% Release mg/tab % Release mg/tab % Release 1 0.0 0.0 9.5 31.7 20.0
67.0 25.0 84.4 2 0.0 0.0 7.7 25.7 15.8 53.0 25.5 85.9 3 0.0 0.0 5.6
18.7 14.4 48.2 27.1 91.1 4 0.0 0.0 8.8 29.3 20.0 67.0 25.8 87.1 5
1.6 5.3 12.4 41.4 23.0 77.2 27.3 92.4 6 0.0 0.0 10.4 34.7 22.4 75.1
26.6 89.9 Average 0.9 30.2 64.6 88.5
[0117] While the invention has been described in detail and with
reference to specific examples thereof, it will be apparent to one
skilled in the art that various changes and modifications can be
made therein without departing from the spirit and scope
thereof.
[0118] Extraction Tests
[0119] A formulation within the scope of the instant invention
containing pseudoephedrine hydrochloride, poloxamer, aminoalkyl
methacrylate copolymer E, JP, hydrochloric acid, polyethylene
oxide, hydroxypropyl cellulose, ethylcellulose, hydroxyethyl
cellulose, silicon dioxide, cellulose, fructose, ferrous chloride,
crospovidone, stearic acid and magnesium stearate was processed and
compressed into tablets. The tablets were film coated using a
commercially available film coating solution containing
hydroxypropyl methylcellulose.
[0120] The finished tablets were ground to a fine powder and this
powder was added to a particular solvent. The pseudoephedrine
hydrochloride was solubilized in the solvent and subsequently
recovered by evaporation of the solvent. The resultant extract was
subjected to two techniques used in the clandestine production of
methamphetamine from pseudoephedrine hydrochloride. Table 3
illustrates the amount of methamphetamine recovered from the
tablets following the particular extraction and conversion
methodologies.
3 TABLE 3 Reaction Methamphetamine Solvent Technique Yield (%)
Methanol Hydriodic Acid + 0.7 Red Phosphorous Lithium + <0.1
Anhydrous Ammonia Chloroform Hydriodic Acid + 0.2 Red Phosphorous
Lithium + 0.1 Anhydrous Ammonia Hot Water Hydriodic Acid + 0.1 Red
Phosphorous Lithium + <0.1 Anhydrous Ammonia
* * * * *