Note: Descriptions are shown in the official language in which they were submitted.
CA 02299713 2000-02-03
Active Substance-Containing ~Jick Systems
The invention relates to pharmaceutically/hygienic-
ally/cosmetically applicable wick systems and a process for
the production thereof. The term "wick" is meant to desig-
nate that there is a strand-like body is present which can
be rolled up and with which the active substance is com-
bined prior to the manufacture of the active substance sys-
tem. Said strand may consist of uniform material or of a
mixture of materials. The active substance may be present
as such or in the form of an active substance preparation.
The active substance may be dissolved in the strand. In the
case of a solid active substance, it is also possible that
an auxiliary substance is dissolved in the active sub-
stance. Both alternatives can be useful to attain a usable
- for example, sufficiently tear-resistant - consistency or
to improve the diffusion properties. It is also possible
for the strand to possess a microporous or even macroporous
structure. Tnlhat is i~portant is that the active substance
can be released from the strand to the environment. Pref-
erably, the strand is flat, but may also be a round wick,
with the active substance usually being stored in the cap-
illaries and transported through the same.
It is important that during the manufacture of the products
according to the invention, the active substance strand can
be applied, like a loop scrim, in a continuous process,
e.g. from a roll, which term also comprises a spool, or
from any other storage vessel, to the patches or system
strands, respectively, and that the separating can be per-
formed subsequently, in a continuous process, e.g. with the
aid of a punching tool or a punching roll, simultaneously
with the separating of the patches.
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In conventional systems, the active substance is present in
a discrete room, e.g. in a reservoir, in the form of a flat
pouch or bag, or in the entire layer on the carrier sheet
(matrix patch); a number of variants and mixtures are also
known. In those cases, however, where an active substance-
containing layer is formed, problems arise:
1. It is necessary to produce a mass, possibly under ad-
dition of solvents and/or a softener, wherein incompati-
bilities between active substance and the mass or adhesive
mass, the resin and the solvent, and the like, may arise.
It is particularly problematic where several active sub-
stances and, in addition, a softener, agents enhancing skin
permeability (enhancers) and/or similar additives are used.
2. It is possible that a - relatively volatile - active
substance is withdrav~m along with those substances intended
to be withdrawn when the system is being dried.
3. If the active substance is toxic or light-sensitive, ad-
ditional protective measures involving considerable effort
must be taken.
4. In hot-melt adhesive systems wherein the active sub-
stance is incorporated in the mass, it is possible that the
active substance is changed or negatively affected by the
high temperature of the molten mass.
5. The feeding of the carrier and the dosing of active sub-
stance and/or active substance carrier can generally only
be accomplished in technically complicated cycles. This
also applies where - as in the case of the "tablet patch" -
a carrier, such as a nonwoven, is initially applied to the
web, and then the active substance applied onto the car-
rier.
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6. In "pouch systems/membrane systems", too, it is gener-
ally not possible to apply the active substance mass con-
tinuously, instead it must be extruded or spray-coated in
cycles, either separately or together with a carrier mass,
or metered otherwise in cycles.
7. In other, in any.case continuous, production processes -
e.g. multichannel systems - it is necessary to seal sur-
faces together, with there still being the problem of nega-
tive affects on the active substance on the sealing sur-
faces.
It is thus the object of the present invention to ensure a
continuous introduction of the active substance onto or,
respectively, in a strand material, from which, subse-
quently, the systems are separated. The term strand here is
understood as meaning narrow webs, with the active sub-
stance strand, however, having less width than the system
strand.
This object is achieved according to the invention in that
the active substance is applied as such, or in a suitable
manner, in a thin, strand-shaped primary carrier having ab-
sorption properties or otherwise similar receptive proper-
ties, depending on the chemical nature, optionally in form
of a solution, similarly to introduction into a wick. This
product will be called active substance strand in the fol-
lowing.
The subject matter of the invention is an active substance-
containing device for dermal application which is charac-
terized in that it is made up of:
a) as active substance strand
b) a system strand, of larger Width, which markedly pro
jects beyond the active substance strand on both
sides, and
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c) if the system strand does not function as the backing
layer, a backing layer on one side, and
d) on the other side of the system a removable protective
layer.
A further subject matter of the invention is a process for
introducing active. substances in systems for dermal appli-
cation by incorporating the active substance in a carrier,
which is characterized in that the active substance is con-
tinuously introduced into a carrier or applied thereto,
thereby producing an active substance strand, that the
strand thus-obtained is combined with a broader system
strand, which projects beyond the active substance strand
on both sides, that this system is, on one side, provided
with a removable protective layer and, if the system strand
does not function as a backing layer, is provided with a
backing layer on the other side, and that the combined
strands are then separated in such a manner that no notice-
~le amounts of active substance may escape at the edges.
The protective layer is thus present in any case, independ-
ent of whether the system strand has the function of a
backing layer or not.
The invention relates especially to a process for the con-
tinuous introduction of active substances into continuously
produced thin systems, preferably having a relatively large
surface, e.g. wafers or active substance patches, by incor-
porating the active substance in an active substance strand
and applying this strand to a system strand, and/or apply-
ing a system strand to as active substance-strand, and pro-
viding the final system with a detachable protective layer
and optionally a backing layer, as well as to products pro-
duced according to this method.
CA 02299713 2000-02-03
The active substance may be applied in or onto the strand-
like carrier, either as such or in the form of an active
substance preparation, using, for instance, dipping meth-
ods, printing methods or similar methods. It is also possi-
ble to prepare a mass into which the active substance is
incorporated, and to extrude this mass, possibly applying
- it directly - under formation of an. active substance strand
- to the system strand, e.g. by spray-coating or extrusion,
or also to spin, weave or - as in a nonwoven - join to-
gether active substance-containing strands from extruded
strands, threads or fibers.
It is also possible to cast the mass onto the system strand
- using solvents, or as a hot-melt, or in form of powder as
in coating - possibly dry it, let it cool down or fix it by
supplying energy, thus producing it in situ, cut it to the
shape of a strand, and later apply it "from the roll".
An active substance strand may also be formed or consist of
fibers, woven fabrics, nonwovens or suitable fabrics - also
polymers - which are loaded with the active substance. In
this respect. suitable active substance carriers are, for
example, the usual plastics, e.g. polymers, copolymers and
block copolymers based on polyisobutylene (PIB), ethylene
vinyl acetate (EVA), polyacrylates or acrylate resins,
silicones, styrene-isobutyl-styrene(SIS) block copolymers
and others. Such carrier materials a.n dermal or transdermal
systems are known to those skilled in the art from:
a) Martin C. Musolf: "Pressure-Sensitive Adhesives:
"Science and Engineering" in Traasdermal Controlled
Systemic Medications, ed. by Y.W. Chien, Marcel Dekker
Inc., New York 1987, p.93-112
b) "Handbook of Adhesives", ed. by Irving Skeist, van
Nostrand Reinhold, New York 1990, 3rd edition.
In oral flat-shaped systems, such as wafers, it is possible
to use, for instance, hydroxypropyl cellulose, methyl cel-
lulose, starch or modified starch.
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According to a preferred embodiment, the active substance
carrier is applied in a continuous process, in a strand, on
the system strand, and, is one operation, dimensioned by
separating/punching to form the individual systems. Here, a
great number of possibilities are considered:
1. The "system strand" usefully consists of one or more
plastics and/or aluminium films/sheets or foils, pos-
sibly laminated together. By applying the active sub-
stance strand to a film or foil and laminating this
with the system strand, the active substance strand
can be enclosed between the films/sheets or foils.
2. The active substance strand may be applied "from the
roll" onto the system strand.
3. Applying the active substance strand to a system
strand which at the same time serves as the backing
layer of the system.
4. Application to a layer of adhesive, which is located
on a protective sheet or foil.
5. Coating the active substance strand with a hot-melt
adhesive coating, which may possibly also be adhesive
at normal temperatures, or with an adhesive coating
mass containing solvents, all-over on the entire ac-
tive substance strand and/or on part of or the entire
surface of the patch web.
6. Spray-coating or extruding the active substance strand
directly onto the system strand.
7. Forming the backing layer-carrier layer by one of
these coatings having the reguired properties such as
strength and impermeability to active substance.
8. Laying-in of proper strand threads.
9. =nserting several, possibly a large number of active
substance strands in a system strand. In this way it
is possible to attain a particularly uniform distribu-
tion of the active substance in the system strand
without interfering with the rate of production. This
is a preferred embodiment wherein, according to a par-
CA 02299713 2000-02-03
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ticularly useful embodiment, active substance strands
are arranged parallelly to the system strand and/or in
the shape of loops, so that patterns are formed, as in
a woven fabric. This, too, improves the uniformity of
the distribution.
10. Combining strands having different active substances,
which otherwise are incompatible with one another or
the combination of which would require special mews-
urea. It is thereby possible, to join, in the same or
in another concentration, active substances contained,
for example, in the matrix or in the liquid of a mem-
brane system with the active substances contained in
the active substance strand to form a combination sys-
tem, e.g. physostigmine and scopolamine, estrogen and
gestagens. This, too, is a preferred embodiment.
11. According to a further preferred embodiment, it is
possible to combine active substance strands with dif-
ferent conventional systems, such as an all-over ma-
trix, membrane etc., so that different systems, e.g.
concentrations and release mechanisms, can be created,
in a siiqple manner, in the surface or in the layers of
the system in order to improve the controlled release;
in this way it is possible, for example, to lay highly
concentrated strands in layers Which are farther away
from the skin and strands With lower concentration in
the layer which is near the skin (or vice versa), so
that initially a low and later a higher release takes
place (or vice versa).
12. According to a further embodiment, light-sensitive
and/or toxic or readily volatile active substances can
be processed such that the active substance strand is
completely or partially encapsulated. Such capsule ma-
terials must of course be permeable to the active sub-
stance at least on one side, and the active substance
strand should be occluded immediately after applica-
CA 02299713 2000-02-03
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tion, for exa~le, by applying an additional layer,
e.g. by laminating.
13. Heat-sensitivity of the active substance contained in
the active substance strand during the processing with
hot-melt adhesives or sensitivity occurring during the
drying process can be taken into account by applying
the active substance to the strand on that side which
is facing away from the liguid hot-melt adhesive. In
this case, the rearward layer of the active substance
strand has a temperature-insulating effect.-
14. In some cases, when separating the systems, a simulta-
neous or additional pressure may be exerted, in the
kind of an embossing, by which the edges are closed in
such a manner that no active substance amounts worth
mentioning may escape from them. In conventional sys-
tems it is frequently demanded to prevent that a
higher concentration of active substance occurs at the
edges. With systems according to the invention, how-
ever, there are practically no precautionary measures
needed in this respect since the transverse diffusion
is low anyway. In this respect, too, the present in-
vention has overcome prejudice.
15. In a further preferred embodiment the active substance
strands can also be applied in form of a scrim net,
loop fabric and the like, continuously, onto the cor-
responding system strands (carrier, intermediate or
adhesive layers). It is possible, here, to proceed
such that a second active substance is integrated in
the same manner , e.g. by
16. applying two or more different scrim nets with active
substances to the system strand or to the correspond-
ing carriers or adhesive layers.
Extremely varied active substances are suitable for this
invention, in particular transdermally applicable active
substance are considered.
CA 02299713 2000-02-03
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- nicotine
- corticosteroids: hydrocortisone, prednisolone, beclo-
methasone propionate, flumethasone, triamcinolone,
triamcinolone acetonide, fluocinolone, fluocinoline
acetonide, fluocinolone acetonide acetate, clobetasol
propionate etc.
- analgesic, anti-infla~mnatory agents: acetaminophen,
mefenamino acid, flufenamino acid, diclofenac, diclo-
fenac sodium alclofenac, oxyphenbutazone, phenyl buta-
zone, ibuprofene, fluorobiprofene, salicylic acid,
1-menthol, caa~pher, sulindac tolmetine sodium, naprox-
ene, fenbufene etc.
- hypnotically active sedatives: Phenobarbital, amobar-
bital, cyclobarbital, triazolam, nitrazepam, loraze-
Pam, haloperidol etc.
opiates such as diamorphine, morphine base, morphine
hydrochloride, dfhydrocodeine, buprenorphine, fentanyl
- tranquilizers: fluphenazine, thioridazine, lorazepam,
fluaitrazepam, chloropromazine etc.
- antihypertinsives: pindolol, indenolol, nifedipiae,
lofexidine, nipradinol, bucumolol, clonidin, bopin-
dolol, bupranolol etc.
- coronary active substances, such as ISDN, nitroglycer-
ine and its compounds
- antihypertensively active diuretics: hydrothiazide,
bendroflumethiazide, cyclopenthiazide etc.
- antibiotics: penicillin, tetracyclin, oxytetracyclin,
fradiomycin sulfate, erythromycin, chloramphenicol
etc.
- aneasthetics: lidocaine, benzocaine, ethylaminobenzo-
ate etc.
- antimicrobial agents: benzalkonium chloride, nitrofu
razone, nystatin, acetosulfamin, clotrimazol etc.
- anti-fuagus agents: pentamycin, amphotericin B, pyr-
rolnitrin, clotrimazol etc.
CA 02299713 2000-02-03
- vitamines: vitamins A, ergocalciferol, chlolecalcif-
erol, octotiamine, riboflavin butyrate etc.
- antiepileptics: nitrazepam, meprobamate, clonazepam
etc.
coronary vasodilators: dipyridamol, erythrite tetrani-
trate, pentaerythrite tetranitrate, propatyl nitrate
etc.
- antihistaminics: diphenylhydramine-hydro-chloride,
chlorpheniramin, diphenylimidazol etc.
- antitussivs: dertromethorphane (hydrobromide), terbu-
taline (sulfate), ephedrine (hydrochloride), salbuta-
nol (sulfate), isoproterenol (sulfate, hydrochloride)
etc.
- sex hormoaes: progesterone, estradiol, testosterone
etc.
- thymoleptics: doxepine etc.
- further remedies: 5-fluorouracil,I, desmopressin, dom-
perdon, scopolamine (hydrobromide), physostigmine,
naltrexon, naloxon, peptides etc.
As a matter of course this list is not comprehensive.
The products according to the present invention are suit-
able for dermal, but particularly for transdermal applica-
tion on the epidermis or mucosis in all forms. This term
also comprises the use as hygiene wafers, i.e. oral hygiene
wafers. These are flat-shaped systems serving to improve
oral hygiene by cleaning and/or odour-reducing or odour-
masking active substances or active substance combinations.
Such oral hygiene Wafers are thus applied orally and may be
completely dissolvable in the mouth; but peroral applica-
tion is also possible, administering, perorally, products
that are not rigid but very plastic and whose components
are selected such that they can be completely dissolved in
the body fluids and physiologically degraded.
Oral wafers of this kind can also contain pharmaceutic ac-
tive substances instead of hygienic active substances.
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The process according to the invention and the products
thus-obtained afford a number of advantages. Thus, the pro-
duction rate of the systems can be increased, since produc-
tion cycles, vertical movements relative to the guidance of
the system web are unnecessary. The necessary separation
can - likewise in a continuous manner - be accomplished by
rotating cutting rolls which possibly also produce an em-
bossing at the edges. Furthermore, a particular advantage
is the improved quality and the prevention of scraps due to
the absolute homogeneity of the distribution of the active
substance in the strand, which strand can be checked prior
to co~nencement of the production. The problem of dosing,
which otherwise occurs in the course of manufacture, is di-
minished by the fact that - once the strand has been pro-
duced in a geometrically defined manner - the final dosing
is accomplished solely by way of the length (respectively,
volume, length, area and thickness) of the strand in the
patch, i.e. preferably by way of the length of the patch,
given a defined width of the "patch web", i.e. the system
strand. If hot-melt adhesive coatings are used, this method
affords a particular advantage because the temperature at
that moment when the coatiag is being applied is already
markedly lower than the temperature prevailing during the
preparation of the mass, interference with the active sub-
stance in the strand is thus less likely.
The invention is also of particular advantage with the con-
ventional (including, flat-shaped) active agent-containing
oral systems since by way of an increased active substance
concentration in the active substance strand - which is
simply inserted in the oral, active substance-containing
system - it is possible to compensate a reduction in con-
centration occurring at the outer surfaces and thereby com-
pensate diminished active substance delivery. This applies,
in particular, where a plurality of active substance
CA 02299713 2000-02-03
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strands, possibly also containing different active sub-
stances, are used, possibly with different concentrations.
By using active substance strands of the most different
kind with respect to the active substance, its concentra-
tion and/or the kind of "wick" material, it is possible to
exert aay influence on the controlled release behaviour.
