Note: Descriptions are shown in the official language in which they were submitted.
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TRANSDERMAL THERAPEUTIC SYSTEM FOR ADMINISTRATION OF
CANDESARTAN
The invention relates to an active ingredient-
containing transdermal system for administration of
candesartan and/or its pharmaceutically suitable esters and/or
salts.
Candesartan (2-ethoxy-l-[[2'-(1H-tetrazol-5-
yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid) is a
highly specific, non-peptide angiotensin II receptor
antagonist. It has a high specificity and a strong affinity
for the AT1 receptor and a long duration of binding, and thus
a long-lasting activity. Candesartan is mainly used to treat
essential hypertension (non-organ-related high blood
pressure), heart diseases, strokes, nephritis (EP-0459136 B1)
and left ventricular hypertrophy.
On oral administration, the ester (candesartan
cilexetil) of candesartan and 1-(cyclohexyl-oxycar-bonyl-
oxy)ethanol is used as prodrug (EP-0459136 B1) in order to
ensure the stability necessary for passing through the
stomach and thus increase the bioavailability (Kubo, K.;
Kohara, Y. and co-workers; J. of Medicinal Chemistry; 36 (16)
2343-2349/1993). This ester is converted completely by ester
hydrolysis in the gastrointestinal tract into its active form
candesartan which is 30% more active than the ester.
Candesartan is then extensively distributed in the tissue and
in blood vessels. The elimination of candesartan from the
blood vessel walls takes place considerably more slowly than
from the plasma, resulting in the long-lasting effect.
Candesartan is partly metabolized further to inactive
metabolites in the liver. Candesartan and its metabolites are
then, after hepatobiliary passage, excreted with feces and
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urine. The ester side chain of candesartan cilexetil which is
eliminated in the intestine is absorbed and distributed in the
tissue mainly as cyclohexanol. In the liver there is then
degradation to cyclohexanediol, cyclohexanetriol and other
degradation products. The bioavailability of candesartan in
this case is only 14%. The maximum therapeutic effect on oral
intake is reached after 4 weeks because a gradual reduction in
blood pressure takes place through the slow occupation of the
receptors.
To date candesartan cilexetil has been administered
exclusively orally or intravenously. Since candesartan is
degraded by gastric acid during passage through the stomach,
either the active ingredient must be esterified or an
elaborate dosage form, such as, for example, an enteric
coating, must be produced. This results in additional costs
both for the machines and workforce and for the additionally
required material. The bioavailability of active ingredients
on oral administration is frequently unsatisfactory. In this
case, it is only 14%. The hepatic metabolism of the active
ingredient on first passage through the liver may lead to
unwanted concentration conditions and toxic byproducts, and to
a reduction in the effect.
The object of the present invention is now to
provide a transdermal system for systemic administration of
candesartan and/or one of its pharmaceutically suitable esters
or salts, the intention being to avoid the disadvantages of
oral or intravenous administration forms used to date. Thus
the present invention relates to a transdermal therapeutic
system with a content of candesartan or one of its
pharmaceutically suitable esters or salts.
It has now been found, surprisingly, that candesartan
and/or its pharmaceutically suitable esters and salts can be
administered by means of a transdermal therapeutic system in
such a way that a therapeutically effective blood level is
reached. The possibility of using the active ingredient
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candesartan and/or its pharmaceutically suitable esters and
salts, which display a direct systemic effect, makes it
possible to increase considerably the bioavailability and
greatly reduce the dose level. The stress on the body and the
adverse effect on the liver due to the metabolism can thus be
considerably reduced. The use of a transdermal therapeutic
system makes controlled delivery of active ingredient
possible, so that large blood plasma variations can be
avoided and a constant blood plasma level can be guaranteed
even for several days. The optimal effect of the active
ingredient is thus achieved conveniently and reliably. The
maximum therapeutic effect is reached after only 3 weeks.
It is likewise to be regarded as advantageous that
the use of plasters is simple and convenient by comparison
with oral or intravenous administration. Since the system is
applied externally, it can carry out its intended function in
this way for a very long time without being changed. This is
completely impossible with oral systems because they leave the
body through the digestive tract after one day at the longest.
In addition, it is simpler and more pleasant for the patient
to have to have to think of taking the medicine only 1-2 times
a week instead of having to take a tablet once a day.
The object on which the invention is based is now
achieved by a transdermal therapeutic system with a content
of candesartan and/or one of its pharmaceutically suitable
esters or salts, in particular by candesartan and/or
candesartan cilexetil.
Possible and suitable salts of candesartan are, in
particular, alkali metal salts such as, for example, the
potassium, sodium and lithium salts, and the ammonium salt.
Candesartan and/or one of its pharmaceutically
acceptable esters or salts as active ingredient can moreover
be administered in combination with other known active
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ingredients, especially diuretics and Ca channel blockers,
for example hydrochlorothiazide (HCTZ) or amlodipine. These
active ingredients exert an additive antihypertensive effect.
The transdermal therapeutic system according to the
invention may be in the form of a plaster. This plaster may
be a matrix or membrane system which has an impermeable
covering layer and a detachable protective layer. A suitable
constituent of the impermeable covering layer is polyester,
polypropylene, polyurethane or polyethylene, each of which
may be metalized or pigmented if required. Suitable for the
detachable protective layer are polyester, polypropylene,
polysiloxane, polyacrylate, ethylene/vinyl acetate,
polyurethane, polyisobutene or paper with silicone and/or
polyethylene coating.
The matrix plaster may consist of an impermeable
covering layer, of one or more than one self-adhesive matrix
layer which contains the active ingredient and/or one of its
pharmaceutically suitable esters or salts and, where
appropriate, other active ingredients and/or permeation
promoters and/or amino acids, or of a matrix layer which is
coated with a contact adhesive, and of a detachable
protective layer. The active ingredient present in the matrix
may be candesartan and/or its pharmaceutically suitable ester
or salts and, in the case of combination, additionally other
active ingredients such as Ca channel blockers or diuretics,
for example amlodipine or HCTZ.
It is possible to use for the matrix the matrix
formers usual in medicine, such as polyacrylate, silicone,
polyisobutylene, rubber, rubber-like synthetic homo-, co- or
block polymers, butyl rubber, styrene/isoprene copolymer,
polyurethanes, copolymers of ethylene, polysiloxanes or
styrene/butadiene copolymer.
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A further embodiment of the invention is in the form
of a membrane system. This may consist of an impermeable
covering layer, of an active ingredient-containing reservoir
or of a reservoir layer, of a semipermeable membrane, of an
5 optional contact adhesive layer and of a detachable
protective layer. The reservoir may contain candesartan
and/or one of its pharmaceutically suitable esters or salts,
where appropriate other active ingredients and/or permeation
promoters, stabilizers, emulsifiers, thickeners and/or
conventional membrane system or reservoir plaster aids. The
reservoir or the reservoir layer is located between the
covering layer and the membrane. Gel formers which can be
used if required are methylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, carboxyvinyl polymer, sodium
glyoxylate, carboxymethylcellulose or a mixture of these.
The membrane, which normally consists of inert
polymers, in particular based on polypropylene, polyvinyl
acetate, polyamide, ethylene/vinyl acetate copolymers or
silicone, may, depending on the pore size, have a controlling
effect on release of active ingredient.
It is possible to choose for the contact adhesive
layer of the matrix or membrane system according to the
invention which is described above a pressure-sensitive
adhesive, for example a polyurethane-based, polyisobutylene-
based, polyvinyl ether-based, silicone-based or acrylate-based
one.
The silicone-based adhesive may be a silicone
adhesive which is based on two main constituents, a polymer
or adhesive, in particular polysiloxane, and a tack-
increasing resin. The polysiloxane adhesive is usually
prepared with a crosslinker for the adhesive, typically with
a high molecular weight polydiorganosiloxane, and with the
resin, in order to afford a three-dimensional silicate
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structure via an appropriate organic solvent. Addition of the
resin to the polymer is the most important factor for
altering the physical properties of the polysiloxane
adhesives; cf., for example, Sobieski, et al., "Silicone
Pressure Sensitive Adhesives", Handbook of Pressure Sensitive
Adhesive Technology, 2nd ed., pp. 508-517 (D. Satas, ed.),
Van Nostrand Reinhold, New York (1989).
Another example of a pressure-sensitive silicone-
based adhesive is trimethylated silicon dioxide which has
been treated with polydimethylsiloxane with terminal
trimethylsiloxy groups.
The acrylate-based adhesives can be any homopolymer,
copolymer or terpolymer consisting of various acrylic acid
derivatives.
Thus, the acrylate polymers can be polymers of one
or more monomers of acrylic acids and other copolymerizable
monomers. The acrylate polymers may additionally comprise
copolymers of alkyl acrylates and/or alkyl methacrylates
and/or copolymerizable secondary monomers or monomers with
functional groups. It is possible by altering the amount of
each type of monomer added to alter the cohesive properties
of the acrylate polymers resulting therefrom. In general, the
acrylate polymer consists of at least 50% by weight of an
acrylate, methacrylate, alkyl acrylate or alkyl methacrylate
monomer, 0 to 20% of a functional monomer copolymerizable
with acrylate, and 0 to 40% of another monomer.
Acrylate monomers which can be used with acrylic
acid, methacrylic acid, butyl acrylate, butyl methacrylate,
hexyl acrylate, hexyl methacrylate, isooctyl acrylate,
isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl
methacrylate, decyl acrylate, decyl methacrylate, dodecyl
acrylate, dodecyl methacrylate, tridecyl acrylate and
tridecyl methacrylate are listed below.
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Thus, functional monomers copolymerizable with the
above-mentioned acrylates, methacrylates, alkyl acrylates or
alkyl methacrylates can be employed, for example acrylic
acid, methacrylic acid, maleic acid, maleic anhydride,
hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide,
dimethylacrylamide, acrylonitrile, dimethylaminoethyl
acrylate, dimethylaminoethyl methacrylate, tert-
butylaminoethyl acrylate, tert-butylaminomethyl methacrylate,
methoxyethyl acrylate and methoxyethyl methacrylate.
Further details and examples of pressure-sensitive
acrylates suitable for the invention are described in Satas
Handbook of Pressure Sensitive Adhesive Technology "Acrylic
Adhesives", 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand
Reinhold, New York (1989).
Permeation promoters which can be used are
monohydric and/or polyhydric aliphatic, cycloaliphatic and/or
aromatic-aliphatic alcohols each with up to 8 C atoms, for
example ethanol, 1,2-propanediol, dexpanthenol and/or
polyethylene glycol; alcohol/water mixtures; saturated and/or
unsaturated fatty alcohols each with 8-18 C atoms; terpenes;
for example cineol, carveol, menthone, terpineol, verbenone,
menthol, limonene, thymol, cymene, terpinen-4-ol, neomenthol,
geraniol, fenchone; mixtures of terpenes and ethanol and/or
propylene glycol; tea tree oil; saturated and/or unsaturated
cyclic ketones; alkyl methyl sulfoxides; saturated and/or
unsaturated fatty acids each with 8-18 C atoms; the esters and
salts thereof; natural vitamin E; synthetic vitamin E and/or
vitamin E derivatives; sorbitan fatty acid esters and
TM
ethoxylated sorbitan fatty acid esters; Azone (laurocapram);
Azone mixed with alcohols; urea; 1-alkylpyrrolidone; block
copolymers of polyethylene glycol and dimethylsiloxane with
cationic groups at one end; folate-polyethylene glycol
liposome, proliposome; polyoxyethylene 10 stearyl ether;
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mi_xture of polyoxyethylene 10 stearyl ether and glyceryl
dilaurate; dodecyl 2-(N,N-dimethylamino)propanoltetra-
decanoate and/or dodecyl 2-(N,N-dimethylamino)propionate; N-
acetylprolinate esters with more than 8 C atoms; nonionic
surfactants, for example lauryl ethers, esters of
polyoxyethylene; ethosome (phospholipid vesicle);
dimethyl(arylimino)sulfurane; mixture of oleic acid analogs
and propylene glycol; mixture of padimate 0, octyl salicylate,
octyl methoxycinnamate and laurocapram and/or mixtures of all
these components.
The invention is explained in detail by the
following examples without, however, restricting the scope of
the invention thereby.
Example i (matrix plaster)
11.1 g of candesartan cilexetil are dissolved in
TM
75 g of extra pure acetone, and 8 g of Copherol F1300 are
added. The clear solution is added to 169 g of an approx. 360
7M
strength acrylate copolymer (Duro-Tak 387-2353, Nat. Starch &
Chemical B.V.) and stirred. The homogeneous solution is
spread on a siliconized polyester sheet (for example 75 um)
or on siliconized paper and dried at 35 C to 85 C to result
2
in a matrix dry weight of 80 10o g/m . The detachable
protective layer (for example polyester 15 um) is then
laminated onto the matrix side.
TTS with an area of 20 cm 2 are punched out.
A plaster of this size contains 16 mg of candesartan and 16 mg
of a-tocopherol.
Example 2 (reservoir plaster)(see drawing)
Firstly 138.4 g of candesartan cilexetil are
dissolved in 861.6 g of a mixture of ethanol abs. 65% (V/W),
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Copherol F1300 10% (V/W) and hydroxypropylcellulose 1% (V/W)
with stirring. This mixture is the active drug solution for
the reservoir. The reservoir is charged with 400 5% mg of
the active drug solution.
The transdermal therapeutic system (see drawing) consists
firstly of the optional adhesive layer which forms the
adhesive ring. Onto this layer is applied a heat-sealable,
impermeable covering layer. On the side facing the skin, the
reservoir is affixed to the covering layer and sealed with a
microporous EVA membrane (Cotran 9702, 3M). A siliconized PET
sheet serves as detachable protective layer.
A plaster thus contains:
Candesartan cilexetil 55.36 mg (equivalent to 40 mg of
candesartan)
Copherol F1300 40 mg
Ethanol abs. 300.64 mg
Hydroxypropylcellulose 4 mg
