Note: Descriptions are shown in the official language in which they were submitted.
CA 02336712 2001-01-05
The invention relates to a preparation containing at least
one active substance which has an influence on the levels of
lipids in the blood of an organism.
This active substance is a member of a group of active
substances which intervene in the lipid metabolism of the
organism and which are used for treating diseases related
thereto.
Said substances are preferably inhibitors of hydroxymethyl-
glutaryl-CoA reductase (HIMG-CoA reductase).
Systemic lipid metabolism disturbances, especially so-called
hyperlipoproteinemias, are of great significance in the
pathogenesis of arteriosclerotic vascular diseases and of
their consequences, such as cardiac infarction, apoplectic
insultus and occlusive arterial diseases. In the USA and
Europe about 15 percent of adults have an increased risk of
suffering cardiovascular incidents because of increased lipid
levels in the blood. A sensible starting point for
prophylaxis, therapy and the treatment of consequences
consists in lowering increased plasma lipid levels.
Basis for any treatment of hyperlipoproteinemia is an
appropriate diet. A normalization of weight, appropriate diet
composition, a proportion of fat <30% of the total number of
calories, a sufficient dietary fibre intake, and a reduced
cholesterol intake, especially <300 mg per.day, must be
ensured. Furthermore it is advisable to increase the intake
of unsaturated - above all monounsaturated - fatty acids,
since these improve the metabolisation of lipoproteins.
If by dietary measures alone it is not possible to achieve a
sufficient normalisation of the lipid blood level and if this
means a higher risk of atherosclerosis, lipid-lowering
medicaments are indicated in addition. By treatment with
CA 02336712 2001-01-05
2
lipid-lowering medicaments a marked reduction of these
diseases can be achieved. Current studies, e.g. LCAS -
Lipoprotein and Coronary Arterosclerosis Study; LIPID - Long-
term Intervention with Pravastatin in Ischemic Disease; CARE
- The Cholesterol and Recurrent Events Trial, were able to
show that drug therapy for prevention of arteriosclerotic
vascular diseases is effective even where the lipid blood
levels prior to treatment are only slightly increased or even
within the normal range.
Long-term success of bypass operations is often restricted by
atherosclerosis in the bypasses. The progression of athero-
sclerosis can be reduced by consistent lowering of the blood
LDL level. It was possible to show that post-operative
treatment with lovastatin keeps bypasses open longer and
thereby leads to an improved prognosis of bypass operations.
Lipid-lowering medicaatents can be classified into substances
lowering the triglyceride as well as the cholesterol blood
levels, and substances which first of all lower the
cholesterol blood level. Among the substances belonging to
the first substance group are, for example, aryloxyalcane
carboxylic acids, e.g. clofibrate, etofibrate, etofylline
clofibrate, bezafibrate, fenofibrate, gemfibrozil, nicotinic
acid, nicotinyl alcohol and acipimox. Examples for substances
influencing mainly the cholesterol blood level are: anion
exchange resins such as colestyramine or colestipol;
inhibitors of hydroxymethylglutaryl-CoA reductase, HIMG-CoA
reductase, inhibitors such as lovastatin, simvastatin,
mevastatin, pravastatin, fluvastatin, cerivastatin or
atorvastatin, probucol, dextrothyroxine and sitosterol.
These substances inhibit hydroxymethylglutaryl-CoA reductase
- an early stage of cholesterol synthesis. These inhibitors
are the most potent substances for treatment of
hypercholesterolemia.
CA 02336712 2001-01-05
3
Commercial administration forms are currently tablets and
capsules with a dosage of 5 to 40 mg. The active substances
are administered either in their active form, i.e. as the
sodium salt of the hydroxy acid (e.g. pravastatin) or as a
prodrug, i.e in their lactone form (e.g. lovastatin). After
oral treatment, however, only about 30% of the dose applied
are absorbed from the gastrointestinal tract. The active
substance portion absorbed is then subject to a considerable
first pass effect. Absolute bioavailability ranges from 10 to
30%. The average elimination half-time of the active
substance form lies within the range of 1- 2 hours;
exception: atorvastatin with 14 h.
Preparations containing HMG-CoA reductase inhibitors and
intended for topical application are prior art. Substances of
this class can be employed for the therapy of skin diseases.
Here, the HMG-CoA reductase inhibitors serve as anti-
psoriatics, for example as anti-aging agents for the skin, or
for the treatment of acne. The active compound here is
incorporated in a classical administration form such as gel,
ointment or cream. A non-therapeutic use consists in
employing the substance class described herein for raising
the percutaneous absorption rate of substances which can
normally only insufficiently be absorbed.
Descriptions of systems considering a transdermal application
of this class of substances are more scarce.
US 5,629,014 describes a system suitable, inter alia, for
controlled release of lovastatin to the skin or mucous
membranes. The system comprises a microcellular polyester or
polyether foam serving as active substance reservoir. Since
this foam is not adhesive itself, an additional means is
necessary for fixing the foam on the surface of application.
This foam-like system turns out to be relatively thick and
inflexible. Application by the patient is thus not very
CA 02336712 2007-01-05
4
practicable since the system, being exposed because of its
height, is prone to being removed unintentionally and does
not yield to movements of the body.
A transdermal application of lipid-lowering agents, indicated
as the overall group, is mentioned in DE 36 34 016 C2. This
system is characterized in that the component responsible for
adhesion is present separately from the non-adhesive active
substance reservoir.
Starting from the above-mentioned prior art, the invention
has the object of providing a preparation containing at least
one active substance which has an influence on the lipid
blood levels of an organism, by which preparation it is
possible to achieve a release of the therapeutically active
substance which takes place at a constantly low rate over
prolonged periods of time and which can be accurately dosed,
and which preparation, in particular, guarantees absolute
bioavaxlability of the substance while affording a user-
friendly mode of application, and with the said preparation
serving as active substance reservoir.
To achieve this object, it is proposed by the invention that
the said preparation be present in the form of a tranadermal
therapeutic patch (TTS) containing the active substance in a
self-adhesive matrix layer which on the side facing away
from the skin can be covered with an active substance-
impermeable backing layer.
The transdermal therapeutic application system according to
the invention ensures an extremely efficient drug therapy
wherein the release of the active substance remains virtually
constant over a long period and can be accurately controlled,
with the absolute bioavailability of the substance being
significantly increased.
2tSBr2lz.1
CA 02336712 2001-01-05
Further embodiments are provided according to the subclaims.
In particular, the self-adhesive mass is characterized in
that it contains at least one hydroxymethylglutaryl-CoA
reductase-inhibiting active substance, and that it contains
structural elements of a beta-hydroxycarboxylic acid (I) or a
tetrahydro-4-hydroxy-6-oxo-2H-pyrans (ii). The active
substance may be present in the form of its salt or in the
form of an ester.
Ho
HO 0
(I) HO (II)
OH
For the inventive patch a self-adhesive mass based on
polyacrylate, silicone, ethylene vinyl acetate, rubber,
rubber-like synthetic homo-, co- or block polymers, or of a
hot-melt adhesive or the like may be used.
Masses based on polyacrylate are characterized in that
acrylic acid and/or alkyl acrylic acid, especially
methacrylic acid or its derivatives, especially the alkyl
esters, are used for their production. Among the alkyl esters
of acrylic acid and/or methacrylic acid those are preferred
which have 1 to 18 carbon atoms in the alkyl residue,
especially methyl, ethyl, n-butyl, isobutyl, pentyl,
2-ethylbutyl, n-hexyl, heptyl, n-octyl, isooctyl,
2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl
acrylate or methacrylate. Apart from these, further
comonomers can participate in the structure of the
CA 02336712 2001-01-05
6
polymer/copolymer. Examples are acrylic and/or methacrylic
amide, hydroxyalkyl esters and polyalkylene glycol esters of
acrylic and/or methacrylic acid, nitrogen-containing monomers
of acrylic and/or methacrylic acid or the salts thereof,
ethylene, vinyl acetate, vinyl propionate, vinyl butyrate,
vinylpyrrolidone, vinyl chloride, vinyl toluene, acrylonitril
or styrene.
Masses based on silicone are characterized in that they have
a large free volume, a low gas transition temperature, high
flexibility and high gas permeability, are biocompatible,
have a low surface tension and good wettability, are
thermostable as well as chemically inert, and have good
tackiness, adhesion and cohesion. Typically, silicone-based
masses contain a polycondensate, comprising a low-viscous
polydimethyl siloxane and a silicate resin, characterized by
a three-dimensional network. To increase the so-called amine
resistance, it is possible for the terminal hydroxyl group of
the polydimethyl siloxane to be condensed with trimethyl
siloxane.
Examples for rubber-like synthetic homo-, co- or block
polymers which may be employed according to the invention are
polyisobutylene, polyisoprene, polystyrene, styrene-
butadiene-styrene copolymers, styrene-isoprene-styrene
copolymers, styrene-ethylene/propylene-styrene copolymers,
styrene-ethylene/butylene-styrene copolymers, polyvinyl
ethers, polyurethane, polybutadiene, styrene-butadiene
copolymers, styrene-isoprene copolymers or.styrene-isoprene-
butylene block copolymers.
Furthermore, a backing layer may be contained which is
connected with the self-adhesive mass. This backing layer may
be impermeable to the active substance and have occlusive
character. Any materials may be used which are employed in
common preparations. Examples for such materials are
CA 02336712 2001-01-05
7
cellulose acetate, ethyl cellulose, polyethylene tereph-
thalate, plasticized vinyl acetate-vinyl chloride copolymers,
nylon, ethylene-vinyl acetate copolymer, plasticized
polyvinyl chloride, polyurethane, polyvinylidene chloride,
polypropylene, polyethylene, polyamide or aluminium.
The composition may further comprise: tackifiers, penetration
enhancers, agents for alleviating skin irritations, metal
ions such as aluminium or titanium, and for increasing
cohesion: plasticizers, paraffins, cyclic hydrocarbons or
vegetable oils.
As agents increasing tack, colophony resins, polyterpene
resins, petroleum resins, coumarone-indene resins, terpene
phenol resins, hydrocarbon resins or liquid polybutene resins
may be used.
Examples for agents enhancing the penetration of the active
substance are: pyrrolidone derivatives, fatty acids, fatty
alcohols, fatty acid esters, fatty ethers, paraffin
derivatives, terpenes, ethylene glykol monoalkyl ethers,
polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers,
polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers,
propylene glycol fatty acid derivatives, glycerol fatty acid
esters, polysorbates, poloxamers, dialkyl sulfoxides, urea
and urea derivatives, glycerol, native oils, laurocaprames,
phospholipides, amides, amino acids, N,N-dimethyl formamide,
N-methyl formamide, acetonides, calcium thioglycolate,
propylene glycol, polyethylene glycol, alkyl sulfate, sodium
lauryl sulfate, tetrahydrofurfuryl alcohol, N,N-diethyl-m-
toluamide, anticholinergics, macrocyclic compounds or polar
solvents such as isosorbitol and panthenol.
The preparation according to the present invention may also
contain agents for alleviating skin irritations, such as
bisabolol, chamomile oil, allantoin, glycerol or dipanthenol
CA 02336712 2007-01-05
8
The invention will be explained in the following by means
of examples:
B}CAMPLE 1
626 g of a solution of a self-adhesive polymer based on
silicone (e.g. BIO PSATM X7-4301, 70k-wt. in n-heptane) and
48 g of 2-pyrrolidone (with 7.ovastatin) were mixed and,
with the aid of a doctor knife, applied as a film of 600 m
thi.cknes$ onto a fluoropolymerized polyester film (e.g.
scotchpack 1022). The moist film was dried for 30 minutes
at 50 C and subsequently laminated with a polyester film
(e.g. HoetaphanTh' RN 15). The weight per unit area of an
adhesive film prepared in this manner was about 300 g/m'.
From the laminate, TTSs of the desired size were punched
out by means of a suitable punch, and in vitro permeation
through isolated cow udder skin waa measured. The flow rate
was on average 0.3 g/cm'/h over a period of 72 hours.
EXAMPLE 2
459.2 g of a solution of a self-adhesive polymer based on
silicone (e.g. BIO PSATM X7-4301, 70*-wt. in n-heptane) and
6.6 g of ethyl oleate (with lovastatin) were mixed and,
with the aid of a doctor knife, applied as a film of 600 m
thickness onto a fluoropolymerized polyester film (e.g.
Scotchpa]ci 1022). The moist film was dried for 30 minutes
at so C and subsequently laminated with a polyester film
(e.g. HostaphaziTN RN 15) . The weight per unit area of an
adhesive film prepared in this manner was about 300 g/m~.
From the laminate, TTSs of the dssired size were punched
out by means of a suitable punch, and in vitro permeation
through isolated cow udder skin was measured. over a period
of 72 hours the incorporated active substance diffused
almost quantitatively through the cow udder skin,
23585276.1
CA 02336712 2007-08-13
9
EXAMPLE 3.
85.34 g of a self-adhesive, carboxyl group-containing
polyacrylate (e.g. Durotak 387-2052, 48.1%-wt. in a mixture
of ethyl.acetate-, n-heptane, 2-propanol and ethanol),
85.34 g of a hydrophile acrylate adhesive mixture (e.g.
PlastoidTM E 35 H, 60%-wt. in ethyl acetate), 12.5 g ethyl
acetate as well as 8.4 g of 2-pyrrolidone (with lovastatin)
were mixed and, with the aid of a doctor.knife, applied as a
film of 400 pm thickness to a siliconized polyester film
(e.g. Hostaphan RN100). The moist film was dried for 30
minutes at-50 C and subsequently laminated with a polyester
film (e.g. Hostaphan RN 15). The weight per unit area of an
adhesive film prepared in this manner was about 130 g/m2.
