Note: Descriptions are shown in the official language in which they were submitted.
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WO 00/56290 PCT/EPOO/02042
Transdermal Therapeutic System and Process for its Production
Specification
The invention relates to a transdermal therapeutic system (TTS) and a process
for its
production.
Therapeutic systems for the transdermal administration of pharmaceuticals,
such as
nicotine, nitroglycerine, sexual hormones, scopolamine, fentanyl are known.
Suitable
systems have for example been described in international application DE
87/00372
(WO 88/01516). Such systems contain as essential features a backing layer
which is
remote from the skin and impermeable for the active substance, at least one
active
substance depot, an active substance distribution device which is in contact
with the
active substance depot, a control device which controls the delivery of the
active
substance by the system, and a pressure-sensitive adhesive fixing device for
the
therapeutic system on the skin. The active substance distribution device may
be
combined with the control device to yield a reservoir matrix which has one or
more
discrete active substance depots arranged in spatially defined manner with
respect
to one another and having a higher active substance concentration than that
which is
present in the reservoir matrix.
It is stated in WO 88/01516 that the depot may also contain inert adjuvants
such as
support materials which make the active substance depot insensitive with
respect to
application of pressure and tension, and carriers. According to US patent
specification 5,820,876 the support material may be a planar fabric (support
fabric) as
an inert adjuvant, by which the distribution of the active substance within
the depot is
effected and favored. A particular embodiment is also disclosed in Figure 5 of
both
documents, according to which an adhesive layer is provided on a backing
layer, upon
which the active substance is present, if desired with adjuvants, such as
material for
facilitating the processability of the active substance, or carrier materials
such as
fabrics. The support fabric may also be present as a non-woven fabric
(fleece). In the
examples fleece materials are disclosed as being suitable (50:50 viscose rayon-
cotton
fiber blend with a substance weight of 80 g/m2, Paratex 11/80 of the company
Lohmann
GmbH & Co. KG, or a 70:30 viscose rayon-cotton fiber blend with a substance
weight of
40 g/m2, Paratex 111/40 of the company Lohmann GmbH & Co. KG). In both
examples it
is additionally stated that the fleece material acts as a support fabric and
also to assist
the uniform distribution of the nicotine, as an inert adjuvant as defined in
the
introductory part of the specification.
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US patent specification 4,597,961 discloses a different form of a transdermal
therapeutic system. In this system the delivery of the active substance is
generally
controlled by a microporous membrane. It is stated in the description of
Figure 2 that
reservoir 114 can contain a suitable absorbent material 122, such as a sponge
or
cotton, on which is absorbed the desired quantity of liquid nicotine.
Additionally it is
pointed out in Example 4 that reservoir 114 contains a dense matrix of inert
fibrous
or porous material, such as cotton, to prevent loss of nicotine. The term
"matrix" is
used in this context however for a completely different technical feature than
in WO
88/01516 and US patent specification 5,820,876.
There is further known a TTS for nicotine from US patent specification
4,915,950, in
which a depot layer (13) is arranged between an adhesive (14), acting as a
control
device, and an anchoring adhesive (12). The active substance depot layer may
consist of a non-woven fabric (fleece) e.g. polyester, polyethylene,
polypropylene,
polyamides, rayon or cotton and may particularly consist of a 100% polyester
non-
woven. There is no disclosure or hint at all of the use of paper in or by this
specification.
It has now been found that a TTS with a quality substantially improved
compared
with the known state of the art is obtained if instead of the known support
materials,
including particularly fabrics such as fleece, the carrier material is paper.
Paper is
distinguished fundamentally from fabrics including non-woven (fleece) by the
fact
that in it the cellulose fibers are joined to form a thin layer by
strengthening. The
cohesion of the fibers in the paper is effected - besides the mechanical
adherence
and the hooking-together of the fibers - by chemical bonds (hydrogen bonds)
which
are formed between the hydroxyl groups of the cellulose molecules in the
course of
the manufacture of the paper. This chemical bond is so strong that the tensile
strength of paper can even exceed that of ordinary construction steel (RM
Consult
Papiermaschinen Info - http: //home.t-online.de/home/rm.consult/rm-info.htm of
November 17, 1998). In addition, paper has the advantage that it has a high
absorption capacity for liquid phases which is characterized by DIN ISO 8787
by the
height of suction.Thus the height of suction in the long direction determined
for paper
with a basis weight of 26 g/m2 was 146 mm/10 min and in cross direction
143 mm/10 min compared with values of about 110 and 80 mm/10 min for the
abovementioned fleece material Paratex 111/40, where the values for the fleece
varied
to a very large extent in the serial tests. Paper ordinarily does not contain
a binding
agent, so that no incompatibilities can occur between active substance and
binding
agent.
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Subject of the invention therefore is a
transdermal therapeutic system containing as essential
features
a) a backing layer remote from the skin and
impermeable for the active substance,
b) at least one active substance depot,
c) a matrix contacting the active substance depot
and controlling the delivery of the active substance, and
d) a pressure-sensitive adhesive fixing device for
the therapeutic system on the skin, the depot or the matrix
or both containing support materials, wherein the support
material consists of paper.
In one product aspect, the invention provides a
transdermal therapeutic system, comprising: (a) a backing
layer remote from the skin and impermeable for an active
substance; (b) at least one active substance depot; (c) a
matrix containing the active substance depot and controlling
the delivery of the active substance; and (d) a pressure-
sensitive adhesive fixing device for the therapeutic system
on the skin, wherein the depot, the matrix or both contain a
support material, wherein the support material consists of
paper and the active substance is lidocaine,
diphenylhydramine hydrochloride, salbutamol, 5-fluorouracil,
one or more sexual horomones or gestagens, or fentanyl.
In one process aspect, the invention provides a
process for the production of the transdermal therapeutic
system as defined above, wherein: (i) a pressure-sensitive
adhesive composition is applied to a dehesively finished
protective layer (A) such that after the evaporation of
solvents a pressure-sensitive layer is
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3a
formed; (ii) an adhesive composition is applied to a further
dehesively finished protective layer (B) such that after
evaporation of solvent a film is produced, and the film is
laminated to the pressure-sensitive adhesive layer applied
to the protective layer (A) forming a lower sheet; (iii) in
a further coating step an adhesive composition is applied to
a further dehesively finished protective layer (C) such that
after evaporation of solvents a film is produced upon which
the backing layer impermeable for the active substance is
laminated forming an upper sheet; (iv) after removal of the
dehesively finished protective layer (B) from the lower
sheet there are positioned centrally disks, made of paper;
(v) subsequently the active substance is dosed onto the
disks of paper by means of a tampon; and (vi) after removal
of the dehesively finished protective layer (C) the upper
sheet is laminated to the lower sheet and the transdermal
therapeutic systems are punched therefrom.
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3b
Using paper as support material and inert adjuvant according to the invention
has
various advantages. When using fabrics, such as fleeces, there is always a
certain
range of deviation of the amount of active substance transferred to the single
TTS,
15 this being so in spite of a good dosing technique. For example, it has been
observed
that the amounts of nicotine transferred to the single TTS have a range of
deviation
of about 4% when using a fleece (70:30 viscose-cotton fiber blend, substance
weight
40 g/m2). If according to the invention paper is used instead, the range of
deviation is
considerably smaller; dependent on the surface weight of th'e paper it is
significantly
20 below 2%, e.g. with a paper having a basis weight of 23 g/m2 below 1.9% and
with
paper having a basis weight of 26 g/m2 even below 1.2%. The preferred papers
have
a basis weight of from 9 to 60, preferably from 15 to 40 and particularly from
20 to 35
9/m2=
25 The use of paper as support material in TTS according to the invention is.,
however,
of importance not only for the uniformity of the TTS produced but also for the
production technique. According to a known process a defined amount of the
active
substance is transferred to the support material by means of a tampon. This
implies
that in this process a certain amount of the support material is rubbed off by
the
30 tampon and is entrained upon detaching of the tampon from the support
material.
This requires the tampon to be cleaned at certain intervals and thus the
production
process has to be interrupted. When using paper according to the invention the
abrasion is significantly reduced, which can be explained by the fact that the
fibers of
paper are more firmly joined with each other than for example the fibers in a
fleece
35 or other fabric. It is known that fibrous fractions emanate from every
fabric. It is made
possible by the use of paper according to the invention that the ability of
the tampon
to function is prolonged at least by 10 times, mostly even by 50 to 100 times,
so that
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its cleaning and accordingly an interruption of the production process are
required
much less frequently.
TTS according to the invention can be of various configurations. Suitable
embodiments are shown in the attached Figures 1 and 2, although other
embodiments are possible, as they are for example disclosed in international
application WO 88/01516. According to Figures 1 and 2 the TTS consist of a
backing
layer (10), a reservoir matrix (12), one or more depots (14) and a fixing
device (16)
which are provided with a protective foil which is removed before
administration so
that the system is then fixed on the skin (18). The protective foil has also
to be
impermeable for the active substance, of course.
For the backing layer, the reservoir matrix, the fixing device and the
protective foils,
materials known to the skilled worker are used.
Subject of the invention is also a process for the improved production of
transdermal
therapeutic systems with a reduced range of deviation of the amounts of active
substance applied, wherein the active substance is applied in conventional
manner
by means of a tampon to a support material which consists of paper. According
to a
preferred embodiment the deviation (relative standard deviation) of the amount
of
active substance applied, as achieved by the procedure of the invention, is
less than
2%, particularly below 1.2%.
A final subject of the invention consists in the use of paper as a support and
distribution medium in transdermal therapeutic systems.
The systems according to the invention are in principle suitable for all
active
substances which can be administered transdermally. Particularly there may be
named, in addition to those mentioned above, lidocaine, diphenylhydramine
hydrochloride, salbutamol, 5-fluorouracil and as sexual hormone estradiol and
also
gestagens such as norethindrone acetate, levonorgestrel.
Example 1
First a pressure-sensitive adhesive preparation HS is prepared by homogenizing
a) 933 g of a commercial product ( Durotak 387-2516 of the company National
Starch
and Chemical, Zutphen, the Netherlands- this is a 40% solution of a self-
crosslinking acrylate polymer based on 2-ethylhexyl acrylate, vinyl acetate,
acrylic
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acid and titanium chelate ester in a solvent mixture of ethyl acetate,
ethanol,
heptane and methanol) with
b) 8 g of a triglyceride of fractionated coconut fatty acids (C8-CIo; Miglyol
812 of
the company Huls AG, Witten, Germany).
In addition 6210 g of Durotak 387-2516, 553 g of ethyl acetate and 311 g of
ethanol
are combined with 66 g of the aforementioned triglyceride and with 626 g of an
acrylic
resin prepared from dimethylaminoethyl methacrylate and neutral methacrylic
acid
esters ( Eudragit E 100 of the company Rbhm-Pharma, Darmstadt, Germany) and
homogenized (adhesive composition MS).
In addition 72 g of Eudragit E 100 are introduced into 101 g nicotine and
dissolved
therein. Thus the active substance preparation is obtained.
The pressure-sensitive adhesive composition HS is applied to a dehesively
finished
protective layer (A) such that after the evaporation of the solvents a
pressure-
sensitive adhesive layer is formed with a substance weight of 40 g/m2.
The adhesive composition MS is applied to a further dehesively finished
protective
layer (B) such that after evaporation of the solvents a film having a
substance weight
of 220 g/m2 is produced. Ths film is laminated to the pressure-sensitive
adhesive layer
applied to the protective layer (A). Thus the lower sheet is obtained.
In a further coating step the adhesive composition MS is applied to a further
dehesively finished protective layer (C) such that after evaporation of the
solvents a
film having a substance weight of 110 g/m2 is produced upon which the backing
layer
impermeable for the active substance is laminated. Here the upper sheet is
produced.
After removal of the dehesively finished protective layer (B) from the lower
sheet
there are positioned centrally disks made of a fleece fabric (70:30 viscose
rayon-
cotton fiber blend- substance weight 40 g/m2) or paper (26 or 24 g/m2
respectively).
Subsequently the active substance preparation is dosed onto the disks of
fleece
material or paper, respectively.
After removal of the dehesively finished protective layer (C) the upper sheet
is
laminated to the lower sheet (finished with disks of fleece material or paper
and
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provided with active substance preparation), and transdermal therapeutic
systems
are punched therefrom. The results are evident from the following table:
Number of Cleaning of the Tampon
TTS produced Fleece material Pa er
1,200 necessary no
2,400 necessary again no
3,600 necessary again no
4,800 necessary again no
more than 100,000 (continually after every no
1,200 TTS)
As is evident from the table it is possible when using fleece material to
produce only
1,200 transdermal therepeutic systems. Then cleaning of the device for
transfer of
the active substance (tampon) is required. Contrary thereto more than 100,000
transdermal therapeutic systems can be produced when using paper, without the
need to shut down the machinery owing to cleaning becoming necessary.
Example 2
Transdermal therapeutic systems were produced according to Example 1 and the
accuracy of the dosing was determined.
The amount of nicotine contained in the single transdermal therapeutic systems
was
determined and the results statistically evaluated. It was found that
transdermal
therapeutic systems which have been produced by using paper have a
significantly
smaller relative standard deviation (S-rel(%)) (see Figure 3).
