Title: Nicotine delivery compositions
United States Patent: 6,479,076
Issued: November 12, 2002
Inventors: Blank; Izhak (4 Simtat Arnon, Kiriat Ono 55000,
Appl. No.: 760203
Filed: January 12, 2001
A composition containing nicotine and an uncrosslinked, water-insoluble
vinylpyrrolidone copolymer is applied on the skin of patients in the form of
a gel, ointment, solution, suspension or film which slowly releases nicotine
and creates levels of the drug in the blood to reduce nicotine-craving in
smokers, thereby assisting in smoking-cessation programs.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, it has now been found that important
advantages and improvements over prior art compositions and pharmaceutical
presentation forms containing nicotine and methods of topical application
thereof can be obtained by admixture with an uncrosslinked,
water-insoluble vinylpyrrolidone copolymer.
Water-insoluble copolymers of vinylpyrrolidone, which can be used in the
practice of this invention, may be prepared by the copolymerization of
vinylpyrrolidone with one or more appropriate comonomers in the
proportions which yield water-insoluble, uncrosslinked copolymers.
Suitable comonomers include acrylic esters, methacrylic esters, vinyl
esters, crotonic esters, vinyl ethers, maleic half esters and diesters,
vinylene carbonate, styrene, allyl esters, allyl ethers, etc. Other
comonomers which are capable of copolymerizing with vinylpyrrolidone and
are well known to those skilled in the art may also be used. Toxicological
considerations restrict the choice of monomers to those which yield
copolymers having a demonstrated lack of toxicological side-effects on
topical application to the skin, good drug compatibility, good adhesion to
the skin and film-forming properties.
The acrylic, methacrylic, crotonic and maleic esters which may be used in
the preparation of the water-insoluble vinylpyrrolidone copolymers which
are effective in the practice of the present invention, include the esters
of C1 -C40 linear, branched or cyclic alkanols, aralkanols,
phenols and substituted phenols. The co-polymers of vinylpyrrolidone and
the acrylic, methacrylic, crotonic and maleic esters may be made by
copolymerization of vinylpyrrolidone with the appropriate ester or by
esterification of copolymers of vinyl.about. pyrrolidone and acrylic,
methacrylic, crotonic and maleic acid or anhydrides, with the appropriate
hydroxylcontaining compound.about. Unesterified carboxylic acid
functionality may be retained in the copolymer.
The vinyl esters and allyl esters which may be used in the preparation of
the water-insoluble vinylpyrrolidone copolymers which are useful in the
practice of this invention, include the esters of C1 -C40
linear, branched or cyclic aliphatic, araliphatic or aromatic carboxylic
acids. The copolymers of vinylpyrrolidone and the vinyl esters may be
prepared by copolymerization of vinylpyrrolidone with the appropriate
vinyl ester or by transesterification of copolymers of vinylpyrrolidone
and vinyl acetate or other vinyl esters or by esterification of hydrolyzed
copolymers of vinylpyrrolidone and vinyl acetate or other vinyl esters.
The copolymers of vinylpyrrolidone and allyl esters may also be prepared
either by direct copolymerization or by transesterification or
esterification, analogous to the preparation of vinyl ester copolymers
Graft copolymers made by grafting vinyl monomers onto polyvinylpyrrolidone
may also be used, e.g. graft copolymers of polyvinylpyrrolidone with
acrylic esters, methacrylic esters, styrene, vinyl acetate and the like.
The water-insoluble copolymers of vinylpyrrolidone which be used in the
practice of the present invention, may be prepared by any of the
conventional methods known in the art, including bulk, solution, emulsion,
suspension or dispersion polymerization, with appropriate free radical
catalysts such as peroxygen compounds, azo compounds, redox systems,
radiation and other catalytic techniques for initiating free radical
polymerization. Since the method of polymerization is not an integral part
of the practice of the present invention, any suitable method known to
those skilled in the art may be used.
The amount of one or more comonomers in the water-insoluble
vinylpyrrolidone copolymers which are useful in the practice of the
present invention may be varied from 20% to 80% by weight. The actual
amount is determined by the nature of the comonomer and the concentration
necessary to produce a water-insoluble copolymer.
The drug used in the practice of the present invention may be nicotine or
its salts and also cotinine. The preferred drug is nicotine.
The compositions described in this application are particularly effective
as aids in smoking-cessation programs. They can also be potentially useful
in the treatment of attention deficit hyperactive disorder, Tourette's
syndrome, schizophrenia, anxiety and depression.
The nicotine compositions which are useful in the practice of the present
invention and provide sustained release of the drug, may be prepared by
dissolving or dispersing the water-insoluble vinylpyrrolidone copolymer in
a solvent such as ethanol, isopropanol, vegetable oils and petrolatum and
admixing the polymer solution or dispersion with nicotine.
The solution, or dispersion, of the uncrosslinked water-insoluble
vinylpyrrolidone copolymer and nicotine, in the presence or absence of an
excipient, may be cast on a suitable surface and the solvent evaporated
under ambient pressure or in vacuo, at ambient or slightly elevated
temperature. The resultant film on the substrate surface or after removal
from the substrate, contains nicotine and may be cut into strips or tapes
which can be affixed to the skin of a patient for sustained release of the
The solution or dispersion of uncrosslinked, water-insoluble
vinylpyrrolidone copolymer and nicotine may be applied directly to the
skin of the patient and permitted to evaporate to form a film thereon,
containing nicotine. The latter is slowly released from the film and
absorbed into the skin of the patient.
A gel or thickened solution of nicotine and water-insoluble
vinylpyrrolidone copolymer may be applied with greater control to a
restricted area of skin than a low viscosity solution. The solution may be
thickened by the addition of a small amount of a soluble high molecular
weight natural or synthetic thickener or a cellulose derivative thickener
of the type well known to those skilled in the art.
High surface area inorganic materials such as finely divided fumed silica
are also effective thickeners. The addition of a small amount of such a
material results in a marked increase in the viscosity of the solution.
The resultant gel or thickened solution is thixotropic and flows readily
during application but does not run after application to the skin. The
large surface area of the silica thickener increases the rate of
evaporation of the solvent and contributes to rapid drying and film
formation. Nicotine in the formulation is slowly released and absorbed
into the skin of the patient. At the end of the treatment time, the film
may be removed by washing with soap and water.
The gel or thickened solution may be applied to the skin in a pre-measured
amount from a tube, a roll-on dispenser, a graduated spatula or via a
The solution of nicotine and water-insoluble vinylpyrrolidone copolymer in
ethanol may be pressurized in an aerosol can and nicotine may be
conveniently applied to the skin using an aerosol formulation containing
one or more low boiling propellants.
In order to control the amount of polymer and nicotine applied to the
skin, it is advantageous to use a metering valve which delivers precise
quantities of solution. When applied in this manner, the propellant and
solvent quickly evaporate leaving a dry film of controlled nicotine
content covering the desired area of skin.
A solution or dispersion of uncrosslinked, water-insoluble
vinylpyrrolidone copolymer and nicotine, in the absence or presence of an
excipient, may be applied to a porous or open-structured substrate such as
gauze, bandage tissue or paper, and upon evaporation of the solvent,
provides an impregnated structure containing nicotine, which is released
over an extended period of time when applied topically to the skin of a
The solution or dispersion of water-insoluble vinylpyrrolidone copolymer
and nicotine may be mixed, with stirring, with one or more ointment bases,
such as petrolatum, vasoline, lanolin, stearin, spermaceti wax or other
waxy or fatty material. The ointment may be applied directly to the skin
of a patient or may be coated on a carrier such as a bandage or polymeric
tape for topical application to the skin of a patient. The nicotine is
slowly released and absorbed into the skin of the patient over an extended
period of time. Although the vinylpyrrolidone copolymer is
water-insoluble, the hydrophilicity of the vinylpyrrolidone units
contained therein results in moisture absorption, e.g. from perspiration
on the skin of the patient, and facilitates release of the nicotine from
the composition into the skin. The rate of release may be varied over a
wide range and is dependent upon the percentage of vinylpyrrolidone in the
copolymer and the ratio between the copolymer and nicotine.
The concentration of water-insoluble vinylpyrrolidone copolymer and
nicotine in the compositions of the present invention, may be varied over
a wide range, depending upon the desired release rate. The nicotine
concentration may range from about 0.1% to about 10% of the total weight
of the composition, while the concentration of the water-insoluble
vinylpyrrolidone copolymer may range from about 3 to about 20% of the
weight of the formulation.
Claim 1 of 21 Claims
What is claimed is:
1. A composition for the sustained transdermal delivery of nicotine,
comprising a gel, ointment, solution, suspension or film, containing a
mixture of nicotine and an uncrosslinked, water-insoluble vinypyrrolidone
copolymer containing at least 20% vinylpyrrolidone and an hydrophobic
comonomer which is copolymerizable therewith, wherein the nicotine
concentration is within the range of 0.1 to about 10% of the total weight
of the composition.
If you want to learn more
about this patent, please go directly to the U.S.
Patent and Trademark Office Web site to access the full