U.S. patent application number 17/589262 was filed with the patent office on 2022-05-19 for multi-day patch for the transdermal administration of rotigotine.
This patent application is currently assigned to LTS Lohmann Therapie-Systeme AG. The applicant listed for this patent is LTS Lohmann Therapie-Systeme AG. Invention is credited to Willi CAWELLO, Marco EMGENBROICH, Kristina KASSNER, Aurelia LAPPERT, Johannes Josef LEONHARD, Walter MULLER, Hans-Michael WOLFF.
Application Number | 20220151949 17/589262 |
Document ID | / |
Family ID | 1000006114430 |
Filed Date | 2022-05-19 |
United States Patent
Application |
20220151949 |
Kind Code |
A1 |
CAWELLO; Willi ; et
al. |
May 19, 2022 |
Multi-Day Patch for the Transdermal Administration of
Rotigotine
Abstract
The present invention relates to a transdermal therapeutic
system formed from (a) a backing layer, (b) a solvent-based
self-adhesive matrix layer containing rotigotine as active
ingredient, and (c) a release liner, in which the self-adhesive
matrix layer has a coating weight of about 75-400 g/m.sup.2 and
comprises a reservoir layer containing about 9-25 wt.-% rotigotine
based on the weight of the reservoir layer; a kit containing two
transdermal therapeutic systems of the present invention; and
methods for the preparation of the transdermal therapeutic system
of the present invention. The present invention further relates to
methods of treatment based upon the application of the inventive
transdermal therapeutic systems once or twice weekly via systems
adapted to allow for the transdermal administration of
therapeutically effective amounts of rotigotine for at least 3
days.
Inventors: |
CAWELLO; Willi; (Monheim,
DE) ; LAPPERT; Aurelia; (Woluwe Saint Pierre, BE)
; KASSNER; Kristina; (Bergisch Gladbach, DE) ;
WOLFF; Hans-Michael; (Monheim, DE) ; MULLER;
Walter; (Andernach, DE) ; LEONHARD; Johannes
Josef; (Bendorf, DE) ; EMGENBROICH; Marco;
(Rheinbach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LTS Lohmann Therapie-Systeme AG |
Andemach |
|
DE |
|
|
Assignee: |
LTS Lohmann Therapie-Systeme
AG
Andernach
DE
|
Family ID: |
1000006114430 |
Appl. No.: |
17/589262 |
Filed: |
January 31, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14443210 |
May 15, 2015 |
|
|
|
PCT/EP2013/003515 |
Nov 21, 2013 |
|
|
|
17589262 |
|
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|
Current U.S.
Class: |
1/1 ; 156/250;
424/449 |
Current CPC
Class: |
A61K 9/7069 20130101;
B32B 37/12 20130101; A61K 9/7084 20130101; A61K 31/381 20130101;
A61K 9/7092 20130101; B32B 2556/00 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/381 20060101 A61K031/381; B32B 37/12 20060101
B32B037/12 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 22, 2012 |
EP |
12193808.8 |
Claims
1. A method for dissolving rotigotine free base of crystalline form
II comprising dissolving the rotigotine free base in a solvent
system consisting of an aprotic polar solvent and a protic polar
solvent, wherein the aprotic polar solvent and the protic polar
solvent are present in a ratio of 2:1 to 9:1 (w/w).
2. The method as claimed in claim 1, wherein the aprotic polar
solvent and the protic polar solvent are present in a ratio of 2:1
to 6:1 (w/w).
3. The method as claimed in claim 1, wherein the aprotic polar
solvent is a carboxylic acid ester and the protic polar solvent is
an aliphatic alcohol.
4. The method as claimed in claim 1, wherein the aprotic polar
solvent is ethyl acetate and the protic polar solvent is
ethanol.
5. The method as claimed in claim 1, wherein the method comprises
dissolving the rotigotine free base in its entirety, with the
dissolving step performed at 40.degree. C.
6. The method as claimed in claim 1, wherein the method comprises
dissolving a first portion of the rotigotine free base while
stirring and subsequently dissolving a second portion of the
rotigotine free base while stirring with both the dissolving steps
performed at room temperature.
7. The method as claimed in claim 1, wherein the solvent system
comprises one or more adhesive(s) in addition to the aprotic polar
solvent and the protic polar solvent.
8. The method as claimed in claim 1, wherein the method comprises
adding a stabilizer to the solvent system.
9. The method as claimed in claim 1, wherein the method comprises
adding polyvinylpyrrolidone to the solvent system.
10. A method of making a transdermal therapeutic system, comprising
preparing a solvent-based self-adhesive matrix layer or layers
containing rotigotine as active ingredient by (i) preparing a
solution of adhesive(s) in a solvent system comprising an aprotic
polar solvent and a protic polar solvent optionally containing
further excipients; (ii) forming a mixture by adding either all or
a first portion of the rotigotine free base of crystalline form II
to the solution of step (i); (iii) adding a stabilizer to the
mixture of step (ii); (iv) optionally adding a second portion of
the rotigotine free base of crystalline form II to the mixture of
step (iii); (v) coating the mixture of step (iii) or step (iv) onto
a release liner; (vi) drying the coated mixture to thereby forming
the solvent-based self-adhesive matrix layer(s); and (vii)
laminating the dried self-adhesive matrix layer(s) to a backing
foil.
11. The method as claimed in claim 10, wherein the aprotic polar
solvent is a carboxylic acid ester and the protic polar solvent is
an aliphatic alcohol.
12. The method as claimed in claim 10, wherein the aprotic polar
solvent is ethyl acetate and the protic polar solvent is
ethanol.
13. The method as claimed in claim 10, wherein the aprotic polar
solvent and protic polar solvent are present in a ratio of 2:1 to
9:1 (w/w).
14. The method as claimed in claim 10, wherein the stabilizer is
polyvinylpyrrolidone and the adhesives(s) is/are one or more
silicone adhesive(s).
15. The method as claimed in claim 10, wherein the method comprises
adding the entirety of the rotigotine free base, with the adding
step (ii) performed while heating.
16. The method as claimed in claim 10, wherein the method comprises
adding the entirety of the rotigotine free base, with the adding
step (ii) performed while heating at 40.degree. C.
17. The method as claimed in claim 10, wherein the method comprises
adding a first portion of the rotigotine free base while stirring
in adding step (ii) and subsequently adding a second portion of the
rotigotine free base while stirring in adding step (iv), with both
steps (ii) and (iv) performed at room temperature.
18. The method as claimed in claim 10, wherein the method has a
total processing time to form the transdermal therapeutic system
ranging from approximately 8.5 to 9 hours.
19. A method of preparing a kit comprising two
rotigotine-containing transdermal therapeutic systems, wherein the
method comprises forming two transdermal therapeutic systems as
claimed in claim 10, the two transdermal therapeutic systems having
the same or a different rotigotine content.
20. A method of preparing a kit as claimed in claim 19, wherein the
two transdermal therapeutic systems have the same rotigotine
content and each of them is adapted to allow for the transdermal
administration of therapeutically effective amounts of rotigotine
for at least 3 days.
21. A method of preparing a kit as claimed in claim 19, wherein the
two transdermal therapeutic systems have a different rotigotine
content and one of them is adapted to allow for the transdermal
administration of therapeutically effective amounts of rotigotine
for at least 3 days and the other one is adapted to allow for the
transdermal administration of therapeutically effective amounts of
rotigotine for at least 4 days.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional application of pending
parent U.S. patent application Ser. No. 14/443,210, filed May 15,
2015, which was filed as a National Stage Application of
International Application No. PCT/EP2013/003515 filed Nov. 21,
2013, which claims priority to European parent application EP
12193808.8, filed Nov. 22, 2012. Each of the foregoing
applications, i.e. U.S. patent application Ser. No. 14/443,210;
PCT/EP2013/003515 and EP 12193808.8, are hereby incorporated by
reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel multi-day
transdermal therapeutic system (TTS), which is adapted to allow for
the transdermal administration of therapeutically effective amounts
of rotigotine for at least 3 days and up to at least 7 days.
TECHNICAL BACKGROUND
[0003] Rotigotine is the International Non-Proprietary Name (INN)
of the compound
(-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-n-
aphthalenol having the structure shown below
##STR00001##
[0004] Rotigotine exists in two different polymorphic states,
Polymorphic Form I and Polymorphic Form II, which can be
differentiated by their melting point, infrared (IR) spectroscopy,
solid state nuclear magnetic resonance (SSNMR) or Raman
spectroscopy as well as differential scanning calorimetry (DSC) and
X-ray powder diffraction (XRD). The different physicochemical
characteristics of the two polymorphic forms of rotigotine are for
example described in WO 2009/068520.
[0005] Rotigotine is a non-ergolinic dopamine D1/D2/D3-receptor
agonist that resembles dopamine structurally and has a similar
receptor profile but a higher receptor affinity.
[0006] In contrast to other non-ergolinic dopamine agonists,
rotigotine has significant D1 activity, which may contribute to a
greater physiological action.
[0007] In contrast to ergolinic compounds, rotigotine has a very
low affinity for 5 HT.sub.2B receptors and thus a low risk of
inducing fibrosis.
[0008] Actions on non-dopaminergic receptors (such as 5-HT.sub.1A
agonism and A.sub.2B antagonism) may contribute to other beneficial
effects, such as antidyskinetic activity, neuroprotective activity
and antidepressive effects.
[0009] Rotigotine is disclosed as active agent for treating
patients suffering from Parkinson's disease (described in WO
2002/089777), Parkinson's plus syndrome (described in WO
2005/092331), depression (described in WO 2005/009424) and the
restless-legs syndrome (described in WO 2003/092677) as well as for
the treatment or prevention of dopaminergic neuron loss (described
in WO 2005/063237).
[0010] Known pharmaceutical compositions containing rotigotine
comprise a single-day, solvent-based transdermal therapeutic system
(TTS) (described in WO 99/49852), a depot form (described in WO
02/15903), an iontophoretic device (described in WO 2004/050083)
and an intranasal formulation (described in WO 2005/063236).
[0011] In WO 2004/012721, a transdermal therapeutic system (TTS) is
described, which contains rotigotine in a self-adhesive layer being
prepared from a hot-meltable adhesive. The transdermal therapeutic
systems of WO 2004/012721 are provided for a single-day or a
multi-day application and allow for a continuous release of
rotigotine for e.g. up to at least 7 days in an in vitro skin
permeation model.
[0012] Compared to the hot-meltable adhesive-based transdermal
therapeutic systems of WO 2004/012721, the solvent-based
transdermal therapeutic systems known from the prior art have a
limited capacity for loading their self-adhesive layer with
rotigotine.
[0013] So far, it was therefore not possible to prepare
solvent-based transdermal therapeutic systems providing for a
continuous release of rotigotine for 3 or more days.
[0014] It was, therefore, an object of the present invention to
provide a solvent-based transdermal therapeutic system comprising
rotigotine in an amount allowing for the continuous administration
of therapeutically effective amounts of rotigotine for at least 3
days and up to at least 7 days after one application.
SUMMARY OF ADVANTAGEOUS EMBODIMENTS OF THE INVENTION
[0015] The present invention is based on the development of
solvent-based self-adhesive matrices for transdermal therapeutic
systems containing increased amounts of rotigotine, which allow for
the transdermal administration of therapeutically effective amounts
of rotigotine for at least 3 days and up to at least 7 days after
one application of a corresponding transdermal therapeutic system
and wherein the transdermal therapeutic system complies with the
needs of a convenient application in view of size, thickness and
skin tolerance and can easily and cost-effectively be prepared.
[0016] Moreover, it was surprisingly found that the total amount of
rotigotine being required for the continuous administration of
therapeutically effective amounts of rotigotine for at least 3 days
and up to at least 7 days by the transdermal therapeutic system of
the present invention was lower than expected/calculated for the
respective number of single-day solvent-based transdermal
therapeutic systems known from the prior art.
[0017] In a first aspect, the present invention therefore provides
a transdermal therapeutic system, comprising
(a) a backing layer, (b) a solvent-based self-adhesive matrix layer
containing rotigotine as active ingredient, and (c) a release
liner, wherein the self-adhesive matrix layer has a coating weight
of about 75-400 g/m.sup.2 and comprises a reservoir layer
containing about 9-25 wt.-% rotigotine based on the weight of the
reservoir layer.
[0018] In a further embodiment the transdermal therapeutic system,
comprising
(a) a backing layer, (b) a solvent-based self-adhesive matrix layer
containing rotigotine as active ingredient, and (c) a release
liner, wherein the self-adhesive matrix layer has a coating weight
of about 100-400 g/m.sup.2 and comprises a reservoir layer
containing about 9-20 wt.-% rotigotine based on the weight of the
reservoir layer.
[0019] In the context of the present application the term "about"
shall mean+/-10% of the respective figure unless otherwise
indicated.
[0020] In one embodiment, the self-adhesive matrix layer of the
transdermal therapeutic system further comprises a skin adhesive
layer containing rotigotine in a concentration of about 0-10 wt.-%
based on the weight of the skin adhesive layer and the skin
adhesive layer is provided between the reservoir layer and the
release liner and has a lower rotigotine concentration than the
reservoir layer.
[0021] In a further embodiment, the reservoir layer of the
transdermal therapeutic system has a coating weight of about 75-300
g/m.sup.2, preferably of about 75-200 g/m.sup.2, more preferably
about 100-150 g/m.sup.2 and contains about 9-25 wt.-% rotigotine,
preferably about 18 wt.-% rotigotine based on the weight of the
reservoir layer.
[0022] In a further embodiment, the reservoir layer of the
transdermal therapeutic system has a coating weight of about 75-200
g/m.sup.2, preferably of about 100-150 g/m.sup.2 and contains about
9-25 wt.-% rotigotine, preferably about 18 wt.-% rotigotine based
on the weight of the reservoir layer and the skin adhesive layer
has a coating weight of about 10-150 g/m.sup.2.
[0023] In a preferred embodiment, the skin adhesive layer of the
transdermal therapeutic system has a coating weight of about 15-120
g/m.sup.2 and contains about 5-10 wt.-% rotigotine based on the
weight of the skin adhesive layer.
[0024] In a further preferred embodiment, the skin adhesive layer
of the transdermal therapeutic system has a coating weight of about
15-50 g/m.sup.2 and contains about 0-5 wt.-% rotigotine based on
the weight of the skin adhesive layer.
[0025] In a further embodiment, the transdermal system contains
about 10-32 mg rotigotine/10 cm.sup.2 surface of the self-adhesive
matrix layer, preferably about 27 mg rotigotine/10 cm.sup.2 surface
of the self-adhesive matrix layer.
[0026] In a preferred embodiment, the reservoir layer or the
reservoir layer and the skin adhesive layer, if it contains
rotigotine, of the transdermal therapeutic system further
contain(s) polyvinylpyrrolidone and the rotigotine to
polyvinylpyrrolidone weight ratio in the respective layer is 9:2 to
9:5, preferably 9:3 to 9:5, or multiples thereof.
[0027] In a further preferred embodiment, the reservoir layer and,
if present, the skin adhesive layer of the transdermal therapeutic
system each contain at least one, preferably two, amine-resistant
silicone pressure sensitive adhesive(s).
[0028] In a further embodiment, the transdermal therapeutic system
is adapted to allow for the transdermal administration of
therapeutically effective amounts of rotigotine for at least 3-7
days.
[0029] In a preferred embodiment, the transdermal therapeutic
system is adapted to allow for the transdermal administration of
therapeutically effective amounts of rotigotine for at least 7
days.
[0030] The multi-day transdermal therapeutic system of the present
invention has the advantage of allowing for a reduced application
frequency compared to daily applied conventional transdermal
therapeutic systems. This is particularly advantageous for patients
suffering from severe dopaminergic disorders, like Parkinson's
Disease, as these patients often experience motor disabilities
which make the frequent handling and administration of transdermal
patches difficult. At the same time, the number of skin application
sites to be treated with patches during a long-term patch
medication is reduced. A prolongation of the medication interval
e.g. from 1 day to at least 3 or even at least 7 days minimizes the
potential risk of skin lesions associated with repeated patch
stripping from the patients' skin at skin application sites
selected for repeated patch administration. In addition, the
influence of inter- and intra-individually differing lag-times on
the absorption of rotigotine, which may be associated with the
daily replacement of rotigotine-containing patches in the case of
low skin permeability and which may cause therapeutically unwanted
fluctuations of the plasma levels of rotigotine, can be eliminated
by the multi-day patches of the present invention. Finally, the
replacement of a daily patch administration by one single
administration for several days, for example by an administration
once or twice weekly, contributes to the reduction of the costs of
the respective medication by saving material and production
time.
[0031] In a second aspect, the present invention provides a kit
comprising two transdermal therapeutic systems of the present
invention, wherein the two transdermal therapeutic systems may have
the same or a different rotigotine content. In one embodiment, the
two transdermal therapeutic systems of the kit have a different
rotigotine content and one of them is adapted to allow for the
transdermal administration of therapeutically effective amounts of
rotigotine for at least days and the other one is adapted to allow
for the transdermal administration of therapeutically effective
amounts of rotigotine for at least 4 days. In a preferred
embodiment, the two transdermal therapeutic systems of the kit have
the same rotigotine content and each of them is adapted to allow
for the transdermal administration of therapeutically effective
amounts of rotigotine for at least 4 days.
[0032] In a third aspect, the present invention provides a method
for the preparation of the transdermal therapeutic system of the
present invention.
[0033] In present invention the preparation method involves the use
of a solvent system consisting of an aprotic polar solvent and a
protic polar solvent.
[0034] In one embodiment, the preparation method involves the use
of a solvent system consisting of an aprotic polar solvent and a
protic polar solvent in a ratio of 2:1 to 9:1.
[0035] In a preferred embodiment, the solvent system consists of a
carboxylic acid ester and an aliphatic alcohol. In a more preferred
embodiment the solvent system consists of ethyl acetate and
ethanol. In a particular preferred embodiment the solvent system
consists of ethyl acetate and ethanol in a ratio of 2:1 to 6:1.
[0036] In a further embodiment, the preparation method involves the
use of a solvent system consisting of heptane and ethanol in a
ratio of 1.5:1 to 1:1.5.
[0037] In another preferred embodiment, the preparation method is
carried out at room temperature and rotigotine is added to the
solvent system in two portions. When rotigotine is added in two
portions, one portion is added before and the other portion is
added after polyvinylpyrrolidone is added.
[0038] In another preferred embodiment, the preparation method is
carried out at room temperature and the total amount of rotigotine
is added to the solvent system in one portion together with
polyvinylpyrrolidone.
[0039] In another preferred embodiment, polyvinylpyrrolidone is
first dissolved in the solvent system and adhesive mixture and
rotigotine is then added to this pre-solution at room
temperature.
[0040] In a further preferred embodiment, rotigotine of polymorphic
Form II is used as starting material in the preparation method of
the present invention.
[0041] In a further aspect, the present invention provides a
transdermal therapeutic system comprising rotigotine as active
ingredient for use in the treatment of patients suffering from
Parkinson's disease, Parkinson's plus syndrome, depression,
fibromyalgia and the restless-legs syndrome and for use in the
treatment or prevention of dopaminergic neuron loss or the
treatment or prevention of cognitive disorders by transdermal
administration of rotigotine once or twice weekly, wherein the
transdermal therapeutic system comprises a backing layer, a
solvent-based rotigotine containing self-adhesive matrix layer as
well as a release liner and is adapted to allow for the transdermal
administration of therapeutically effective amounts of rotigotine
for at least 3 days.
[0042] In one embodiment, the transdermal therapeutic system for
the above use is administered once weekly and is adapted to allow
for the transdermal administration of therapeutically effective
amounts of rotigotine for at least 7 days.
[0043] In a further embodiment, the transdermal therapeutic system
for the above use is administered twice weekly and the two
transdermal therapeutic systems which are administered per week
have the same or a different rotigotine content and are adapted to
together allow for the transdermal administration of
therapeutically effective amounts of rotigotine for at least 7
days.
[0044] In one embodiment, the two transdermal therapeutic systems
for the above use which are administered per week have the same
rotigotine content.
[0045] In another embodiment, two transdermal therapeutic systems
for the above use which are administered per week have a different
rotigotine content and one of them is adapted to allow for the
transdermal administration of therapeutically effective amounts of
rotigotine for at least 3 days and the other one is adapted to
allow for the transdermal administration of therapeutically
effective amounts of rotigotine for at least 4 days.
[0046] In a further embodiment, the self-adhesive matrix layer of
the transdermal therapeutic system for the above use has a coating
weight of about 75-400 g/m.sup.2 and comprises a reservoir layer
containing about 9-25 wt.-% rotigotine based on the weight of the
reservoir layer.
[0047] In a another embodiment, the self-adhesive matrix layer of
the transdermal therapeutic system for the above use has a coating
weight of about 100-400 g/m.sup.2 and comprises a reservoir layer
containing about 9-20 wt.-% rotigotine based on the weight of the
reservoir layer.
[0048] In a further embodiment, the self-adhesive matrix layer of
the transdermal therapeutic system for the above use further
comprises a skin adhesive layer containing rotigotine in a
concentration of about 0-10 wt.-% based on the weight of the skin
adhesive layer and the skin adhesive layer is provided between the
reservoir layer and the release liner and has a lower rotigotine
concentration than the reservoir layer.
[0049] In a preferred embodiment, the skin adhesive layer of the
transdermal therapeutic system for the above use has a coating
weight, which is no more than the coating weight of the reservoir
layer.
[0050] In a further embodiment, the transdermal therapeutic system
for the above use contains about 10-32 mg rotigotine/10 cm.sup.2
surface of the self-adhesive matrix layer, preferably about 27 mg
rotigotine/10 cm.sup.2 surface of the self-adhesive matrix
layer.
[0051] In a preferred embodiment, the reservoir layer or the
reservoir layer and the skin adhesive layer, if it contains
rotigotine, of the transdermal therapeutic system for the above use
further contain(s) poly (N-vinyl-2-pyrrolidone) abbreviated here as
polyvinylpyrrolidone or PVP and the rotigotine to
polyvinylpyrrolidone weight ratio in the respective layer is 9:2 to
9:5, preferably 9:3 to 9:5, or multiples thereof.
[0052] In a further preferred embodiment, the reservoir layer and,
if present, the skin adhesive layer of the transdermal therapeutic
system for the above use each contain at least one, preferably two,
amine-resistant silicone pressure sensitive adhesive(s).
BRIEF DESCRIPTION OF THE FIGURES
[0053] FIG. 1 shows a flow chart of a method for the preparation of
a multi-day rotigotine containing patch of the present invention
using a solvent system consisting of ethyl acetate and ethanol in a
ratio of 5:1 and involving the addition of rotigotine in one
portion under heating;
[0054] FIG. 2a shows a flow chart of a method for the preparation
of a multi-day rotigotine containing patch of the present invention
using a solvent system consisting of ethyl acetate and ethanol in a
ratio of 5:1 and involving the addition of rotigotine in two
portions, one before and the other after PVP is added, at room
temperature without heating;
[0055] FIG. 2b shows a flow chart of a method for the preparation
of a multi-day rotigotine containing patch of the present invention
using a solvent system consisting of ethyl acetate and ethanol,
involving the addition of rotigotine in one portion to a PVP
solution and a silicone adhesives mixture, at room temperature
without heating;
[0056] FIG. 3 shows a flow chart of a method for the preparation of
a multi-day rotigotine containing patch of the present invention
using a solvent system consisting of heptane and ethanol in a ratio
of 1:1.5;
[0057] FIG. 4a shows the plasma concentration time profiles of
rotigotine over 4 days after the administration of one 4-day
mono-layer TTS of Example 1 (Treatment A) in comparison to the
daily administration of four 1-day patches of Comparative Example 1
(Treatment B) (n=12);
[0058] FIG. 4b shows the plasma concentration time profiles of
rotigotine after the administration of one 4-day mono-layer TTS of
Example 1 (Treatment A, n=12) and one 7-day bi-layer TTS of Example
2 (Treatment C, n=16);
[0059] FIG. 5a shows the individual rotigotine plasma concentration
ratios over 4 days obtained after the single administration of the
4-day mono-layer TTS of Example 1 in comparison to the once daily
application of four 1-day patches of Comparative Example 1 in Study
1 (n=12);
[0060] FIG. 5b shows the individual rotigotine plasma concentration
ratios over 7 days obtained after the single administration of the
7-day bi-layer TTS of Example 2 in comparison to the once daily
application of seven 1-day patches of Comparative Example 1 in
Study 2 (n=16);
[0061] FIG. 6 shows the membrane permeation profile of the 7-day
bi-layer TTS of Example 2;
[0062] FIG. 7 shows the membrane permeation profile of the 7-day
bi-layer TTS of Example 2 in comparison to the 7-day bi-layer TTS
of Example 6;
[0063] FIG. 8 shows the cumulative permeation profile of the 7-day
bi-layer TTS of Example 2 and the 7-day mono-layer TTS of Example 4
in comparison to the 1-day TTS of Comparative Example 2;
[0064] FIG. 9 shows the cumulative release (Q) of rotigotine from
the 7-day bi-layer TTS of Example 2 comprising a skin adhesive
layer in comparison to the 7-day mono-layer TTS of Example 3
comprising no skin adhesive layer; and
[0065] FIG. 10 shows schematic drawings of possible multi-day patch
variants
DETAILED DESCRIPTION OF ADVANTAGEOUS EMBODIMENTS
[0066] The present invention provides in a first aspect a
transdermal therapeutic system, comprising
(a) a backing layer, (b) a solvent-based self-adhesive matrix layer
containing rotigotine as active ingredient, and (c) a release
liner, wherein the self-adhesive matrix layer has a coating weight
of about 75-400 g/m.sup.2 and comprises a reservoir layer
containing about 9-25 wt.-% rotigotine based on the weight of the
reservoir layer.
[0067] In a further embodiment of present invention the transdermal
therapeutic system, comprises
(a) a backing layer, (b) a solvent-based self-adhesive matrix layer
containing rotigotine as active ingredient, and (c) a release
liner, wherein the self-adhesive matrix layer has a coating weight
of about 100-400 g/m.sup.2 and comprises a reservoir layer
containing about 9-20 wt.-% rotigotine based on the weight of the
reservoir layer.
[0068] The term "transdermal therapeutic system" (TTS) as used
herein refers to a matrix-type patch having a continuous
self-adhesive matrix layer in its centre portion. Such a patch
consists of a backing layer, the self-adhesive matrix layer and a
release liner, which is removed before use. In the present
application, the terms "transdermal therapeutic system", "TTS" and
"patch" are equivalently used in order to describe the transdermal
therapeutic system of the present invention.
[0069] The term "solvent-based" as used herein to describe the
self-adhesive matrix layer of the transdermal therapeutic system of
the present invention means that during the manufacturing process
of the transdermal therapeutic system of the present invention
rotigotine and the other components of the self-adhesive matrix
layer are dissolved or dispersed and mixed in an organic
solvent.
[0070] The term "self-adhesive matrix layer" as used herein
describes the sum of adhesive containing layers, e.g. reservoir
layer, skin adhesive layer and rotigotine containing skin adhesive
layer and all combinations thereof as shown in FIG. 10. In case the
transdermal therapeutic system contains only one reservoir layer,
this reservoir layer represents the self-adhesive matrix layer.
[0071] The term "release liner" is used synonymous with protective
foil or sheet.
[0072] This is in contrast to hot-melt manufacturing processes
during which the components of a self-adhesive matrix layer of a
transdermal therapeutic system are mixed in the absence of any
solvent(s) in a heat molten state. Adhesives being suitable for use
in a hot-melt manufacturing process exhibit a dynamic viscosity of
no more than 60 Pas, no more than 80 Pas, no more than 100 Pas, no
more than 120 Pas or at most 150 Pas at a temperature of
160.degree. C. Depending on the dynamic viscosity of the employed
adhesive(s) at 160.degree. C., the addition of a softener, such as
waxes, silicone oils, glycerin, condensates from glycerin with
fatty acids or polyols, or laurylacetate, or, in particular,
glycerolmonolaurate, laurylacetate, waxes of the formula
R--C(O)--OR', alkylmethylsiloxane waxes, siloxated polyether waxes,
organic waxes or glycerin, may be required to adjust the viscosity
of the adhesive(s), in particular of silicone adhesive(s), in a
suitable manner during hot-melt manufacturing processes.
[0073] Silicone adhesives being suitable for preparing the
solvent-based self-adhesive matrix layer of the transdermal
therapeutic system of the present invention without any additive(s)
exhibit a dynamic viscosity of above 150 Pas at a temperature of
160.degree. C. and therefore require the addition of a softener in
order to be suitable for a hot-melt manufacturing process.
[0074] In one embodiment, the solvent-based self-adhesive matrix
layer of the transdermal therapeutic system of the present
invention does therefore not contain an adhesive having a dynamic
viscosity of no more than 60 Pas, no more than 80 Pas, no more than
100 Pas, no more than 120 Pas or at most 150 Pas at a temperature
of 160.degree. C.
[0075] In another embodiment, the adhesive(s) used for preparing
the solvent-based self-adhesive matrix layer of the transdermal
therapeutic system of the present invention does/do not contain a
softener, which after the addition to an adhesive lowers the
viscosity of said adhesive to no more than 60 Pas, no more than 80
Pas, no more than 100 Pas, no more than 120 Pas or at most 150 Pas
at a temperature of 160.degree. C. Said softener may be selected
from the group consisting of waxes, silicone oils, glycerin,
condensates from glycerin with fatty acids or polyols, and
laurylacetate or which may in particular be selected from the group
consisting of glycerolmonolaurate, laurylacetate, waxes of the
formula R--C(O)--OR', alkylmethylsiloxane waxes, siloxated
polyether waxes, organic waxes and glycerin.
[0076] The transdermal therapeutic system of the present invention
comprising a solvent-based self-adhesive matrix layer and a
transdermal therapeutic system obtained by a hot-melt manufacturing
process are characterized by different physico-chemical properties,
such as different drug release properties, even if the qualitative
and quantitative composition of the respective transdermal
therapeutic systems is identical.
[0077] The addition of one or more softeners to an adhesive will
lower the dynamic viscosity of the adhesive in the heat molten
state, but will at the same time also lower the cohesion of the
self-adhesive matrix layer of an accordingly prepared final TTS
thereby causing a loss of structural integrity due to an increased
cold flow of the adhesive layer. This constraint is avoided by the
solvent-based manufacturing process leading to the transdermal
therapeutic system of the present invention.
[0078] The backing layer of the transdermal therapeutic system of
the present invention is inert to the components of the
self-adhesive matrix layer. It is a film being impermeable to
rotigotine. Such a film may consist of polyester, polyamide,
polyethylene, polypropylene, polyurethane, polyvinyl chloride or a
combination of the aforementioned materials. These films may or may
not be coated, e.g. with an aluminum film or with aluminum vapour
or with a silicone layer. The thickness of the backing layer may be
between 10 and 100 .mu.m, preferably between 15 and 40 .mu.m.
[0079] In one embodiment, the self-adhesive matrix layer is formed
by a solid dispersion consisting of a dispersing agent and a
dispersed phase, which is immiscible with the dispersing agent.
[0080] The dispersing agent of the solid dispersion may be any
solid or semi-solid semi-permeable polymer or copolymer. The
dispersing agent should provide sufficient activity and stability
for the solid dispersion as well as sufficient release of
rotigotine. Usually this polymer will be a pressure sensitive
adhesive (PSA) or a mixture of such adhesives.
[0081] The solid dispersion forming the self-adhesive matrix layer
of the transdermal therapeutic system of the present invention
comprises an adhesive or a mixture of adhesives as dispersing agent
and rotigotine as well as polyvinylpyrrolidone in the dispersed
phase.
[0082] In a preferred embodiment, the self-adhesive matrix layer of
the transdermal therapeutic system of the present invention
contains about 10-32 mg rotigotine/10 cm.sup.2 surface of the
self-adhesive matrix layer, preferably about 13.5 mg or about 27 mg
rotigotine/10 cm.sup.2 surface of the self-adhesive matrix
layer.
[0083] Preferably, the self-adhesive matrix layer of the
transdermal therapeutic system of the present invention contains
about 6-25 wt.-%, more preferred about 9-25 wt.-%, even more
preferred about 9-20 wt.-% and most preferred about 9 or about 18
wt.-% rotigotine based on the weight of the self-adhesive matrix
layer
[0084] In one embodiment, the self-adhesive matrix layer comprises
a reservoir layer. The reservoir layer represents a matrix layer
and is formed by a solid dispersion in terms of the foregoing. In a
preferred embodiment, the self-adhesive matrix layer only comprises
one reservoir layer and does not contain any additional matrix
layer, i.e., in a preferred embodiment, the self-adhesive matrix
layer represents a "mono-layer" matrix.
[0085] In another embodiment, the self-adhesive matrix layer may
contain more than one reservoir layer, for example 2, 3, 4 or 5
reservoir layers.
[0086] The reservoir layer contains about 9-25 wt.-%, preferably
about 9-20 wt.-% and most preferably about 9 wt.-% or about 18
wt.-% rotigotine based on the weight of the reservoir layer.
[0087] The reservoir layer has a coating weight of about 75-400
g/m.sup.2, preferably about 100-400 g/m.sup.2, more preferably
about 75-300 g/m.sup.2, more preferably about 75-200 g/m.sup.2,
even more preferably 100-150 g/m.sup.2 and most preferably about
150 g/m.sup.2.
[0088] In a further embodiment, the reservoir layer of the
transdermal therapeutic system has a coating weight of about 75-300
g/m.sup.2, preferably about 75-200 g/m.sup.2, more preferably about
100-150 g/m.sup.2 and most preferably about 150 g/m.sup.2 and
contains about 9-25 wt.-% rotigotine, preferably about 9-20 wt.-%
rotigotine, more preferably about 9 wt.-% or about 18 wt.-%
rotigotine based on the weight of the reservoir layer.
[0089] In a another embodiment, the reservoir layer of the
transdermal therapeutic system has a coating weight of about 75-300
g/m.sup.2, preferably of about 75-200 g/m.sup.2, more preferably
about 100-150 g/m.sup.2 and most preferably about 150 g/m.sup.2 and
contains about 9-25 wt.-% rotigotine, preferably about 9-20 wt.-%
rotigotine, more preferably about 9 wt.-% or about 18 wt.-%
rotigotine based on the weight of the reservoir layer and a skin
adhesive layer that has a coating weight of about 10-150
g/m.sup.2.
[0090] In a further embodiment, the self-adhesive matrix layer
further comprises a skin adhesive layer. Similar to the reservoir
layer, the skin adhesive layer represents a matrix layer and is
preferably formed by a solid dispersion in terms of the foregoing.
The skin adhesive layer is provided between the reservoir layer and
the release liner. In one embodiment, the skin adhesive layer
contains no active ingredient, i.e. no rotigotine. In another
embodiment, the skin adhesive layer contains rotigotine.
[0091] In a preferred embodiment, the self-adhesive matrix layer
comprises a reservoir layer and a skin adhesive layer and does not
contain any additional matrix layer, i.e., in a preferred
embodiment, the self-adhesive matrix layer represents a "bi-layer"
matrix.
[0092] The skin adhesive layer avoids a direct skin contact of the
reservoir layer, which contains in some embodiments a high
concentration of rotigotine, which would potentially cause local
skin irritation, or might show diminished skin adhesiveness due to
the high drug load. The skin adhesive layer therefore contains
either no rotigotine or, if it contains rotigotine, has a lower
rotigotine concentration than the reservoir layer, if the
rotigotine concentration of the latter exceeds 9 wt.-%. For
example, results obtained for the daily application of a TTS having
a self-adhesive matrix layer only comprising a reservoir layer,
i.e. a "mono-layer" matrix, containing 9 wt.-% rotigotine and 4
wt.-% PVP, have shown a good skin tolerability. The composition of
the respective reservoir layer thus also represents a reasonable
composition for a skin adhesive layer of a self-adhesive bi-layer
matrix of the transdermal therapeutic system of the present
invention. In a preferred embodiment, the self-adhesive matrix
layer therefore is built up of one or more reservoir layer(s) and a
skin adhesive layer, wherein the rotigotine/PVP concentration is
increasing from the skin towards the backing layer in order to
provide for sufficient skin tolerability, sufficient tack of the
skin adhesive layer and a high drug concentration in the reservoir
layer. Moreover, adequately adjusting the rotigotine/PVP content in
the reservoir layer(s) and the skin adhesive layer allows for
modifying the onset of drug release and the release profile of the
transdermal therapeutic system of the present invention in
vivo.
[0093] The skin adhesive layer contains rotigotine in a
concentration of about 0-10 wt.-%, preferably about 0-9 wt.-% and
most preferably about 6-9 wt.-% based on the weight of the skin
adhesive layer, and has a lower rotigotine concentration than the
reservoir layer.
[0094] Due to the lower rotigotine concentration in the skin
adhesive layer, the transdermal therapeutic system of the present
invention comprising a reservoir layer and a skin adhesive layer
represents a gradient system being characterized by an increase of
the rotigotine concentration from the surface of the skin adhesive
layer being in contact with the patient's skin upon administration
towards the reservoir layer and the backing layer.
[0095] The skin adhesive layer has a coating weight of about 10-150
g/m.sup.2, preferably about 15-120 g/m.sup.2, such as e.g. about
15-50 g/m.sup.2 or about 50-100 g/m.sup.2.
[0096] In a preferred embodiment, the coating weight of the skin
adhesive layer is no more than the coating weight of the reservoir
layer.
[0097] In a further preferred embodiment, the reservoir layer has a
coating weight of about 75-200 g/m.sup.2, preferably 100-150
g/m.sup.2, and more preferably 150 g/m.sup.2 and contains about 18
wt.-% rotigotine based on the weight of the reservoir layer.
[0098] In another preferred embodiment, the reservoir layer has a
coating weight of about 75-200 g/m.sup.2, preferably 100-150
g/m.sup.2, and more preferably 150 g/m.sup.2 and contains about 18
wt.-% rotigotine based on the weight of the reservoir layer and the
skin adhesive layer has a coating weight of about 10-150
g/m.sup.2.
[0099] In another preferred embodiment, the reservoir layer and the
skin adhesive layer have the same coating weight. For example, the
reservoir layer and the skin adhesive layer may each have a coating
weight of 100 g/m.sup.2 or 150 g/m.sup.2.
[0100] In another preferred embodiment, the skin adhesive layer has
a coating weight of about 15-120 g/m.sup.2 and contains about 5-10
wt.-% rotigotine based on the weight of the skin adhesive
layer.
[0101] In another preferred embodiment, the skin adhesive layer has
a coating weight of about 15-50 g/m.sup.2 and contains about 0-5
wt.-% rotigotine based on the weight of the skin adhesive
layer.
[0102] The term "coating weight" as used herein in connection with
the skin adhesive layer or reservoir layer or self-adhesive matrix
layer refers to the mass per area unit of each individual layer or
the sum of individual layers after removal of the solvent, except
backing layer and release liner. In this connection coating weight
is synonymous with area weight.
[0103] The following table 1A shows particular preferred
embodiments of the self-adhesive matrix layer of the transdermal
therapeutic system of the present invention.
TABLE-US-00001 TABLE 1A Composition of preferred embodiments of the
self-adhesive matrix layer of the transdermal therapeutic system of
the present invention Embodiment (corresp. Example) Ingredient
[mg/10 cm.sup.2] , 4 5 except stated otherwise 1 (1) 2 (2) 3 (3)
(4, 8, 9) (5, 6) 6 (7) Reservoir Rotigotine 13.5 27.0 27.0 27.0
27.0 18.0 layer Rotigotine 9.0 18.0 18.0 18.0 9.0 18.0 content
[wt.-%] PVP 3.0 6.0 12.0 12.0 12.0 8.0 PVP 2.0 4.0 8.0 8.0 4.0 8.0
content [wt.-%] Rotigotine:PVP 9:2 9:2 9:4 9:4 9:4 9:4 Coating
weight 150.0 150.0 150.0 150.0 300.0 100.0 [g/m.sup.2] Skin
Rotigotine -- -- -- -- -- 9.0 adhesive Rotigotine -- -- -- -- --
9.0 layer content [wt.-%] PVP -- -- -- -- -- 4.0 PVP content -- --
-- -- -- 4.0 [wt.-%] Rotigotine:PVP -- -- -- -- -- 9:4 Coating
weight -- 18.0 18.0 -- -- 100.0 [g/m.sup.2]
[0104] A TTS having a self-adhesive matrix layer according to
embodiment 1 of the above table allows for the transdermal
administration of therapeutically effective amounts of rotigotine
for at least 4 days, i.e. it represents a 4-day patch.
[0105] A TTS having a self-adhesive matrix layer according to any
of embodiments 2, 3, 4, 5 or 6 of the above table allows for the
transdermal administration of therapeutically effective amounts of
rotigotine for at least 7 days, i.e. it represents a 7-day
patch.
[0106] The term "at least" as used herein in connection with the
respective number of days to describe the duration of the
transdermal administration of therapeutically effective amounts of
rotigotine means that rotigotine is administered for the respective
number of days or more. For example, "at least 7 days" means that
therapeutically effective amounts of rotigotine are administered
for 7 days or more.
[0107] The term "administration of therapeutically effective
amounts of rotigotine" as used herein refers to the adjustment
rotigotine plasma concentrations in a patient suffering from a
disease to be treated with rotigotine, which lie within the
therapeutic window of rotigotine for the treatment of the
respective disease. For example, by administering a therapeutically
effective amount of rotigotine in the treatment of Parkinson's
disease, a rotigotine plasma concentration of between about 0.2 and
1.2 ng/ml during maintenance phase is adjusted and by administering
a therapeutically effective amount of rotigotine in the treatment
of RLS, a rotigotine plasma concentration of between about 0.1 and
0.5 ng/ml during maintenance phase is adjusted.
[0108] The commercial rotigotine-containing NEUPRO.RTM. patches of
the applicant allow for the transdermal administration of
therapeutically effective amounts of rotigotine for 1 day and
contain 4.5 mg/10 cm.sup.2 rotigotine. Based on this content, a
theoretical amount of rotigotine of 18.0 mg being required for a
4-day patch and of 31.5 mg for a 7-day patch can be calculated.
[0109] However, it was surprisingly found that a rotigotine amount
of about 13.5 mg in a TTS of the present invention was sufficient
to allow for the transdermal administration of therapeutically
effective amounts of rotigotine for 4 days and that a rotigotine
amount of about 27.0 mg in a TTS of the present invention was
sufficient to allow for the transdermal administration of
therapeutically effective amounts of rotigotine for 7 days.
[0110] Table 1B gives an overview on the combination of modifying
the coating weight of the reservoir layer and the rotigotine
content within the reservoir layer in wt.-% to obtain the
therapeutically effective amounts of rotigotine for application
periods between 1 and 7 days.
TABLE-US-00002 TABLE 1B Content of rotigotine in reservoir layer
depending on the coating weight to achieve the therapeutically
effective amounts for the targeted application period Content of
rotigotine in reservoir layer [wt.-%] Appli- API cation content
period [mg/ Coating weight of reservoir layer [g/m.sup.2] [days] 10
cm.sup.2] 50 75 100 150 200 250 300 1*.sup.1 4.50 9.00 6.00 4.50
3.00 2.25 1.80 1.50 3*.sup.1 13.5 27.00 18.00 9.00 9.00 6.75 5.40
4.50 3.5*.sup.1 15.75 31.50 21.00 13.50 10.50 7.88 6.30 5.25
4*.sup.1 18.00 36.00 24.00 15.75 12.00 9.00 7.20 6.00 7*.sup.1
31.50 63.00 42.00 18.00 21.00 15.75 12.60 10.50 3*.sup.2 11.57
23.14 15.43 31.50 7.71 5.79 4.63 3.86 3.5*.sup.2 13.50 27.00 18.00
11.57 9.00 6.75 5.40 4.50 4*.sup.2 15.43 30.86 20.57 13.50 10.29
7.71 6.17 5.14 7*.sup.2 27.00 54.00 36.00 15.43 18.00 13.50 10.80
9.00 *.sup.1therapeutically effective amounts in TTS *.sup.2reduced
sufficient therapeutically effective amounts in TTS, e.g. 27 mg
sufficient for 7 days
[0111] In case of a gradient patch comprising a rotigotine
containing skin adhesive layer according to FIG. 10 the required
rotigotine amount in the reservoir layer can be reduced by the
rotigotine amount in the skin adhesive layer to obtain required
therapeutically effective amount.
[0112] That is, a sub-additive increase of the total rotigotine
content in the transdermal therapeutic system of the present
invention led to the targeted constant in vivo drug release
profiles over application periods of at least 3 days and up to at
least 7 days. This allows for the saving of about one daily dose of
rotigotine, and associated cost of goods, for a twice weekly or
once weekly administered patch according to the present invention
compared to the daily administration of the patches known from the
prior art.
[0113] The adhesives used in the present invention should
preferably be pharmaceutically acceptable in a sense that they are
biocompatible, non-sensitising and non-irritating to the skin of
the patient. Particularly advantageous adhesives for use in the
present invention should further meet the following requirements:
[0114] 1. Retained adhesive and co-adhesive properties in the
presence of moisture or perspiration under normal temperature
variations, and [0115] 2. Good compatibility with rotigotine, as
well as with the further excipients.
[0116] Although different types of pressure sensitive adhesives may
be used in the present invention, it is preferred to use lipophilic
adhesives having both low drug and low water absorption capacity.
Preferably, the adhesives have solubility parameters which are
lower than those of rotigotine. Such preferred pressure sensitive
adhesives are amine-resistant silicone pressure sensitive
adhesives.
[0117] The term "amine-resistant" as used herein means that the
respective adhesives being characterized as amine-resistant
adhesives do not react in any way with the tertiary amino-group of
rotigotine.
[0118] In one embodiment the dispersing agent comprises at least
one silicone pressure sensitive adhesive and preferably a mixture
of at least one high tack and at least one medium tack silicone
pressure sensitive adhesive.
[0119] In a preferred embodiment, the reservoir layer and, if
present, the skin adhesive layer of the transdermal therapeutic
system of the present invention each contain at least one,
preferably two, amine-resistant silicone pressure sensitive
adhesive(s) and most preferably, a mixture of at least one high
tack and at least one medium tack silicone pressure sensitive
adhesive.
[0120] Especially preferred pressure sensitive silicone adhesives
are of the type forming a soluble polycondensed
polydimethylsiloxane (PDMS)/resin network, wherein the hydroxy
groups are capped with e.g. trimethylsilyl (TMS) groups. Preferred
adhesives of this kind are the BIO-PSA.RTM. silicone pressure
sensitive adhesives manufactured by Dow Corning, particularly the
7-4201 and 7-4301 BIO-PSA.RTM. qualities as well as the 7-4202 and
7-4302 BIO-PSA.RTM. qualities.
[0121] In another embodiment, blends or copolymers of the above
silicone adhesives with other silicone adhesives or further
pressure sensitive adhesives selected from the group consisting of
a styrenic polymer, a polyisobutylene, or mixtures thereof as well
as an acrylate-based non-aqueous polymer adhesive may be used for
preparing the reservoir layer and, if present, the skin adhesive
layer of the transdermal therapeutic system of the present
invention. Suitable styrenic polymers are for example styrenic
triblock copolymers such as styrene-ethylene-styrene (SES),
styrene-butadiene-styrene (SBS), styrene-isoprene-styrene (SIS),
styrene-ethylene/butylene-styrene (S-EB-S),
styrene-ethylene/butylene/propylene-styrene (S-EBP-S),
styrene-isoprene/butadiene-styrene (S-IB-S), or mixtures thereof,
optionally in combination with a styrenic diblock copolymer such as
styrene-ethylene (SE), styrene-butadiene (SB), styrene-isoprene
(SI), styrene-ethylene/butadiene-styrene (SE-BS),
styrene-ethylene/propylene (S-EP), or mixtures thereof. A suitable
acrylate-based polymer adhesive preferably contains at least two of
the following monomers: acrylic acid, acrylamide, hexylacrylate,
2-ethylhexylacrylate, hydroxyethylacrylate, octylacrylate,
butylacrylate, methylacrylate, glycidylacrylate, methacrylic acid,
methacrylamide, hexylmethacrylate, 2-ethylhexylmethacrylate,
octylmethacrylate, methylmethacrylate, glycidylmethacrylate,
vinylacetate or vinylpyrrolidone.
[0122] In a preferred embodiment, the reservoir layer and the skin
adhesive layer are both based on the same adhesive(s). For example,
the reservoir layer and the skin adhesive layer may both contain
one or more amine-resistant silicone pressure sensitive
adhesive(s). Likewise, if any of the above blends or copolymers is
used as adhesive in the reservoir layer, the skin adhesive layer
would preferably also be based on this blend or copolymer.
[0123] Tack has been defined as the property that enables an
adhesive to form a bond with the surface of another material upon
brief contact under light pressure (see e.g. "Pressure Sensitive
Tack of Adhesives Using an Inverted Probe Machine", ASTM D2979-71
(1982); H. F. Hammond in D. Satas "Handbook of Pressure Sensitive
Adhesive Technology" (1989), 2.sup.nd ed., Chapter 4, Van Nostrand
Reinhold, N.Y., page 38).
[0124] Medium tack of a silicone pressure sensitive adhesive
indicates that the immediate bond to the surface of another
material is weaker compared to a high tack silicone adhesive.
[0125] Specific tack values of silicone pressure sensitive
adhesives for use in the present invention can for example be
determined by the Corporate Test Method (CTM) 0991 of Dow
Corning.
[0126] The resin/polymer ratio of the especially preferred pressure
sensitive silicone adhesives for use in the present invention is
59-61/41-39 for medium tack adhesives, whereas it is 54-56/46-44
for high tack adhesives. It is known to the skilled person that
both tape and rheological properties are significantly influenced
by the resin/polymer ratio (K. L. Ulman and R. P. Sweet "The
Correlation of Tape Properties and Rheology" (1998), Information
Brochure, Dow Corning Corp., USA).
[0127] Blends comprising a high tack and a medium tack silicone
type pressure sensitive adhesive comprising polysiloxane with a
resin are advantageous in that they provide for the optimum balance
between good adhesion and little cold flow. Excessive cold flow
based on too soft solid dispersions is disadvantageous since it may
lead to a loss of the structural integrity of the self-adhesive
matrix layer of a TTS at the application site and as a consequence
to silicone residues sticking on the patient's skin or clothes.
[0128] Preferably, the weight ratio of a high tack to a medium tack
silicone pressure sensitive adhesive in these blends is about 1:1.
However, this does not exclude employing any other weight
ratio.
[0129] A mixture of the aforementioned 7-4201/7-4202 (medium tack)
and 7-4301/7-4302 (high tack) qualities proved to be especially
useful for the preparation of the self-adhesive matrix layer of the
transdermal therapeutic system of the present invention. In such a
mixture, the overall resin/polymer ratio preferably is
56-58/44-42.
[0130] For the preparation of the self-adhesive matrix layer of the
transdermal therapeutic system of the present invention, the
employed silicone adhesives are dissolved in an organic solvent.
The transdermal therapeutic system of the present invention
therefore represents a solvent-based transdermal therapeutic system
as it was defined in the foregoing and is different from
transdermal therapeutic systems obtained by a hot melt process.
During preparation of the self-adhesive matrix layer, the organic
solvent is finally evaporated.
[0131] Suitable organic solvents for use in the preparation of the
transdermal therapeutic system of the present invention are
alkanes, carboxylic acid ester, alcohols and ketones, for example,
heptane, ethyl acetate, ethanol and acetone, as well as mixtures
thereof.
[0132] In a preferred embodiment, a mixture of heptane and ethanol
is used as organic solvent, and in a particularly preferred
embodiment, a mixture of ethyl acetate and ethanol is used as
organic solvent.
[0133] The solid or semi-solid semi-permeable polymer representing
the dispersing agent of the solid dispersion forming the
self-adhesive matrix layer has to satisfy the following
requirements: [0134] 1. Sufficient solubility and permeability for
the free base form of rotigotine. [0135] 2. Impermeability for the
protonated form of rotigotine.
[0136] In one embodiment the solubility of rotigotine (without
stabilizer) in the dispersing agent is about 5 wt.-% or below and
in another embodiment about 3 wt.-% or below. In still another
embodiment the solubility of rotigotine (without stabilizer) in the
dispersing agent is about 2 wt.-% or below and in another
embodiment it is about 0.1 wt.-% or below.
[0137] The dispersed phase of the solid dispersion comprises
rotigotine in non-crystalline form and a stabilizer, for example
polyvinylpyrrolidone, and optionally further pharmaceutically
acceptable excipients, such as permeation enhancers and
antioxidants.
[0138] Polyvinylpyrrolidone is able to stabilize solid dispersions
of the non-crystalline form of rotigotine by preventing rotigotine
from crystallization. In one embodiment the stabilizer is selected
from polyvinylpyrrolidone and in a preferred embodiment from water
soluble polyvinylpyrrolidone. Copolymers of polyvinylpyrrolidone
and vinyl acetate, polyethyleneglycol, polypropyleneglycol,
glycerol and fatty acid esters or copolymers of ethylene and
vinylacetate might also be considered for such use.
[0139] Polyvinylpyrrolidone (PVP) is a polymer made from the
monomer N-vinylpyrrolidone. It increases the cohesion of silicone
adhesives. The molecular weight of polyvinylpyrrolidone can be in
the range from 2,000 to 2,500,000 Dalton (g/mol) (given as weight
average), in one embodiment in the range from 700 000 to 1,500,000,
in another embodiment in the range from 1,000,000 to 1,500,000
Dalton. Various grades of PVP are commercially available from e.g.
BASF Aktiengesellchaft of Ludwigshafen, Germany, e.g. under the
name of KOLLIDON.RTM.. For example, the following grades of
KOLLIDONS.RTM. are water soluble forms of PVP: K-12 PF (molecular
weight=2,000-3,000); K-17 PF (molecular weight=7,000-11,000); K-25
(molecular weight=28,000-34,000); K-30 (molecular
weight=44,000-54,000); and K-90F (molecular
weight=1,000,000-1,500,000). In a preferred embodiment, the
molecular weight of polyvinylpyrrolidone is in the range from
28,000 to 1,500,000 Dalton (g/mol). Particularly preferred are the
KOLLIDON.RTM. grades K-25, K-30 and K-90F.
[0140] The rotigotine to polyvinylpyrrolidone weight ratio in the
dispersed phase is 9:2 to 9:5, preferably 9:3 to 9:5, and
particularly preferred 9:4, or multiples thereof. The term
"multiples thereof" as used in this context means that based on a
weight ratio of rotigotine to polyvinylpyrrolidone of for example
9:4, also a weight ratio of 18:8 or 27:12, etc. is encompassed.
[0141] In a preferred embodiment, the self-adhesive matrix layer of
the transdermal therapeutic system of the present invention
comprises a reservoir layer and the reservoir layer contains
rotigotine and polyvinylpyrrolidone and the rotigotine to
polyvinylpyrrolidone weight ratio in the reservoir layer is 9:2 to
9:5, preferably 9:3 to 9:5, and particularly preferred 9:4, or
multiples thereof.
[0142] In another preferred embodiment, the self-adhesive matrix
layer of the transdermal therapeutic system of the present
invention comprises a reservoir layer and a skin adhesive layer and
the reservoir layer and the skin adhesive layer, if it contains
rotigotine, further contain polyvinylpyrrolidone and the rotigotine
to polyvinylpyrrolidone weight ratio in the respective layer is 9:2
to 9:5, preferably 9:3 to 9:5, and particularly preferred 9:4, or
multiples thereof.
[0143] A decrease of the rotigotine to polyvinylpyrrolidone weight
ratio from 9:2 to 9:4 has shown to provide for good physical
stability of the corresponding single-day transdermal therapeutic
systems (see WO 2011/076879). An equivalent stabilizing effect
could also be shown for the multi-day transdermal therapeutic
system of the present invention having a higher rotigotine/PVP load
per cm.sup.2.
[0144] Suitable permeation enhancers may be selected from the group
of fatty alcohols, fatty acids, fatty acid esters, fatty acid
amides, glycerol or its fatty acid esters, N-methylpyrrolidone,
terpenes such as limonene, [alpha]-pinene, [alpha]-terpineol,
carvone, carveol, limonene oxide, pinene oxide, 1,8-eucalyptol and
most preferably ascorbyl palmitate. In a preferred embodiment, the
TTS of the present disclosure does not contain a penetration
enhancer.
[0145] Suitable antioxidants are sodium metabisulfite, ascorbyl
palmitate and DL-alpha tocopherol.
[0146] In one embodiment of the invention the water content of the
solid dispersion is less than 1.0 wt.-% and in another embodiment
it is less than 0.5 wt.-% related to the total weight of the
self-adhesive matrix layer. In one embodiment, the self-adhesive
matrix layer is substantially free of water, i.e. no water is used
during the manufacturing process or the water is removed during the
manufacturing process as complete as possible.
[0147] In a particular preferred embodiment, the self-adhesive
matrix is free of particles, which can absorb salts of rotigotine
on the TTS/skin interface. Examples of particles, which can absorb
salts of rotigotine on the TTS/skin interface, include silica. Such
particles, which can adsorb salts of rotigotine, may represent
diffusion barriers for the free base form of the drug and may
result in the formation of channels inducing some permeability of
the self-adhesive matrix for the protonated form of rotigotine,
which is disadvantageous.
[0148] Preferably, the TTS contains less than 1 wt.-% of inorganic
silicates, most preferably it is completely free from inorganic
silicates.
[0149] The release liner will be removed immediately prior to use,
i.e. immediately before the TTS will be brought into contact with
the patient's skin. The release line may consist of polyester,
polyethylene or polypropylene, which may or may not be coated, e.g.
with aluminum film or aluminum vapour or fluoropolymers or with a
silicone layer. Typically, the thickness of such a release liner
ranges between 50 and 150 .mu.m.
[0150] So as to facilitate removal of the release liner when
wishing to apply the TTS, the release liner may comprise separate
release liner having overlapping edges, similar to the kind used
with the majority of conventional plasters.
[0151] In one embodiment, the transdermal therapeutic system of the
present invention has a basal surface area of 5-50 cm.sup.2,
preferably 5-40 cm.sup.2 such as for example 5 cm.sup.2, 10
cm.sup.2, 15 cm.sup.2, 20 cm.sup.2, 30 cm.sup.2 or 40 cm.sup.2. The
term "basal surface area" as used herein refers to the surface of
the self-adhesive matrix layer being in contact with the patient's
skin upon administration.
[0152] Any references to rotigotine in the context of this
invention and the claims of this application mean rotigotine in the
form of its free base. In some cases, however, traces of rotigotine
hydrochloride may be contained in a rotigotine preparation but
these traces typically do not exceed 5 wt.-% based on the amount of
the free base. More preferably the content of hydrochloride
impurities should be less than 2 wt.-%, even more preferably less
than 1 wt.-% and most preferably the rotigotine used in the present
invention contains less than 0.1 wt.-% or no hydrochloride
impurities at all.
[0153] A further step, which may be taken for reducing the amount
of the salt form of rotigotine, is isolating the free base form of
rotigotine in solid form prior to the preparation of the solid
dispersion. Alternatively, the free base of rotigotine may be
produced in situ during the manufacture of the solid dispersion by
neutralizing an acid addition salt of rotigotine.
[0154] It will be understood by a person skilled in the art that
rotigotine exists in various stereoisomeric forms. It thus has also
to be understood that besides the S-enantiomer, i.e. rotigotine,
the R-enantiomer or a mixture of the different stereoisomers may be
used in the present invention. Hence, the S- or R-enantiomer or the
racemate or any other enantiomeric mixture of rotigotine may be
used. Most preferred, the pure S-enantiomer, i.e. rotigotine, is
used.
[0155] In the dispersed phase of the solid dispersion forming the
self-adhesive matrix layer of the transdermal therapeutic system of
the present invention, rotigotine is present in non-crystalline
form.
[0156] In one embodiment the non-crystalline form of rotigotine is
amorphous rotigotine.
[0157] The rotigotine starting material used for preparing the
transdermal therapeutic system of the present invention exists in
two different polymorphic states, polymorphic Form I and
polymorphic Form II. Polymorphic Form II of rotigotine is described
in WO 2009/068520 and has at least one of the following
characteristics: [0158] a X-ray powder diffraction spectrum
comprising a peak at least at one of the following .degree.
2.theta. angles (.+-.0.2): 12.04, 13.68, 17.72 and/or 19.01,
measured with Cu-K.alpha. irradiation (1.54060 .ANG.); [0159] a
Raman spectrum comprising at least one peak at the following wave
numbers (.+-.3 cm.sup.-1): 226.2, 297.0, 363.9, 737.3, 847.3,
1018.7 and/or 1354.3; [0160] a differential scanning calorimetry
(DSC) peak with a T.sub.onset at 97.degree. C..+-.2.degree. C.
measured with a heating rate of 10.degree. C./min; and/or [0161] a
melting point of 97.degree. C..+-.2.degree. C.
[0162] In a preferred embodiment, rotigotine of polymorphic Form II
is used as starting material for preparing the transdermal
therapeutic system of the present invention.
[0163] While not wishing to be bound by theory it is believed that
free rotigotine is molecularly dispersed in the dispersing agent of
the solid dispersion forming the self-adhesive matrix layer of the
transdermal therapeutic system of the present invention and that a
non-crystalline form of rotigotine is reversibly associated with
PVP by forming an inner phase or microreservoir.
[0164] In one embodiment the non-crystalline form of rotigotine is
amorphous rotigotine. One advantage of a stable solid drug
dispersion is that it can significantly reduce constraints often
caused by low drug solubility in polymers suitable for transdermal
delivery.
[0165] The term "microreservoirs" as used herein is meant to be
understood as particulate, spatially and functionally separate
compartments consisting of a mixture of rotigotine and
polyvinylpyrrolidone, which are dispersed (as dispersed phase) in
the dispersing agent of the solid dispersion as defined above. The
term "microreservoirs" as used herein is further meant to be
understood as amorphous micro-spheres dispersed in a polymer matrix
and which can be differentiated from the surrounding outer phase by
their high drug load in accordance to their reservoir function.
[0166] In one embodiment the solid dispersion contains 10.sup.3 to
10.sup.9 microreservoirs per cm.sup.2 of its surface, in another
embodiment 10.sup.6 to 10.sup.9 microreservoirs per cm.sup.2 of its
surface. This further illustrates the very small or "micro"-scopic
appearance of microreservoirs of present invention.
[0167] The maximum diameter of the microreservoirs is less than the
thickness of the solid dispersion, preferably up to 85% of the
thickness of the solid dispersion, particularly preferred 5 to 74%
of the thickness of the solid dispersion. For an exemplary
thickness of the solid dispersion of 50 .mu.m this corresponds to a
maximum diameter of the microreservoirs in the range of preferably
up to approximately 40 to 45 .mu.m.
[0168] The term "maximum diameter" as used herein is meant to be
understood as the diameter of the microreservoirs in that dimension
(x-, y-, or z-dimension), which is the largest. It is clear to the
skilled person that in case of spherical diameters the maximum
diameter corresponds to the microreservoir's diameter. However, in
the case of microreservoirs, which are not shaped in the form of
spheres, i.e. of different geometric forms-, the x-, y- and
z-dimensions may vary greatly.
[0169] In a particularly preferred embodiment of the invention, the
mean diameter of the rotigotine containing microreservoirs
distributed in the solid dispersion is in the range of 1 to 40%,
even more preferred 1 to 20%, of the thickness of the solid
dispersion. For an exemplary thickness of the solid dispersion of
50 .mu.m this corresponds to a mean diameter of the microreservoirs
in the range of preferably 0.5 to 20 .mu.m.
[0170] The term "mean diameter" as used herein is defined as the
mean value of the x, y, z-average diameters of all microreservoirs.
The target particle size can be adjusted by the solid content and
the viscosity of the solid dispersion.
[0171] The maximum and mean diameters of the microreservoirs as
well as the number of microreservoirs per surface area of the solid
dispersion can be determined as follows: The surface of the solid
dispersion is examined with a light microscope (Leica microscope
type DM/RBE equipped with a camera type DS Camera Head DS-5M). The
measurement is performed by incidental polarized light analysis
using a microscope at 200.times. magnification. A picture analysis
is performed using the software Nikon LuciaG, Version 5.30,
resulting in mean and maximum diameters for each sample.
[0172] In a preferred embodiment rotigotine and
polyvinylpyrrolidone are contained in the transdermal therapeutic
system of the present invention in a multitude of
microreservoirs.
[0173] Due to the presence of rotigotine and polyvinylpyrrolidone
in the self-adhesive matrix layer of the transdermal therapeutic
system of the present invention in the form of distinct
microreservoirs, the homogenous distribution of rotigotine within
the self-adhesive matrix layer remains constant during storage.
That is, the transdermal therapeutic system of the present
invention is characterized by very good storage stability
properties.
[0174] The transdermal therapeutic system of the present invention
contains rotigotine as active ingredient. Rotigotine is a dopamine
D1/D2/D3-receptor agonist and the transdermal therapeutic system of
the present invention is therefore useful in the treatment of
diseases susceptible to the action of dopamine receptor
agonists.
[0175] In particular, the transdermal therapeutic system of the
present invention can be used in the treatment of patients
suffering from Parkinson's disease, Parkinson's plus syndrome,
depression, fibromyalgia and the restless-legs syndrome.
Furthermore, the transdermal therapeutic system of the present
invention can be used in the treatment or prevention of
dopaminergic neuron loss or cognitive disorders.
[0176] The use of solvent-based transdermal therapeutic systems
containing rotigotine as active ingredient in the treatment of the
above disease and in particular in the treatment of Parkinson's
disease and in the treatment of the restless leg syndrome is known
from the prior art. This treatment usually is a permanent treatment
during which one single-day transdermal therapeutic system is
administered every day. In particular, the permanent treatment
involves the application of one or sometimes more transdermal
therapeutic system(s) at a certain place of the patient's body, the
removal of the respective patch(es) after one day of wearing and
the application of one or more new patch(es) at another place of
the patient's body.
[0177] In contrast, the multi-day solvent-based transdermal
therapeutic system of the present invention is adapted to allow for
the transdermal administration of therapeutically effective amounts
of rotigotine for at least 3-7 days, including at least 3, at least
4, at least 5, at least 6 and at least 7 days. That is, by the
transdermal therapeutic system of the present invention, the
frequency of administration and the number of patches to be
administered in the permanent treatment of the above diseases can
be reduced, thereby providing for an improved treatment in that
patient's comfort and compliance are enhanced. Moreover, due to the
specific construction of the multi-day solvent-based transdermal
therapeutic system of the present invention its skin tolerance is
comparable to the skin tolerance of the single-day solvent-based
transdermal therapeutic systems known from the prior art.
[0178] The transdermal administration of therapeutically effective
amounts of rotigotine for at least 3-7 days by the transdermal
therapeutic system of the present invention is achieved by choosing
an appropriate composition of the self-adhesive matrix layer. As it
was described above, this in particular includes appropriately
adjusting the coating weight, the rotigotine content and the
optional provision of a skin adhesive layer.
[0179] In a preferred embodiment, the transdermal therapeutic
system of the present invention is adapted to allow for the
transdermal administration of therapeutically effective amounts of
rotigotine for at least 3, at least 4 or at least 7 days.
[0180] Most preferred, the transdermal therapeutic system of the
present invention is adapted to allow for the transdermal
administration of therapeutically effective amounts of rotigotine
for at least 7 days.
[0181] Based on the respective composition, the multi-day
solvent-based transdermal therapeutic system of the present
invention can be applied in the following dosage regimens:
TABLE-US-00003 TABLE 2 Possible dosage regimens of the transdermal
therapeutic system of the present invention Sequence of Patch(es) *
administration 3-day patch Every 3.sup.rd day 3.5-day patch Twice
weekly at two predetermined days, e.g. every 3.sup.rd and 4.sup.th
day or every 4.sup.th and 3.sup.rd day 4-day patch Every 4.sup.th
day or twice weekly at two predetermined days, e.g. every 3.sup.rd
and 4.sup.th day or every 4.sup.th and 3.sup.rd day 5-day patch
Every 5.sup.th day or once weekly at a predetermined day 6-day
patch Every 6.sup.th day or once weekly at a predetermined day
7-day patch Once weekly at a predetermined day, i.e. every 7.sup.th
day One 3-day patch and Twice weekly at two one 4-day patch
predetermined days, e.g. every 3.sup.rd and 4.sup.th day or every
4.sup.th and 3.sup.rd day * The drug content of the patches allows
for the transdermal administration of therapeutically effective
amounts of rotigotine for 3, 3.5, 4, 5, 6 or 7 days. Based on their
respective drug content, the patches are accordingly identified as
3-day patch, 3.5 day patch, 4-day patch, 5-day patch, 6-day patch
or 7-day patch.
[0182] As discussed in the foregoing, the patches of the present
invention are usually applied in a chronic treatment and should
therefore preferably be administered at about the same time, e.g.
at almost the same hour in the morning or in the evening. This in
particular applies, when administering the patches of the present
invention in accordance with one of the dosage regimens shown in
Table 2.
[0183] In a particular preferred embodiment, one patch of the
present invention allowing for the transdermal administration of
therapeutically effective amounts of rotigotine for 7 days, i.e. a
7-day patch is administered per week at a predetermined day,
corresponding to a once weekly administration of a transdermal
therapeutic system of the present invention.
[0184] In another preferred embodiment, one 3-day patch and one
4-day patch, or two 3.5-day patches, or particularly preferred two
4-day patches are administered per week, corresponding to a twice
weekly administration of a transdermal therapeutic system of the
present invention. Independent of administering one 3-day patch and
one 4-day patch, two 3.5-day patches, or two 4-day patches, the
respective patches are administered every 3.sup.rd and 4.sup.th day
or every 4.sup.th and 3.sup.rd day at two predetermined days per
week.
[0185] The present invention therefore also provides in a second
aspect a kit comprising two transdermal therapeutic systems of the
present invention, wherein the two transdermal therapeutic systems
may have the same or a different rotigotine content. In one
embodiment, the two transdermal therapeutic systems of the kit have
a different rotigotine content and one of them is adapted to allow
for the transdermal administration of therapeutically effective
amounts of rotigotine for at least 3 days and the other one is
adapted to allow for the transdermal administration of
therapeutically effective amounts of rotigotine for at least days.
In a preferred embodiment, the two transdermal therapeutic systems
of the kit have the same rotigotine content and each of them is
adapted to allow for the transdermal administration of
therapeutically effective amounts of rotigotine for at least 4
days.
[0186] In a third aspect, the present invention provides a method
for preparing the transdermal therapeutic system described
herein.
[0187] The preparation method of the present invention comprises
preparing a rotigotine containing solid dispersion, i.e. the
reservoir layer and optionally the skin adhesive layer (if it
contains rotigotine) forming the self-adhesive matrix layer,
optionally preparing a skin adhesive layer containing no
rotigotine, coating, drying or cooling and laminating to get the
bulk product, converting the obtained laminate into patches via
cutting, and packaging.
[0188] Preparing a skin adhesive layer containing no rotigotine,
involves the preparation of a solution of one or more adhesive(s),
coating this solution on a release liner and drying the resulting
laminate.
[0189] Coating, drying and laminating as well as converting the
obtained laminate into separate patches via cutting and packaging
are well known steps in the preparation of transdermal therapeutic
systems and these steps can be carried out as described in the
prior art. Reference can for example be made to the detailed
description of the preparation of the example patches in the
international patent application WO 99/49852.
[0190] The rotigotine containing solid dispersion of the
self-adhesive layer of the transdermal therapeutic system of the
present invention can be prepared in accordance with one of the
methods depicted in the flow charts of FIGS. 1-3.
[0191] The preparation methods described therein involve two
different solvent systems, one consisting of ethyl acetate and
ethanol, like for example in a ratio of 5:1 and the other
consisting of heptane and ethanol, like for example in a ratio of
1:1.5.
[0192] The comparison between the different preparation methods
shown in FIGS. 1-3 reveals that the solvent system consisting of
ethyl acetate and ethanol, like for example in a ratio of 5:1
allows for a significant reduction of time needed for
incorporating/dissolving PVP and thus in preparing the final
patches. This reduction in time is based on the surprising finding
that the solubility of PVP in the aprotic polar solvent ethyl
acetate is enhanced by rotigotine by one order of magnitude.
Moreover, a solvent system consisting of an aprotic polar solvent
and a protic polar solvent like the solvent system consisting of
ethyl acetate and ethanol, for example in a ratio of 2:1 to 5:1 is
required for incorporating high rotigotine concentrations of up to
about 18 wt.-% in the self-adhesive matrix layer of the transdermal
therapeutic system of the present invention.
[0193] In a preferred embodiment, the preparation method of the
present invention therefore involves the use of a solvent system
consisting of an aprotic polar solvent and a protic polar solvent
in a ratio of 2:1 to 9:1. In a more preferred embodiment, the
preparation of the present invention involves the use of a solvent
system consisting of a aprotic polar solvent and a protic polar
solvent in a ratio of 2:1 to 6:1, preferably in a ratio of 2:1 to
5:1, more preferably in a ratio of 3:1 to 5:1, particularly
preferred in a ratio of 3:1 or 5:1.
[0194] In a more preferred embodiment, the preparation method of
the present invention involves the use of a solvent system
consisting of a carboxylic acid ester and an aliphatic alcohol. In
a particular preferred embodiment, the preparation method of the
present invention involves the use of a solvent system consisting
of ethyl acetate and ethanol in a ratio of 2:1 to 9:1. In a further
preferred embodiment, the preparation method of the present
invention involves the use of a solvent system consisting of ethyl
acetate and ethanol in a ratio of 2:1 to 6:1, preferably in a ratio
of 2:1 to 5:1, more preferably in a ratio of 3:1 to 5:1,
particularly preferred in a ratio of 3:1 or 5:1.
[0195] The addition of a small portion of ethanol to ethyl acetate
enables the formation of rotigotine/PVP droplets in ethyl
acetate-based silicone adhesive solutions and allows for
homogenously dispersing the rotigotine/PVP conjugate in the
silicone adhesive solution at room temperature.
[0196] As shown in FIGS. 2a and 2b, the preparation method of the
present invention can therefore be carried out at room temperature
without heating. When doing so, the method may involve either (i)
the addition of rotigotine in two portions, one before and the
other after polyvinylpyrrolidone is added to the mixture of
silicone adhesives and antioxidants prepared in the solvent system
(see FIG. 2a), or (ii) the addition of rotigotine in one portion
together with polyvinylpyrrolidone to the mixture of silicone
adhesives and antioxidants prepared in the solvent system or (iii)
the addition of rotigotine in one portion to a PVP solution and a
silicone adhesives mixture (see FIG. 2b).
[0197] Thus, in a further preferred embodiment, the preparation
method of the present invention is carried out at room temperature
and involves the addition of rotigotine in two portions, one before
and the other after polyvinylpyrrolidone is added or in another
preferred embodiment the addition of rotigotine in one step and the
use of a polyvinylpyrrolidone solution and silicone adhesives
mixture
[0198] When adding rotigotine in one portion before
polyvinylpyrrolidone is added, moderate heating to about 40.degree.
C. may be useful (FIG. 1). However, this does not have any
influence on the reduced time needed for the subsequent
incorporation/dissolution of PVP, which is carried out at room
temperature.
[0199] In a another embodiment of the present invention, the
preparation method for the preparation of a transdermal therapeutic
system comprising [0200] (a) a backing layer, [0201] (b) a
solvent-based self-adhesive matrix layer containing rotigotine as
active ingredient, and [0202] (c) a release liner, comprises the
steps of [0203] i) addition of polyvinylpyrrolidone to a mixture of
carboxylic acid ester and an aliphatic alcohol, preferably ethyl
acetate and ethanol, [0204] ii) addition of sodium metabilsufite
solution to mixture of step i, [0205] iii) addition of tocopherol
and ascorbylpalmitate to mixture of step ii, [0206] iv) combining
of mixture of step iii with a mixture of silicone adhesives in
carboxylic acid ester, preferably ethyl acetate, [0207] v) addition
of rotigotine to combination of step iv, [0208] vi) coating of the
mixture of step v onto a substrate, preferably the release liner
and removal of the solvents to obtain the reservoir layer thereby
forming the solvent-based self-adhesive matrix layer, [0209] vii)
lamination of reservoir layer from step vi with a cover layer,
preferably backing layer and [0210] viii) punching of laminate from
step vii into individual transdermal therapeutic systems.
[0211] In a further embodiment, the preparation method of the
present invention involves the use of a solvent system consisting
of heptane and ethanol in a ratio of 1.5:1 to 1:1.5, more preferred
in a ratio of 1.4:1 and particularly preferred in a ratio of 1:1.5.
A preparation method of the present invention, wherein a solvent
system consisting of heptane and ethanol in a ratio of 1:1.5 is
used, is shown FIG. 3.
[0212] The water content in the final patches obtained by the
preparation method of the present invention is in general low
enough so that no evaporation of water during preparation of the
patches is necessary. Typically, the water content in a freshly
prepared patch is below about 2 wt.-%.
[0213] In one embodiment, the water content of the transdermal
therapeutic system of the present invention therefore is below
about 2 wt.-%, preferably below about 1 wt.-% and more preferred
below about 0.6 wt.-%.
[0214] For preparing the transdermal therapeutic system of the
present invention, either of the two crystalline forms of
rotigotine, i.e. polymorphic Form I or polymorphic Form II, may be
employed as a starting material.
[0215] In a preferred embodiment, rotigotine of polymorphic Form II
is used as starting material for preparing the transdermal
therapeutic system of the present invention.
[0216] Based on the above described dosage regimens, the present
invention provides in another aspect a transdermal therapeutic
system comprising rotigotine as active ingredient for use in the
treatment of patients suffering from Parkinson's disease,
Parkinson's plus syndrome, depression, fibromyalgia and the
restless-legs syndrome and for use in the treatment or prevention
of dopaminergic neuron loss or cognitive disorders following stroke
by transdermal administration of rotigotine once or twice weekly,
wherein the transdermal therapeutic system comprises a backing
layer, a solvent-based rotigotine containing self-adhesive matrix
layer as well as a release liner and is adapted to allow for the
transdermal administration of therapeutically effective amounts of
rotigotine for at least 3 days.
[0217] All aspects, embodiments and preferred embodiments as well
as combinations thereof described in the foregoing for the
transdermal therapeutic system of the present invention also apply
to the rotigotine-containing transdermal therapeutic system for use
according to the fourth aspect of the present invention.
[0218] The invention and the best mode for carrying it out will be
explained in more detail in the following non-limiting
examples.
EXAMPLES
Example 1
[0219] 4-Day mono-layer TTS comprising a reservoir layer having a
coating weight of 150 g/m.sup.2 and containing 9 wt.-% rotigotine
and 2 wt.-% PVP; solvent system used for the preparation method:
heptane/ethanol (1.4:1 (w/w)) 18.44 kg silicone adhesive 7-4301 (73
wt.-% in heptane) were mixed with the following components under
permanent stirring until a homogeneous dispersion was obtained:
[0220] 1. 2.44 kg of an ethanolic solution containing 25 wt.-%
polyvinylpyrrolidone (KOLLIDON.RTM. F. 90), 0.11 wt.-% aqueous
sodium metabisulfite solution (10 wt.-%), 0.25 wt.-% ascorbyl
palmitate and 0.62 wt.-% DL-alpha-tocopherol; [0221] 2. 9.131 kg of
an ethanolic solution containing 2.724 kg rotigotine obtained by
dissolving rotigotine of polymorphic Form I; [0222] 3. 18.43 kg of
silicone adhesive 7-4201 (73 wt.-% in heptane); and [0223] 4. 1.579
kg heptane.
[0224] For the manufacture of the self-adhesive matrix layer, the
obtained dispersion was coated onto a suitable release liner (e.g.
SCOTCHPAK.TM. 9744) and the solvents were continuously removed in a
drying oven at temperatures up to 80.degree. C. in order to obtain
a dry drug containing matrix having a coating weight of 150
g/m.sup.2. The dried matrix layer was then laminated with a
polyester-type backing foil being siliconized on the inner surface
and aluminium vapor coated on the opposite surface.
[0225] Finally, individual patches having a size of 10 cm.sup.2
were punched out of the obtained laminate and were sealed into
pouches under nitrogen flow.
Example 2
[0226] 7-Day bi-layer TTS comprising (a) a reservoir layer having a
coating weight of 150 g/m.sup.2 and containing 18 wt.-% rotigotine
and 4 wt.-% PVP and (b) a skin adhesive layer containing no
rotigotine and having a coating weight of 18 g/m.sup.2; solvent
system used for the preparation method: heptane/ethanol (1.4:1
(w/w))
Preparation of the Reservoir Layer Matrix (Step 1)
[0227] 9.66 kg silicone adhesive 7-4301 (73 wt.-% in heptane) were
mixed with the following components under permanent stirring until
a homogeneous dispersion was obtained: [0228] 1. 2.90 kg of an
ethanolic solution containing 25 wt.-% polyvinylpyrrolidone
(KOLLIDON F 90), 0.11 wt.-% aqueous sodium metabisulfite solution
(10 wt.-%), 0.25 wt.-% ascorbyl palmitate and 0.62 wt.-%
DL-alpha-tocopherol; [0229] 2. 6.98 kg of an ethanolic solution
containing 3.26 kg rotigotine obtained by dissolving rotigotine of
polymorphic Form I; [0230] 3. 9.66 kg of silicone adhesive 7-4201
(73 wt.-% in heptane); and [0231] 4. 0.82 kg heptane.
Preparation of the Skin Adhesive Layer (Step 2)
[0232] 11.51 kg silicone adhesive 7-4301 (73 wt.-% in heptane) were
mixed with 7.67 kg silicone adhesive 7-4201 (73 wt.-% in heptane)
and 0.82 kg heptane. The adhesive solution was then coated onto a
suitable polyester release liner (e.g. SCOTCHPAK.TM. 9744) up to a
coating weight of 18 g/m.sup.2. The solvent was continuously
removed in a drying oven at a temperature of up to 80.degree. C.
(.+-.3.degree. C.) to obtain a dry adhesive film having a coating
weight of 18 g/m.sup.2.
Preparation of the Final TTS (Step 3)
[0233] The dispersion obtained in Step 1 was coated onto two sheets
of a suitable polyester release liner (e.g. SCOTCHPAK.TM. 9744) to
obtain two drug-containing reservoir layers each having a coating
weight of 75 g/m.sup.2. The coated release liner sheets were placed
in a drying oven and dried at a temperature of up to 80.degree. C.
(.+-.3.degree. C.) to obtain two dry adhesive films each having a
coating weight of 75 g/m.sup.2. The first dried drug-containing
reservoir layer was laminated with (1) a polyester-type backing
foil being siliconized on the inner surface and aluminum vapor
coated on the opposite surface and (2) the second drug-containing
reservoir layer after removal of the release liner from the surface
of the first reservoir layer to be laminated in order to obtain a
drug-containing reservoir layer having a coating weight of 150
g/m.sup.2.
[0234] Afterwards, the skin adhesive layer was laminated with the
drug-containing reservoir layer after removal of its release liner
to obtain a laminate consisting of a backing foil, a
rotigotine-containing reservoir layer having a coating weight of
150 g/m.sup.2, a skin adhesive layer having a coating weight of 18
g/m.sup.2 and a release liner. The whole laminate was dried at a
temperature of up to 80.degree. C. (.+-.3.degree. C.). Finally,
individual patches having a size of 10 cm.sup.2 were punched out of
the complete laminate and sealed into pouches.
Comparative Example 1
[0235] Single-day mono-layer TTS comprising a reservoir layer
having a coating weight of 50 g/m.sup.2 and containing 9 wt.-%
rotigotine and 2 wt.-% PVP; solvent system used for the preparation
method: heptane/ethanol (1.4:1 (w/w))
[0236] The patches of Comparative Example 1 were manufactured
according to the method described in Example 1, but with a coating
weight of 50 g/m.sup.2 instead of 150 g/m.sup.2.
[0237] The composition of the patches of Examples 1 and 2 as well
as Comparative Example 1 are depicted in Table 3.
TABLE-US-00004 TABLE 3 Composition of the patches of Examples 1 and
2 and Comparative Example 1 Example Ingredient [mg/10 cm.sup.2],
Comp. except stated otherwise Ex. 1 Ex. 2 Ex. 1 Reservoir
Rotigotine (Form I*) 13.5 27.0 4.5 layer Rotigotine (Form I*) 9.0
18.0 9.0 content [wt.-%] PVP 3.0 6.0 1.0 PVP content [wt.-%] 2.0
4.0 2.0 Rotigotine:PVP ratio 9:2 18:4 9:2 [wt.-%] Silicone adhesive
66.7 58.39 22.24 7-4301 Silicone adhesive 66.7 58.39 22.23 7-4201
Sodium metabisulfite 0.00133 0.00264 0.00045 Ascorbyl palmitate
0.030 0.060 0.01 DL-.alpha.-Tocopherol 0.075 0.150 0.025 Coating
weight [g/m.sup.2] 150.0 150.0 50.0 Skin Rotigotine (Form I*) -- --
-- adhesive Rotigotine (Form I*) -- -- -- layer content [wt.-%] --
-- -- PVP -- -- -- PVP content [wt.-%] -- -- -- Rotigotine:PVP
ratio -- -- -- [wt.-%] -- -- -- Silicone adhesive -- 10.8 -- 7-4301
Silicone adhesive -- 7.2 -- 7-4201 Sodium metabisulfite -- -- --
Ascorbyl palmitate -- -- -- DL-.alpha.-Tocopherol -- -- -- Coating
weight [g/m.sup.2] -- 18.0 -- *For the preparation of the
respective example patches rotigotine of polymorphic Form I was
used as starting material. The final patches contain rotigotine in
non-crystalline form.
In Vivo Drug Absorption Test
[0238] In order to monitor the absorption of rotigotine by the
human skin using the transdermal therapeutic systems of Examples 1
and 2 and Comparative Example 1 two pilot bioavailability (BA)
studies over 4 days (Study 1) and 7 days (Study 2), respectively,
were carried out.
Study 1
[0239] A single application of one TTS of Example 1 for 4 days was
compared in healthy male subjects with a once-daily application of
the TTS of Comparative Example 1 over 4 days in a single-site,
open-label, randomized, crossover trial to evaluate the
pharmacokinetics of the two different patch formulations. Subjects
received one patch of Example 1 for 4 days (Treatment A) or four
single patches of Comparative Example 1 at 4 consecutive days
(Treatment B) in a randomized sequence (A-B or B-A). Individual
rotigotine plasma concentrations were analysed for 12 subjects by
means of liquid chromatography and mass spectroscopy. The lower
limit of quantification (LOQ) was 0.01 ng/ml.
Study 2
[0240] A single application of one TTS of Example 2 for 7 days was
compared in healthy male subjects with a once-daily application of
the TTS of Comparative Example 1 over 7 days in a single-site,
open-label, randomized, crossover trial to evaluate the
pharmacokinetics of the two different patch formulations. Subjects
received one patch of Example 2 for 7 days (Treatment C) or seven
single patches of Comparative Example 1 at 7 consecutive days
(Treatment D) in a randomized sequence (C-D or D-C). Individual
rotigotine plasma concentrations were analysed for 16 subjects by
means of liquid chromatography and mass spectroscopy. The lower
limit of quantification (LOQ) was 0.01 ng/ml.
[0241] In addition the residual drug content remaining in the
patches after application in Study 1 was determined by a validated
HPLC method. From these data the mean apparent dose which was
released by the patch to the skin application site was estimated by
the difference between declared drug content of the patch and its
mean content after removal from the skin.
[0242] The in vivo drug absorption was calculated from the plasma
concentration data according to the Wagner-Nelson method (Malcom
Rowland, Thomas N. Tozer (Eds.) "Estimation of Adsorption Kinetics
from Plasma Concentration Data" in Clinical Phamacokinetics, pp.
480-483, Williams & Wilkins, 1995); 100%=absorption rate
measured after 4 days.
Results--Plasma Concentration Time Profiles
[0243] The plasma concentration time profiles measured for
Treatments A and B in Study 1 are depicted in FIG. 4a. The
administration of a single 4-day patch manufactured as described
under Example 1 was found to be bioequivalent to the daily
administration of 4 single-day patches of Comparative Example
1.
[0244] The administration of a single 7-day patch manufactured as
described under Example 2 (Treatment C) was found in Study 2 to be
almost bioequivalent to the daily administration of 7 single-day
patches of Comparative Example 1 (Treatment D), although only 27 mg
of rotigotine were administered by the 7-day patch of Example 2
instead of 7.times.4.5 mg, i.e. 31.5 mg, rotigotine, which were
administered by 7 single-day patches of Comparative Example 1. That
is, one daily dose of rotigotine of 4.5 mg could be saved during
Treatment C in comparison to Treatment D.
[0245] Upon normalization by the apparent dose, the values for AUC
and C.sub.max showed a supra bioavailability, i.e. an appreciably
larger bioavailability, of 120% for the AUC and 126% for
C.sub.max.
[0246] When the rotigotine content of a 7-day patch was adapted in
accordance with the rotigotine content of 7 single-day patches,
subjects/patients would thus receive about 20% more rotigotine than
could be expected based on the bioavailability of rotigotine upon
administration by a single-day patch.
[0247] The plasma concentration time profiles measured for the
4-day patch of Example 1 in Study 1 and for the 7-day patch of
Example 2 in Study 2 are depicted in FIG. 4b.
[0248] By comparing the variations of the mean plasma
concentrations within one day for the single and the once daily
application over 4 and 7 days, it becomes evident that the mean
plasma concentrations of the multi-day patches of Examples 1 and 2
are on average characterized by fewer fluctuations within a 24 h
interval than the mean plasma concentrations obtained for the once
daily administered patches of Comparative Example 1. That is, due
to the removal of one patch and the consecutive application of a
fresh patch onto another skin application site, the daily
administration of the patches of Comparative Example 1 apparently
led to larger variations.
[0249] Accordingly, individual plasma concentrations measured over
4 and 7 days after the single administration of the multi-day
patches of Examples 1 and 2 and after the daily administration of
four or seven single-day patches of Comparative Example 1 at the
time of patch replacement of the single day patches of Comparative
Example 1 were found to be consistently higher for the multi-day
patches of Examples 1 and 2 in most cases. Consequently, as shown
in FIGS. 5a and 5b, the rotigotine plasma concentration ratio of
the patch of Example 1 to the patches of Comparative Example 1 and
of the patch of Example 2 to the patches of Comparative Example 1
was above 1 during the 4-day treatment as well as during the 7-day
treatment for the majority of subjects.
Results--Apparent Dose Determination
[0250] The mean apparent drug doses released to the skin in BA
Study 1 as well as the mean drug depletion rate calculated on the
basis of the nominal rotigotine content in the respective patches
are shown in Table 4a. The applied total dose, i.e. the nominal
rotigotine content of the applied patches, as well as the mean drug
quantity saved by the multi-day patch of Example 1 in comparison to
the 4 single-day patches of Comparative Example 1 are shown in
Table 4b.
TABLE-US-00005 TABLE 4a Result of apparent dose determinations (=
estimated drug release in vivo) and corresponding mean depletion
rates in BA Study 1 Mean apparent dose Mean [mg/10 cm.sup.2]
depletion rate Sample over 4 days SD [%] n Example 1 7.5 2.5 55.6
12 (Treatment A) Comparative 8.7 2.1 48.6 12 Example 1 (Treatment
B)
TABLE-US-00006 TABLE 4b Comparison of the total (nominal)
rotigotine doses applied during Treatment A and Treatment B in BA
Study 1 and corresponding mean drug quantity saved by the multi-day
patch of Example 1 in comparison to the 4 single-day patches of
Comparative Example 1 Applied total dose [mg/10 cm.sup.2] Mean drug
(= total quantity saved (nominal) drug Coating by Treatment A
content of the weight in comparison Sample patch(es)) 150
[g/m.sup.2] to Treatment B n Example 1 13.5 150 4.5 mg/4 d 12
(Treatment A) 1.1 mg/24 h Comparative 18.0 50 --/-- 12 Example 1
(Treatment B)
[0251] Despite a lower mean apparent dose delivered by the TTS of
Example 1, bioequivalence to the daily application of 4 patches of
Comparative Example 1 over 4 days could be demonstrated. This
observation indicates that the daily administration of a single-day
TTS requires more drug than the single administration of one
multi-day TTS over the same period of time for obtaining
bioequivalent rotigotine plasma concentrations. From the difference
in the mean apparent dose between the two bioequivalent medications
shown in Table 4a the mean additional need of rotigotine drug
substance for the once daily administration with single-day patches
can be estimated to be approximately 0.4 mg/10 cm.sup.2/day in the
steady state.
Tolerability and Skin Adhesiveness
[0252] In BA Studies 1 and 2, the patches of Examples 1 and 2 as
well as Comparative Example 1 were generally well tolerated. Skin
tolerability and adhesiveness of all patches were good during
either treatment.
[0253] Surprisingly, incidence of overall adverse effects was lower
for the single administration of the multi-day patches of Examples
1 and 2 compared to the daily administration of the single-day
patches of Comparative Example 1. As such, the pilot BA studies did
not indicate any inferiority concerning tolerability of the
multi-day transdermal therapeutic systems of the present invention
in comparison to the daily administration of conventional
single-day transdermal therapeutic systems.
[0254] Good adhesiveness of the multi-day patches of Example 1
having a coating weight of 150 g/m.sup.2 and Example 2 having a
coating weight of 168 g/m.sup.2 in vivo was consistent with good
peel adhesion properties observed in vitro.
Example 3
[0255] 7-Day bi-layer TTS comprising (a) a reservoir layer having a
coating weight of 150 g/m.sup.2 and containing 18 wt.-% rotigotine
and 8 wt.-% PVP and (b) a skin adhesive layer containing no
rotigotine and having a coating weight of 18 g/m.sup.2; solvent
system used for the preparation method: ethyl acetate/ethanol (5:1
(w/w))
Preparation of the Reservoir Layer Matrix (Step 1)
[0256] 0.061 g DL-a-Tocopherol, 0.024 g ascorbyl palmitate and
0.020 g of an aqueous sodium metabisulfite solution (10 wt.-%) were
mixed with 6.0 g anhydrous ethanol to obtain a clear solution.
[0257] 38.0 g silicone adhesive 7-4202 (59.1 wt.-% in ethyl
acetate) and 36.9 g silicone adhesive 7-4302 (60.9 wt.-% in ethyl
acetate) were added to the obtained solution of antioxidants and
stirred at 400 rpm. After approximately 10 min, 11.0 g rotigotine
of polymorphic Form II were added while stirring. The mixture was
heated up to 40.degree. C. and stirred at 400 rpm until a
homogenous dispersion was obtained. Thereafter 4.9 g polyvinyl
pyrrolidone (KOLLIDON 90F) were added to this mixture while
stirring. The mixture was stirred at 600 rpm until a homogeneous
dispersion was obtained.
Preparation of the Skin Adhesive Layer (Step 2)
[0258] 33.84 g of silicone adhesive 7-4202 (59.1 wt.-% in ethyl
acetate) were mixed with 49.26 g of silicone adhesive 7-4302 (60.9
wt.-% in ethyl acetate). The adhesive solution was then coated onto
a suitable polyester release liner (e.g. SCOTCHPAK.TM. 9744) up to
a coating weight of 18 g/m.sup.2. The coated release liner was
placed in a drying oven and dried at 50.degree. C. for about 30 min
and at 115.degree. C. for about 10 min.
Preparation of the Final TTS (Step 3)
[0259] The dispersion obtained in Step 1 was coated onto two sheets
of a suitable polyester release liner (e.g. SCOTCHPAK.TM. 9744) to
obtain two drug-containing reservoir layers each having a coating
weight of 75 g/m.sup.2. The coated release liner sheets were placed
in a drying oven and dried at 50.degree. C. for about 30 min and
then at 115.degree. C. for about 10 min. The first dried
drug-containing reservoir layer was laminated with (1) a
polyester-type backing foil and (2) the second drug-containing
reservoir layer after removal of the release liner from the surface
of the first reservoir layer to be laminated in order to obtain a
drug-containing reservoir layer having a coating weight of 150
g/m.sup.2.
[0260] The lamination with only (1) a polyester-type backing foil
results in only one drug-containing reservoir layer having a
coating weight of 75 g/m.sup.2 which leads to a transdermal
therapeutic system with a shorter application time of exemplarily
3.5 days.
[0261] Afterwards, the skin adhesive layer was laminated with the
drug-containing reservoir layer after removal of its release liner
to obtain a laminate consisting of a backing foil, a
rotigotine-containing reservoir layer having a coating weight of
150 g/m.sup.2, a skin adhesive layer having a coating weight of 18
g/m.sup.2 and a release liner. The whole laminate was dried at a
temperature of 115.degree. C. for about 10 min. Finally, individual
patches having a size of 10 cm.sup.2 were punched out of the
complete laminate and sealed into pouches.
Example 4
[0262] 7-Day mono-layer TTS comprising a reservoir layer having a
coating weight of 150 g/m.sup.2 and containing 18 wt.-% rotigotine
and 8 wt.-% PVP; solvent system used for the preparation method:
ethyl acetate/ethanol (5:1 (w/w))
[0263] The patches of Example 4 were manufactured according to the
method described in Example 3, but without adding a skin adhesive
layer.
Example 5
[0264] 7-Day mono-layer TTS comprising a reservoir layer having a
coating weight of 300 g/m.sup.2 and containing 9 wt.-% rotigotine
and 4 wt.-% PVP; solvent system used for the preparation method:
ethyl acetate/ethanol (5:1 (w/w))
Preparation of the Reservoir Layer Matrix (Step 1)
[0265] 0.030 g DL-a-Tocopherol, 0.012 g ascorbyl palmitate and
0,010 g of an aqueous sodium metabisulfite solution (10 wt.-%) were
mixed with 7.1 g anhydrous ethanol to obtain a clear solution.
[0266] 44.7 g silicone adhesive 7-4202 (59.1 wt.-% in ethyl
acetate) and 43.4 g silicone adhesive 7-4302 (60.9 wt.-% in ethyl
acetate) were added to the above solution of antioxidants and
stirred at 400 rpm. After approximately 10 min, 5.5 g rotigotine of
polymorphic Form II were added while stirring. The mixture was
heated up to 40.degree. C. and stirred at 400 rpm until a
homogenous dispersion was obtained. Thereafter, 2.4 g polyvinyl
pyrrolidone (KOLLIDON.RTM. 90F) were added to this mixture while
stirring. The mixture was stirred at 600 rpm until a homogeneous
dispersion was obtained.
Preparation of the Final TTS (Step 2)
[0267] The dispersion obtained in Step 1 was coated onto 4 sheets
of a suitable polyester release liner (e.g. SCOTCHPAK.TM. 9744) to
obtain 4 drug-containing reservoir layers each having a coating
weight of 75 g/m.sup.2. The coated release liner sheets were placed
in a drying oven and dried at 50.degree. C. for about 30 min and
then at 115.degree. C. for about 10 min. The first dried
drug-containing reservoir layer was laminated with a polyester-type
backing foil on one side and, consecutively, with the 3 remaining
drug-containing reservoir layers on the other side after removing
the release liner foils from the surface to be laminated of the
respective reservoir layers in order to obtain a laminate
consisting of a backing foil, a drug-containing reservoir layer
having a coating weight of 300 g/m.sup.2 and a release liner. The
whole laminate was dried at a temperature of 115.degree. C. for
about 10 min. Finally, individual patches having a size of 10
cm.sup.2 were punched out of the complete laminate and sealed into
pouches.
Example 6
[0268] 7-Day mono-layer TTS comprising a reservoir layer having a
coating weight of 300 g/m.sup.2 and containing 9 wt.-% rotigotine
and 4 wt.-% PVP; solvent system used for the preparation method:
heptane/ethanol (1:1.5 (w/w))
Preparation of the Reservoir Layer Matrix (Step 1)
[0269] To 19.0 g of an ethanolic PVP solution (containing 12.8
wt.-% polyvinylpyrrolidone (KOLLIDON.RTM. 90F), 0.06 wt.-% aqueous
sodium metabisulfite solution (10 wt.-%), 0.06 wt.-% ascorbyl
palmitate and 0.16 wt.-% DL-alpha-tocopherol), 5.5 g of rotigotine
of polymorphic Form II were added. The mixture was stirred for 1.5
h at 60.degree. C. Then, 36.0 g of silicone adhesive 7-4201 (73.6
wt.-% in heptane) and 36.1 g of silicone adhesive 7-4301 (73.3
wt.-% in heptane) were added and the mixture was stirred without
heating until a homogenous dispersion was obtained.
Preparation of the Final TTS (Step 2)
[0270] The final patches of Example 6 were manufactured according
to the method described in Step 2 of Example 5.
Example 7
[0271] 7-Day bi-layer TTS comprising (a) a reservoir layer having a
coating weight of 100 g/m.sup.2 and containing 18 wt.-% rotigotine
and 8 wt.-% PVP and (b) a skin adhesive layer having a coating
weight of 100 g/m.sup.2 and containing 9 wt.-% rotigotine and 4
wt.-% PVP ("gradient system"); solvent system used for the
preparation method: ethyl acetate/ethanol (5:1 (w/w))
Preparation of the Reservoir Layer Matrix (Step 1)
[0272] The reservoir layer was manufactured according to the method
described in Step 1 of Example 3.
Preparation of the Skin Adhesive Layer (Step 2)
[0273] The skin adhesive layer was manufactured according to the
method described for the reservoir layer matrix in Step 1 of
Example 5.
Preparation of the Final TTS (Step 3)
[0274] The final patches of Example 7 were manufactured according
to the method described in Step 3 of Example 3, but with only one
coating step for each of the reservoir layer and the
drug-containing skin adhesive layer resulting in a coating weight
of 100 g/m.sup.2 for each of the two layers.
Example 8
[0275] 7-Day mono-layer TTS comprising a reservoir layer having a
coating weight of 150 g/m.sup.2 and containing 18 wt.-% rotigotine
and 8 wt.-% PVP; solvent system used for the preparation method:
ethyl acetate/ethanol (5:1 (w/w)); solubilizing rotigotine and PVP
without heating; adding rotigotine in 2 portions before and after
the addition of PVP
Preparation of the Reservoir Layer Matrix (Step 1)
[0276] 0.061 g DL-a-Tocopherol, 0.024 g ascorbyl palmitate and
0.020 g of an aqueous sodium metabisulfite solution (10 wt.-%) were
mixed with 6.0 g anhydrous ethanol to obtain a clear solution. 38.0
g silicone adhesive 7-4202 (59.1 wt.-% in ethyl acetate) and 36.9 g
silicone adhesive 7-4302 (60.9 wt.-% in ethyl acetate) were added
to the obtained solution of antioxidants and stirred at 400 rpm.
After approximately 10 min, 5.0 g rotigotine of polymorphic Form II
were added while stirring at 400 rpm until a homogenous dispersion
was obtained (approx. 15 min). Thereafter, 4.9 g
polyvinylpyrrolidone (KOLLIDON.RTM. 90F) were added to this mixture
while stirring at 600 rpm until a homogeneous dispersion was
obtained (approx. 45 min). Then, 6.0 g rotigotine of polymorphic
Form II were added to the mixture while stirring at 600 rpm until a
homogeneous dispersion was obtained (approx. 60 min).
Preparation of the Final TTS (Step 2)
[0277] The final patches of Example 8 were manufactured according
to the method described in Step 3 of Example 3, but without adding
a skin adhesive layer.
Example 9
[0278] 7-Day mono-layer TTS comprising a reservoir layer having a
coating weight of 150 g/m.sup.2 and containing 18 wt.-% rotigotine
and 8 wt.-% PVP; solvent system used for the preparation method:
ethyl acetate/ethanol (3:1 (w/w)).
Preparation of the Reservoir Layer Matrix (Step 1)
[0279] To 19.6 g of an ethanolic PVP solution (containing 23.5
wt.-% polyvinylpyrrolidone (KOLLIDON.RTM. 90F), 0.12 wt.-% aqueous
sodium metabisulfite solution (10 wt.-%), 0.12 wt.-% ascorbyl
palmitate and 0.29 wt.-% DL-alpha-tocopherol and 21.4 wt-% ethyl
acetate), 35.6 g of silicone adhesive 7-4202 (59.1 wt.-% in ethyl
acetate) and 34.6 g of silicone adhesive 7-4302 (60.9 wt.-% in
ethyl acetate) were added and shortly stirred. Then, 10.3 g
rotigotine of polymorphic Form II were added to the mixture while
stirring. The final mixture was stirred until a homogenous
dispersion was obtained.
Preparation of the Final TTS (Step 2)
[0280] The final patches of Example 9 were manufactured according
to the method described in Step 3 of Example 3, but without adding
a skin adhesive layer.
[0281] Instead of coating reservoir layers each having a coating
weight of 75 g/m.sup.2 and laminating two coated layers together to
achieve the final coating weight of 150 g/m.sup.2, the coating of
only one reservoir layer having a coating weight of 150 g/m.sup.2
is also possible.
Comparative Example 2
[0282] Single-day mono-layer TTS comprising a reservoir layer
having a coating weight of 50 g/m.sup.2 and containing 9 wt.-%
rotigotine and 4 wt.-% PVP; solvent system used for the preparation
method: heptane/ethanol (1.4:1 (w/w))
[0283] Comparative Example 2 corresponds to Comparative Example 1,
except for the use of rotigotine of polymorphic Form II instead of
rotigotine of polymorphic Form I as starting material and an
increased PVP content resulting in a rotigotine to PVP wt.-% ratio
of 9:4.
Comparative Example 3
[0284] 7-Day mono-layer TTS comprising a reservoir layer having a
coating weight of 150 g/m.sup.2 and containing 18 wt.-% rotigotine
and 8 wt.-% PVP; solvent system used for the preparation method:
heptane/ethanol (1:1.5 (w/w))
Preparation of the Reservoir Layer Matrix (Step 1)
[0285] 11.0 g of rotigotine of polymorphic Form II and 7.9 g
ethanol were added to 21.5 g of an ethanolic PVP solution
(containing 22.7 wt.-% polyvinylpyrrolidone (KOLLIDON.RTM. 90F),
0.1 wt.-% aqueous sodium metabisulfite solution (10 wt.-%), 0.1
wt.-% ascorbylpalmitate and 0.3 wt.-% DL-alpha-tocopherol). The
mixture was stirred for 1.5 h at 60.degree. C. Then, 30.5 g of
silicone adhesive 7-4201 (73.6 wt.-% in heptane) and 30.7 g of
silicone adhesive 7-4301 (73.3 wt.-% in heptane) were added and the
mixture was stirred without heating until a homogenous dispersion
was obtained.
Preparation of the Final TTS (Step 2)
[0286] The final patches of Comparative Example 2 were manufactured
according to the method described in Step 3 of Example 3, but
without adding a skin adhesive layer.
[0287] The respective compositions of Examples 3-9 and Comparative
Examples 2 and 3 are summarized in Table 5.
TABLE-US-00007 TABLE 5 Composition of the patches of Examples 3-9
and Comparative Examples 2 and 3 Example Ex. 4 Ex. 8 Ex. 9
Ingredient [mg/10 cm.sup.2] , Comp. Comp. Ex. 5 except stated
otherwise Ex. 2 Ex. 3 Ex. 3 Ex. 6 Ex. 7 Reservoir Rotigotine (Form
II*) 4.5 27.0 27.0 27.0 18.0 layer Rotigotine (Form II*) 9.0 18.0
18.0 9.0 18.0 content [wt.-%] PVP 2.0 12.0 12.0 12.0 8.0 PVP
content [wt.-%] 4.0 8.0 8.0 4.0 8.0 Rotigotine:PVP ratio 9:4 18:8
18:8 9:4 18:8 [wt.-%] Silic. adhesive 7-430x 21.74 55.39 55.39
130.39 36.928 Silic. adhesive 7-420x 21.73 55.39 55.39 130.39
36.928 Sodium metabisulfite 0.00045 0.005 0.005 0.005 0.004
Ascorbyl palmitate 0.01 0.060 0.060 0.060 0.040
DL-.alpha.-Tocopherol 0.025 0.150 0.150 0.150 0.100 Coating weight
[g/m.sup.2] 50.0 150.0 150.0 300.0 100.0 Skin Rotigotine (Form II*)
-- -- -- -- 9.0 adhesive Rotigotine (Form II*) -- -- -- -- 9.0
layer content [wt.-%] PVP -- -- -- -- 4.0 PVP content [wt.-%] -- --
-- -- 4.0 Rotigotine:PVP ratio -- -- -- -- 9:4 [wt.-%] Silic.
adhesive 7-430x -- 10.8 -- -- 43.464 Silic. adhesive 7-420x -- 7.2
-- -- 43.464 Sodium metabisulfite -- -- -- -- 0.0018 Ascorbyl
palmitate -- -- -- -- 0.020 DL-.alpha.-Tocopherol -- -- -- -- 0.050
Coating weight [g/m.sup.2] -- 18.0 -- -- 100.0 *For the preparation
of the respective example patches rotigotine of polymorphic Form II
was used as starting material. The final patches contain rotigotine
in non-crystalline form. X = 1 for silicone adhesive in heptane X =
2 for silicone adhesive in ethyl acetate
[0288] In Table 6, the composition and selected physical properties
of the dispersions forming the drug containing self-adhesive matrix
layer of representative example patches are shown. The dispersions
were prepared in accordance with the methods described in Example 3
as well as Comparative Example 3 and were investigated in the
liquid state before laminating them and before the solvents were
evaporated in a drying step. The self-adhesive matrix layer of the
transdermal therapeutic system described herein represents a
dispersion of rotigotine/PVP droplets in a matrix of silicone
adhesives and can therefore be considered as a non-aqueous
emulsion. From the data shown in Table 6, it becomes apparent that
the use of an ethyl acetate/ethanol solvent mixture, in contrast to
a heptane/ethanol solvent mixture, leads to physically stable
emulsions also at high concentrations of rotigotine in the inner
and the outer phase of the emulsion (cf. Example 3 in comparison to
Comparative Example 3).
TABLE-US-00008 TABLE 6 Solvents and selected physical properties of
the dispersions (i.e. non-aqueous emulsions) forming the
self-adhesive matrix layer of the TTS of Example 3 as well as
Comparative Example 3 Drug conc. [wt.-%] Outer Inner/outer Droplet
Example.sup.1/ Inner Phase.sup.2 phase ratio size Solvent API:PVP
Phase.sup.2 (silic. API Density Inner system %-ratio (PVP) adhes.)
conc. (23.degree. C.) phase Remark Ex. 3 18:8 33.0 2.4 13.8 0.947
<35 .mu.m stable EtAc:EtOH 5:1 Comp. Ex. 3 18:8 25.1 1.3 19.3
0.919 <20 .mu.m Instable.sup.3 Heptane:EtOH 1:1.5 API =
Rotigotine .sup.1The dispersions forming the self-adhesive matrix
layer of the transdermal therapeutic systems of Example 3 as well
as Comparative Example 3 were prepared in accordance with the
methods described in the respective examples and were investigated
in the liquid state before laminating them and before the solvents
were evaporated in a drying step. .sup.2Inner and outer phase were
separated by centrifugation; drug content was determined in each
phase by HPLC .sup.3Crystallization of rotigotine was observed at
room temperature after a storage/holding time of 2 days at room
temperature
[0289] Surprisingly, it was found that the solubility of PVP in
ethyl acetate is enhanced by rotigotine by one order of magnitude.
That is, rotigotine apparently functions as a co-solvent for PVP in
an aprotic polar solvent such as ethyl acetate. This indicates that
rotigotine forms an adduct with the PVP polymer and reveals a
different solubility in dipolar organic solvents on the one hand
and in a heptane/ethanol mixture on the other hand. Furthermore,
the addition of a small portion of ethanol to ethyl acetate enables
the formation of rotigotine/PVP droplets in ethyl acetate-based
silicone adhesive solutions and allows for homogenously dispersing
the rotigotine/PVP conjugate in the silicone adhesive solution at
room temperature.
[0290] In vitro drug permeation testing across an ethylene vinyl
acetate (EVA) membrane
[0291] In vitro Drug release was evaluated by a membrane permeation
test performed over an extended period of time using a 51 .mu.m
thick membrane consisting of an ethylene vinyl acetate (EVA)
copolymer with 9% vinyl acetate (COTRAN.TM. Membrane, 3M) and the
Paddle over Disk apparatus described in the United States
Phamacopeia (USP). Phosphate buffer pH 4.5 was used as acceptor
medium (900 ml; 32.degree. C.; 50 rpm). The drug permeation rates
into the acceptor medium were determined in regular intervals using
a validated UV photometric or HPLC method.
In Vitro Drug Release Testing
[0292] The drug release test was performed under equivalent
conditions as described for the drug permeation test, but without
placing an EVA membrane between the release surface of the
respective TTS and the acceptor medium. The cumulative amount of
drug released into the acceptor medium was determined in regular
intervals using a validated HPLC method.
Results--In Vitro Drug Permeation Across an EVA Membrane
[0293] The results of the EVA membrane tests performed with sample
patches of Example 3 are depicted in FIG. 6.
[0294] The data show a constant drug permeation profile for the TTS
of Example 3 over 7 days without any significant decline over the
entire test period.
[0295] The results of the EVA membrane tests performed with sample
patches of Examples 3 and 7 are depicted in FIG. 7.
[0296] The data show constant and comparable drug permeation
profiles for the TTS of Example 3 and the TTS of Example 7 over 7
days without any significant decline over the entire test
period.
[0297] In comparison to the TTS of Example 3 comprising a skin
adhesive layer containing no rotigotine, the initial flux rate was
higher for the TTS, i.e. the gradient system, of Example 7. That
is, a gradient system according to Example 7 offers the possibility
of slightly increased drug absorption immediately after
application.
[0298] In FIG. 8, the cumulative permeation profiles of the 7-day
bi-layer TTS of Example 3, the 7-day mono-layer TTS of Example 5,
and the 1-day TTS of Comparative Example 2 are depicted.
[0299] The data demonstrate that a prolongation of the functional
life time of a TTS can be obtained by (a) increasing the
thickness/coating weight of the self-adhesive matrix layer from 50
to 300 g/m.sup.2 (Example 5) without changing the 9:4 wt.-% ratio
of rotigotine to PVP known from Comparative Example 2 or (b) with a
bi-layer self-adhesive matrix comprising a reservoir layer having a
coating weight of 150 g/m.sup.2 containing rotigotine and PVP in a
wt.-% ratio of 18:8 and a skin adhesive layer having a coating
weight of 18 g/m.sup.2 containing no rotigotine.
Results--In Vitro Drug Release into an Acceptor Medium
[0300] In FIG. 9, the cumulative release (Q) of rotigotine from the
7-day bi-layer TTS of Example 3 and the 7-day mono-layer TTS of
Example 4 is depicted. The patches of Examples 3 and both comprise
a reservoir layer having an identical composition and only differ
in that the patch of Example 3 further comprises a skin adhesive
layer containing no rotigotine.
[0301] The data show that the drug release from the patches of
Examples 3 and 4 in both cases follows a typical square root of
time kinetics up to a drug depletion rate of more than 80% related
to the total drug content of the reservoir layer. The slope of the
regression lines is very similar and the onset of the release is
only slightly delayed by the skin adhesive layer of the patch of
Example 3 having a coating weight of 18 g/m.sup.2. That is,
adhesion properties as well as the initial burst of the drug
release can be adapted by a skin adhesive layer in accordance with
drug safety needs and without compromising the release performance
of a corresponding TTS.
* * * * *