Note: Descriptions are shown in the official language in which they were submitted.
1333688
The invention relates to a device for the release
- of substances in a uniform or irregular distribution from
hot melt pressure-sensitive adhesives, a process for the
preparation of the device and to the use thereof.
Typical examples of such devices include active
substance-containing plasters, indicator systems, perfume-
releasing devices and the like, and are particularly used in
the medical field for the controlled or uncontrolled release
of substances. Particular significance has been attached to
controlled devices in the form of transdermally controlled
systems. The application of an active substance-containing
layer from a melt to such devices is known. For example,
EP-OS 0177893 discloses a nonadhesive cellulose ether gel
which can be applied from a melt and in which active
substances can be distributed. This gel is hot processed
and is nonadhesive. As well, DE-OS 32 22 800 describes a
transdermal system, in which active substance packed in
microcapsules is present in a thermally shapeable, adhesive
matrix material, which is applied from the melt. For
temperature-sensitive active substances with a low melting
point or which can be easily decomposed, attempts have also
been made to produce nonadhesive active substance-containing
matrices at ambient temperature. For example, it is taught
in US Patent No. 4,379,454 (Campbell et. al.) that an active
substance solution brought to a desired viscosity value by
means of gelling agents at ambient temperature can be used
for the active substance layer. It is known from US Patent
13336~8
No. 4,559,222 (Enscore et. al.) to use a mixture of mineral
- oil/polyisobutylene and colloidal silicon dioxide prepared
at ambient temperature as a viscous active substance layer
for oil-soluble active substances, whereby said layers can
also be made in pressure-sensitive adhesive manner. DE-OS
32 22 800 (ALZA) describes an active substance layer from an
active substance solution thickened by means of a
rheological agent, such as cellulose, a polysaccharide or a
silicon compound, which is nonadhesive and is also suitable
for rapid active substance release.
US Patent No. 3,923,939 discloses the shaping of
active substances, such as tetracycline, in an ethylene-
vinyl acetate copolymer layer by melt pressing. EP-OS 86
468 describes an oral antidiabetes sulphonyl urea derivative
in a nonadhesive hot melt mass and with a melting point of
30 to 90C filled into capsules in predetermined doses from
the melt. As well, US Patent No. 3,957,966 teaches that
active substances can be processed in nonadhesive hot melt
masses.
DE-OS 30 07 363 describes the use of a pressure-
sensitive adhesive mixture of a thermoplastic elastomer,
preferably a block polymer of general formula A-B-A, a
tackifying resin with oil or higher fatty acids and an
active substance for producing a simple transdermal system.
The pressure-sensitive adhesive mixture described is only
suitable for relatively temperature-resistant active
substances, which are able to withstand temperatures of
,,
133368S
120C and higher. US Patent No. 3,699,963 teaches mixing
- oxytocin with pressure-sensitive adhesive for producing a
transdermal therapeutic system and the shaping thereof at a
temperature above 90C. The thus produced transdermal
systems are inexpensive to produce and ensure a constant
active substance transfer via the whole-area adhesion of the
system to the skin.
The prior art processes for producing such systems
are not suitable for transdermal systems containing
temperature-sensitive substances, such as scopolamine.
Therefore, hitherto, pressure-sensitive adhesive active
substance layers with temperature sensitive active
substances have preferably been formed from the solution and
the solvent evaporated.
The use of solvents in the preparation of active
substance-containing adhesive layers is disadvantageous for
several reasons. The preparation of the solutions requires
at least one additional, complicated process stage. It
requires significant technical effort and expenditure in
terms of the handling of the solvents, and when used for
medical purposes it is additionally necessary to use
extremely pure and, accordingly, expensive solvents; in
order to ensure a corresponding freedom from residue in the
apparatus for the dissolving of the adhesive or its starting
materials. Another problem is in achieving freedom from
solvent in the device, for which purpose it is necessary to
use expensive drying sections and suction installations.
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1333688
Costs are also incurred through the recovery or separation
- of the solvent, in order to avoid pollution of the
environment. An additional risk is in the flammability of
most solvents. Furthermore, most organic solvents are
harmful to the human organism, so that complicated and
costly protective measures must be taken for personnel
working in the plant.
An object of the present invention, therefore, is
to eliminate the aforementioned disadvantages of the devices
and processes of the prior art.
Accordingly, the invention provides a device for
the release of a substance from a hot melt pressure
sensitive adhesive having a non-uniform or uniform
distribution of the substances in the hot melt pressure
sensitive adhesives, wherein a mixture of hot melt pressure
sensitive adhesive and substance or a solution of the
substance in the hot melt pressure sensitive adhesive is
present, the hot melt pressure sensitive adhesive having a
processing temperature between about 40 and 80C, preferably
between about 40 and 60C and more preferably between about
40 and 55C.
The invention makes it possible to work without
solvents at low temperature such that there is a
considerable saving on materials, a speedier production of
the device without the time consuming drying stages, as well
as a production of the inventive devices which leads to less
1333688
pollution of the environment, which inter alia leads to a
significantly less expensive and solvent-free product.
The process for the production of the device of
the invention involves the continuous or discontinuous
application of melted hot melt pressure-sensitive adhesive,
containing the substance to be released at a hot melt
pressure-sensitive adhesive temperature between about 40 and
80C, preferably between about 40 and 60C and in the
particularly preferred manner between about 40 and 55C, to
lo a carrier and, optionally, application of protective layer
material.
A further embodiment of the process of the
invention involves the continuous or discontinuous
application of melted hot melt pressure-sensitive adhesive,
containing the substance to be released at a hot melt
pressure-sensitive adhesive temperature between about 40 and
80C, preferably between about 40 and 60C and in the
particularly preferred manner between about 40 and 55C, to
a protective layer material and, optionally, application of
the carrier.
When using highly volatile and/or thermally
unstable substances to be released, the following measures
are appropriate for processing purposes:
A) working at very low temperatures,
B) increasing the external pressure in order to
reduce evaporation,
i,"
1~2~ o~
~ ~ o ~
C) saturation of the vapour chamber over the melt
- with the vaporous substance, and
D) working with a minimum quantity of volatile
substance in the melt.
Clearly these measures, such as, e.g. working in
an encapsulated plant, are limited by the rules known to the
expert according to the intended use of the device to be
produced and material circumstances.
The inventive devices, particularly transdermal
systems can, for example, be used for local or systemic
transdermal active substance administration in human or
veterinary medicine or for cosmetic use and are, preferably,
used for the release of temperature-sensitive and/or highly
volatile substances.
Hot melt pressure-sensitive adhesive is herein
understood to mean any pressure-sensitive adhesive which is
adequately liquid when hot to permit problem free
application at a temperature above approximately 40C.
As inventively operable hot melt pressure-
sensitive adhesives may be used inter alia those which are
known to the expert as well as those described inter alia in
DE-OS 15 94 268 (SUN OIL CO.), DE-OS 24 13 979 (E.I. DU PONT
DE NEMOURS), DE-OS 24 35 863 (DYNAMIT NOBEL AG), DE-OS 28 00
302 (CIBA GEIGY), EP-A-104 005 (PERSONAL PRODUCTS CO.), JP
6104 2583 and JP 61 281 810, EP-OS 131 460 (EXXON), EP-OS
234 856 (EXXON), EP-OS 185 992 (EASTMAN KODAK), as well as
US Patents Nos. 3,699,963 and 4,358,557 (EASTMAN KODAK) and
1333~88
explicit reference is made to this prior art to avoid
unnecessary repetition.
The basic polymers may be composed of, for
example, polyamides, polyesters, polycaprolactams, poly-
caprolactone, ethylene-vinyl acetate copolymers (EVA),
ethylene-ethylacrylate copolymers (EEA), polyvinylethers,
polyacrylate esters, polyvinylacetals, polyvinylacetates,
styrene-butadine block polymers, isoprene block polymers,
polyurethanes, ethylcellulose, cellulose acetate-butyrate,
synthetic rubbers (e.g. neoprene rubber) polyisobutylene,
butyl rubber, acrylonitrile-butadiene copolymers, epoxy
resins, melamine resins, phenol-formaldehyde resins and
resorcinol-formaldehyde resins and inter alia the following
modifying resins can be used: hydrogenated colophony,
polymerized colophony, dimerized resin acids, dis-
proportionated colophony, colophony methyl esters,
hydrogenated colophony glycerol esters, hydrogenated
colophony methyl esters, pentalesters, hydrogenated
colophony triethyleneglycolesters, hydroabiethyl alcohol and
its derivatives, glycerol esters, ditriolesters and penta-
esters of resin acids, polymerized colophony pentalesters,
dimerized colophony pentalesters, dimerized colophony
glycerol esters, esters of maleic acid or phenol-modified
colophony, aromatic and aliphatic hydrocarbon resins,
hydrogenated resins, polyterpene resins, modified terpene
resins, waxes, low molecular weight polyethylene and poly-
propylene and alkyl-styrene copolymers. To these resins can
, . ~
8~
optionally be added platicizers, such as e.g. adipic acid
esters, phosphoric acid esters, phthalic acid esters,
polyesters, fatty acid esters, citric acid esters or epoxide
plasticizers. It is also possible to admix stabilizers,
such as tocopherol, substituted phenols, hydroquinones,
pyrocatechols, aromatic amines and, optionally, also
fillers, such as e.g. titanium dioxide, magnesium oxide,
zinc oxide and silicon dioxide.
The formation of components of the device,
containing hot melt pressure-sensitive adhesive with a
processing temperature between about 40 and 80~C, can take
place by extrusion, pouring, roller application, knife
coating, spraying or by printing processes.
A limiting value for the processability of the hot
melt pressure-sensitive adhesive in many of these processes
is a viscosity of approximately 80,000 Pa.
If the substrate to be treated with the adhesive,
a component of the device, could be damaged by the
temperature of the hot-applied adhesive, either by
decomposition, reaction or partial melting, it is possible
to use a cooled substrate. Cooling can take place by E~_
se known processes, such as by the introduction of cold
inert gases or by contact with a cooling surface.
The hot melt pressure-sensitive adhesive can, for
example, be applied in layer form or in individual areas, in
accordance with a predetermined pattern, to the protective
layer or the covering material. In a preferred embodiment,
133~688
the hot melt pressure-sensitive adhesive containing the
substance or substances to be delivered is present in the
form of one or more layers.
Depending upon the function of the intended use
(and, e.g., if the substance to be released is to be
released through the backing layer, such as can be the case
with essential oils, such as fragrances), the hot melt
pressure-sensitive adhesive may be finished with a carrier
permeable with respect to the substance or substances to be
released. However, in the embodiment of the device as a
transdermal system, where the substance is only to be
delivered to the skin, preference is given to a backing
layer which is impermeable for the substance to be
delivered.
In another preferred embodiment the device further
comprises a removable protective layer.
The inventive process makes it possible to obviate
the use of solvent-containing pressure-sensitive adhesive
materials in the processing of temperature-sensitive, highly
volatile substances. This significantly increases the
safety of production since it is now certain that no toxic
solvent residues can remain in the medicinal administration
form. As well, the application process is greatly
simplified and considerable cost savings in terms of
production is achieved. Naturally, the process can also be
used in an advantageous manner for less temperature-
1~33688
sensitive substances as this also leads to considerable costsavings.
The term "substances" in connection with the
present invention is understood to mean chemical elements,
organic or inorganic compounds, which can migrate out of the
components containing them in such a device and can thereby
bring about a sought after effect. Among the uses of the
inventive device particular significance is attached to
human and veterinary medicine, a realization of the
invention in plaster form being particularly preferred.
Typical substances which can be administered by
means of the devices of invention include: aceclidine,
amphetaminil, amphetamine, amylnitrite, apophedrin, atebrin,
alprostadil, azulene, arecoline, anethole, amylenehydrate,
acetylcholine, acridine, adenosintriphosphoric acid, L-malic
acid, alimemazine, allithiamine, allyl isothiocyanate,
amino-ethanol, apyzine, apiol, azatadine, alprenolol,
ethinazone, benzoylperoxide, benzyl alcohol, bisabolol,
bisnorephedrine, butacetoluid, benactyzine, campher,
colecalciferol, choralhydrate, clemastine, chlorobutanol,
capsaicin, cyclopentamine, clobutinol, chamazulene,
cimethocaine, codeine, chloropromazine, quinine,
chlorothymol, cyclophosphamide, cinchocaine, chlorambucil,
chlorphenesin, diethylethane, divinylethane,
dexchlorpheniramine, dinoprostone, dixyrazine, ephedrine,
ethosuximide, enallylpropymal, emylcamate, erytroltetra-
nitrate, emetine, enflurane, eucalyptol, etofenamate,
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~J '
I33368~
ethylmorphine, fentanyl, fluanisone, guajazulene, holathane,
hyoscyamine, histamine, fencarbamide, hydroxycaine,
hexylresorcinol, isoaminlcitrate, isosorbidedinitrate,
ibuprofin, iodine, iodoform, isoaminile, lidocaine,
lopirine, levamisole, methadone, methyprylone, methyl-
phenidate, mephenesine, methylephedrine, meclastine,
methopromazine, mesuximide, nicethamide, norpseudoephedrine,
menthosl, methoxyflurane, methylpentinol, metixen,
misoprostol, oxytetracaine, oxyprenolol, oxyphenbutazone,
oxyquinoline, pinene, prolintane, procylidine, piperazine,
pivazide, phensuzimide, procaine, phenindamine,
promethazine, pentetrazole, profenamine, perazine, phenol,
pethidine, pilocarpine, prenylamine, phenoxybenzamine,
resochin, scopolamine, salicylic acid ester, sparteine,
trichloroethylene, timolol, trifluperazine, tetracaine,
trimipramine, tranylcypromine, trimethadione, tybamate,
thymol, thioridazine, valproic acid, verapamil, as well as
other active substances which can be taken up through the
skin. Obviously, this list is not exhaustive.
Typical compositions for the hot melt pressure-
sensitive adhesives to be used are those prepared from
between about 10 and 100% by weight, preferably about 20 to
80% by weight and in the particularly preferred manner about
20 to 50% by weight of polymer; between about 10 and 80% by
weight, preferably about 15 to 60% by weight of plasticizer;
between about 10 and 80% by weight, preferably about 15 to
60% by weight of tackifier; and, optionally, about 0.1 to 5%
11 --
1333688
by weight of anti-agers and/or about 0 to 70% by weight of
fillers; the sum of the percentages of the components always
being 100.
Preferably, the hot melt pressure-sensitive
adhesive contains about 10 to 50% by weight of styrene-
isoprene-styrene synthetic rubber, such as is commercially
available under the name CARIFLEX TR~ 1107 of SHELL; between
about 10 and 80% by weight of a hydrogenated alcohol, such
as is commercially available under the name ABITOL~ from
HERCULES; between about 10 and 80% by weight of a hydro-
carbon resin, e.g., HERCURES C~ from HERCULES; between about
1 and 40% by weight of esters of vegetable fatty acids, e.g.
MIGLYOL~ 812 of DYNAMIT NOBEL; and, optionally, up to about
5% by weight of anti-agers, such as hydroquinone, etc., as
well as up to about 70% by weight of fillers.
In a further preferred embodiment of the invention
the hot melt pressure-sensitive adhesive has about 10 to 50%
by weight of a polycaprolactone, e.g. CAPA~ 650 of INTEROX;
between about 10 and 80% by weight of a hydrogenated
alcohol, e.g. ABITOL~ of HERCULES; between about 10 and 80%
by weight of a hydrocarbon resin, e.g. HERCURES C~ of
HERCULES; between about 1 and 40% by weight of esters of
vegetable fatty acids, such as MIGLYOL~ 812 of DYNAMIT
NOBEL; and, optionally, up to about 5% by weight of anti-
agers, as well as up to about 70% by weight of fillers.
It can be advantageous for the hot melt pressure-
sensitive adhesive to have about 10 to 50% by weight of
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1333688
polyethylene-vinyl acetate, such as EVATANE~ 28-25 of
ATOCHEM; between about 10 and 80% by weight of a
hydrogenated alcohol, e.g. ABITOL~ of HERCULES; between
about 10 and 80% by weight of a hydrocarbon resin, e.g.,
HERCURES C~ of HERCULES; between about 1 and 40% by weight
of esters of vegetable fatty acids, e.g. MIGLYOL~ 812 of
DYNAMIT NOBEL; and, optionally, up to about 5% by weight of
anti-agers, such as hydroquinone, etc., and up to about 70%
by weight of fillers.
A suitable hot melt pressure-sensitive adhesive
can contain about 10 to 50% by weight of polyurethane, such
as e.g. LUPHEN P~ 1110 of BASF; between about 10 and 80% by
weight of a hydrogenated alcohol, e.g. ABITOL~ of HERCULES;
between about 10 and 80% by weight of a hydrocarbon resin,
e.g. HERCURES C~ of HERCULES; between about 1 and 40% by
weight of esters of vegetable fatty acids, e.g. MIGLYOL~ 812
of DYNAMIT NOBEL; and, optionally, up to about 5% by weight
of anti-agers, as well as up to about 70% by weight of
fillers.
It is also possible for the hot melt pressure-
sensitive adhesive to contain about 10 to 50% by weight of
polyamide, such as e.g. EURELON~ 930 of SCHERING; between
about 10 and 80% by weight of a hydrogenated alcohol, e.g.
ABITOL~ of HERCULES; between about 10 and 80% by weight of
a hydrocarbon resin, e.g. HERCURES C~ of HERCULES; between
about 1 and 40% by weight of esters of vegetable fatty
acids, e.g. MIGLYOL~ 812 of DYNAMIT NOBEL; and, optionally,
-` 1333688
up to about 5% by weight of anti-agers, as well as up to
about 70% by weight of fillers.
It is also possible to use a hot melt pressure-
sensitive adhesive with about 10 to 50% by weight of
epoxide, e.g. EUREPOX~ 7001 of SCHERING; between about 10
and 80% by weight of hydrogenated alcohol, e.g. ABITOL~ of
HERCULES; between about 10 and 80% by weight of a hydro-
carbon resin, e.g. HERCURES C~ of HERCULES; between about 1
and 40% by weight of esters of vegetable fatty acids, e.g.
MIGLYOL~ 812 of DYNAMIT NOBEL; and, optionally, up to about
5% by weight of anti-agers, such as hydroquinone, etc., as
well as up to about 70% by weight of fillers.
Another hot melt pressure-sensitive adhesive
operable in the production of the inventive transdermal
systems has about 10 to 50% by weight of polyisobutine with
a tacky, rubber-like consistency, such as e.g. OPPANOL B 50~
of BASF; between about 10 and 80% by weight of a
hydrogenated alcohol, e.g. ABITOL~ of HERCULES; between
about 10 and 80% by weight of a hydrocarbon resin, e.g.
HERCURES C~ of HERCULES; between about 1 and 40% by weight
of esters of vegetable fatty acids, e.g. MIGLYOL~ 812 of
DYNAMIT NOBEL; and, optionally, up to about 5% by weight of
anti-agers, as well as up to about 70% by weight of fillers.
Finally, it is preferred to use hot melt pressure-
sensitive adhesives with a polyester base and which, e.g.,contain between about 10 and 80% by weight of a hydrogenated
alcohol, e.g. ABITOL~ by weight of a hydrocarbon resin, e.g.
- 14 -
1333688
HERCURES C~ of HERCULES; between about 1 and 40% by weight
of esters of vegetable fatty acids, e.g. MIGLYOL~ 812 of
DYNAMIT NOBEL; and, optionally, up to about 5% by weight of
anti-agers, as well as up to about 70% by weight of fillers.
The devices of the invention may also contain one
or more substance depots in which the substance is
present in a higher concentration than the active substance-
containing hot melt pressure-sensitive adhesive layer, so
that higher substance doses can be processed and
consequently the device can remain in use longer before it
has to be changed. Typical constructions appear e.g. in DE-
OS 36 29 304.
In drawings which illustrate embodiments of the
invention,
Figure 1 is a sectional view through the layers of
a preferred device of invention with a substance depot;
Figure 2 is a sectional view through the layers of
a further preferred device of the invention with an active
substance depot: and
Figure 3 is a sectional view through the layers of
another embodiment of the inventive device without a
substance depot.
With reference to Figure 1, a preferred embodiment
of the device of the invention is shown which is in the
form of a plaster-like, active substance-containing,
transdermal, therapeutic system. It comprises a hot melt
pressure-sensitive adhesive layer 12, an active substance
- 15 -
1333688
depot 14 in which the active substance has a higher
concentration than in the hot melt pressure-sensitive
adhesive layer 12, as well as an active substance-
impermeable carrier 10, on which rests the active substance
depot 14 and which is affixed to the skin 18. Active
substance continuously migrates at a predetermined rate
through the skin 18 such that the active substance content
of layer 12 decreases. The active substance decrease is
compensated by an after-flow of active substance from the
active substance depot 14, so that over a predetermined
period of time there is an equilibrium concentration of the
active substance in the hot melt pressure-sensitive adhesive
layer 12, which ensures the delivery of a constance active
substance quantity of the skin 18.
Referring now to Figure 2, another embodiment of
the inventive device is shown, in which an active substance
depot 14 is surrounded on all sides by the hot melt
pressure-sensitive adhesive layer 12. This embodiment is
particularly suitable if a large pressure-sensitive surface
between the active substance depot and the hot melt
pressure-sensitive adhesive layer is desired for a rapid
active substance delivery to the hot melt pressure-sensitive
adhesive layer.
With reference to Figure 3, a further embodiment
of the inventive device is shown, in which an active
substance-containing hot melt pressure-sensitive adhesive
layer 12 is applied to an impermeable carrier material 10 in
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1333688
such a way that the latter covers the layer 12 on three
sides. With the free hot melt pressure-sensitive adhesive
surface it is affixed to the skin 18, so that a whole-area
contact is ensured over the application time and the
transfer of the active substance to the skin always takes
place over a constant surface and at a constant speed.
The inventively improved production of the device
of the invention will now be described. Firstly, the
mixture of the components of the hot melt pressure-sensitive
adhesive and the substance to be administered is prepared.
This mixture is then brought to the processing temperature
and applied from the melt to a carrier material. The
necessary further processing, such as the application of an
adhesively finished protective layer material, may take
place in the conventional manner.
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