TRANSDERMAL THERAPEUTIC SYSTEMS

DISPOSITIFS THERAPEUTIQUES TRANSDERMIQUES

English Abstract

The invention concerns a transdermal therapeutic system containing ergoline
derivatives,
preferably lisuride, with a stabilized ergoline compound. Stabilization of the
oxidation sensitive
ergoline combination is done through a combination of at least one fat-
soluble, radical-trapping
antioxidant, preferably Di-tert.-butylmethylphenols, Di-tert.-
butylmetoxyphenols, tocopherols or
ubichinones and a basic polymer. Use of a transdermal therapeutic system (TTS)
comprising a
pharmaceutical layer containing at least one matrix having an active
ingredient and/or an active
ingredient reservoir; a diffusion barrier that is permeable to said active
ingredient and arranged
on the skin side of the active ingredient reservoir; and an ergoline
derivative or salt thereof as an
active ingredient for producing an agent for obtaining and maintaining the
circadian rhythm
under dopamine therapy. The invention relates to the use of a transdermal
therapeutic system
(TTS) comprising a medicinal layer, which contains at least one matrix
comprising an active
ingredient and/or an active ingredient reservoir and a diffusion barrier
situated on the skin side of
the active ingredient reservoir and permeable to active ingredients, in
addition to, an
ergoline-derivative or physiologically compatible salt with an acid thereof,
as an active ingredient, for
producing a means for treating the Restless Leg Syndrome and Periodic Limb
Movement
Disorder. The invention relates to the use of a dopamine agonist in the form
of an agent
consisting of at least two spatially discrete compositions, of which one is a
transdermal
therapeutic system (TTS) containing the dopaminergic agent and another one or
more are
preparations for oral and/or parenteral application containing that same
dopaminergic agent for
the treatment of dopaminergically treatable diseases with the following
elements: a) the TTS is
continuously applied, b) within the duration of application in a) the
composition for oral or
parenteral dosage is administered.

Claims

WHAT IS CLAIMED IS:
1. A transdermal delivery device for delivering an effective amount of an
ergoline
compound to a subject, the device comprising: (a) a backing layer and (b) a
matrix adhered to
one surface of the backing layer, wherein the matrix comprises: (i) an
effective amount of an
ergoline compound; (ii) a skin permeation-enhancing amount of a skin
penetration enhancer; (iii)
a basic polymer selected from the group consisting of a basic polymer a basic
copolymer and
mixtures thereof and (iv) a lipophilic antioxidant.
2. The transdermal delivery device of claim l, wherein the device provides
substantially continuous transdermal delivery of the ergoline compound to the
bloodstream of a
mammal, for a predetermined period of time, wherein the effective amount
prevents and or
alleviates at least one symptom of a disease or condition associated with
dopamine deficiency.
3. The transdermal delivery device of claim 1, wherein the matrix further
comprises
an adhesive.
4. The transdermal delivery device of claim 1, wherein the device further
comprises
an adhesive layer.
5. The transdermal delivery device of claim 1 wherein the device further
comprises a
removable protective cover.
6. The transdermal delivery device of claim 1, wherein the device further
comprises
a diffusion burner.
7. The transdermal delivery device of claim l, wherein the basic polymer is
selected
from the group consisting of a basic polyacrylate, a basic acrylate copolymer.
8. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant
inhibits the oxidation of the ergoline compound.
47

9. The transdermal delivery device of claim 1, wherein the combination of the
lipophilic antioxidant and the basic polymer inhibits the oxidation of the
ergoline compound.
10. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant is
selected from the group consisting of Di-tert-butylmethylphenol (BHT), Di-tert-
butylmetoxyphenol, a tocopherol, a ubichinone and mixtures thereof.
11. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant is
selected from the group consisting of Vitamin E, .alpha.-tocopherol, .gamma.-
tocopherol, .delta.-tocopherol, .alpha. -
tocopherol acetate, .alpha.-tocotrienol, .beta.-tocotrienol, .delta.
tocotrienol, .gamma. -tocotrienol, Nutriene
(Tocotrienols), .gamma.-Oryzanol, Trolox, 2,2,5,7,8-pentamethyl-6-chromanol,
Di-tert-
butylmethylphenol (BHT), Di-tert-butylmetoxyphenol, a ubichinone and mixtures
thereof.
12. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant is
selected from the group consisting of 2,2,5,7,8-pentamethyl-6-chromanol; 2,2'-
Azobis (2-
amidino-propane) dihydrochloride (AAPH); 2,6-di- tert-butyl-4-methylphenol
(BHT); ethanolic
BHT; 2-tert-butyl-4-methylphenol; 4-Difluoro-S-(4-phenyl-1,3-butadienyl)-4-
bora-3a,4a-diaza-
s-indacene-3-undecanoic acid; ~-oryzanol; ascorbyl palmitate; .alpha.-
carotene; .beta.-carotene;
Coenzyme Q10; Coenzyme Q10H2; coenzyme Q9 (CoQ9H2); copper; .beta.-
Cryptoxanthin; a-
lipoic acid; Lutein/zeaxanthin; luteine; lycopene; malondialdehyde (MDA); meth-
6-hydroxy-
2,5,7,8-tetramethyl-2-carboxylic acid (Trolox); Nutriene (Tocotrienols);
.gamma.-Oryzanol; Retinol; R-
tocopherol acetate; R-tocopherol; selenium; .alpha.-tocopherol; a -tocopherol
acetate; .gamma.-tocopherol; d-
tocopherol; Trolox; ubiquinol; Ubiquinol 10; vitamin E; and zinc.
13. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant is
2,6-di- tert-butyl-4-methylphenol (BHT).
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14. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant is
2-tert-butyl-4-methylphenol.
15. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant is
present in an amount from about 0.25% to about 5% w/w.
16. The transdermal delivery device of claim 1, wherein the basic polymer is
selected
from the group consisting of a basic polymers, a basic polyacrylates, a
hydrophilic polyacrylate
with basic substituents, butyl methacrylate-(2-diamino ethyl)methacrylate-
methacrylate-
copolymer; a copolymer of dimethyl aminomethyl methacrylate with neutral
methacrylate esters;
GELVA® multipolymer, and mixtures thereof.
17. The transdermal delivery device of claim 1, wherein the device further
comprises
an adhesive layer, wherein the adhesive layer comprises a basic polymer.
18. The transdermal delivery device of claim 1, wherein the matrix further
comprises
a crystallization inhibitor.
19. The transdermal delivery device of claim 1, wherein the matrix further
comprises
a crystallization inhibitor and the crystallization inhibitor is selected from
the group consisting of
polyvinyl pyrrolidone, vinyl pyrrolidone vinylacetate copolymers and polyvinyl
pyrrolidone
vinylacetate copolymers, polyvinyl alcohols, dextrines, dextranes, sterines,
and bile acids.
20. The transdermal delivery device of claim 1, wherein the matrix further
comprises
a crystallization inhibitor and the crystallization inhibitor is Kollidon®
VA 64.
21. The transdermal delivery device of claim 1, wherein the matrix further
comprises
a crystallization inhibitor and wherein the crystallization inhibitor is
present in an amount from
about 0.25% to about 5% w/w.
49

22. The transdermal delivery device of claim 1, wherein the matrix further
comprises
an adhesiveness enhancer.
23. The transdermal delivery device of claim 1, wherein the adhesive layer
further
comprises an adhesiveness enhancer.
24. The transdermal delivery device of claim 1, wherein the adhesiveness
enhancer is
selected from the group consisting of resins, polyacrylates and mixtures
thereof.
25. The transdermal delivery device of claim 1, wherein the adhesiveness
enhancer is
present in an amount from about 1% to about 20% w/w.
26. The transdermal delivery device of claim 1, wherein the adhesiveness
enhancer is
present in an amount from about 2% to about 10% w/w.
27. The transdermal delivery device of claim 1, wherein the ergoline compound
is
selected from the group consisting of lisuride, proterguride, bromolisuride (3-
(2-bromo-9,10-
didehydro-6-methyl-8.alpha.-erg- olinyl)-1,1-diethyl urea), terguride (3-(6-
methyl-8.alpha.-ergolinyl)-1,1--
diethyl urea) and proterguride (3-(6-propyl-8.alpha.-ergolinyl)-1,1-diethy-1
urea).
28. The transdermal delivery device of claim 1, wherein the ergoline compound
is
selected from the group consisting of lisuride (3-(9,10-didehydro-6-methyl-
8.alpha.-ergolinyl)-1,1-
diethyl urea), a physiologically compatible salt of lisuride, and mixtures
thereof.
29. The transdermal delivery device of claim 1, wherein the backing layer is
impermeable, further comprising an adhesive layer permeable for the ergoline
compound,
wherein the ergoline compound is stabilized by the presence of the lipophilic
antioxidant and the
basic polymer.
30. A method for treating a disease or condition associated with dopamine
deficiency,
the method comprising the step of adhering the transdermal delivery device of
claim 1 onto the
50

skin of a mammal, wherein the device provides substantially continuous
transdermal delivery of
the ergoline compound to the bloodstream of the mammal, for a predetermined
period of time, in
a effective amount, wherein the effective amount prevents and or alleviates at
least one
symptom of a disease or condition associated with dopamine deficiency.
31. A method for treating a dopaminergic disease, the method comprising the
step of
adhering the transdermal delivery device of claim 1 onto the skin of a mammal,
wherein the
device alleviates at least one symptom associated with the dopaminergic
disease being treated.
32. A method of treating a condition associated with dopamine deficiency, the
method comprising the step of adhering the transdermal delivery device of
claim 1 onto the skin
of a mammal, wherein the device alleviates at least one symptom associated
with the
dopaminergic disease being treated.
33. A method for treating Parkinson's Disease, the method comprising the step
of
adhering the transdermal delivery device of claim 1 onto the skin of a mammal,
wherein the
device alleviates at least one symptom associated with Parkinson's Disease.
34. A method for alleviating and/or preventing the symptoms of Restless Legs
Syndrome and/or Periodic Limb Movement Disorder, the method comprising the
step of
adhering the transdermal delivery device of claim 1 onto the skin of a mammal,
wherein the
device alleviates and/or prevents at least one symptom associated with
Restless Leg Syndrome
and/or Periodic Limb Movement Disorder.
35. A method for treating and/or preventing migraines, the method comprising
the
step of adhering the transdermal delivery device of claim 1 onto the skin of a
person who has
recurring migraines, wherein the device prevents, aborts and/or alleviates at
least one symptom
associated with migraines.
51

36. A method for preventing and/or alleviating the symptoms of Premenstrual
Syndrome, the method comprising the step of adhering the transdermal delivery
device of claim
1 onto the skin of a female human, wherein the device alleviates and/or
prevents at least one
symptom associated with Premenstrual Syndrome.
37. A method for inhibiting lactation, the method comprising the step of
adhering the
transdermal delivery device of claim 1 onto the skin of a female mammal,
wherein the device
inhibits lactation in the mammal.
38. A method for treating hyperprolactinemia, the method comprising the step
of
adhering the transdermal delivery device of claim 1 onto the skin of a mammal,
wherein the
device decreases or inhibits lactation in the mammal.
39. A method for treating gynecomastia, the method comprising the step of
adhering
the transdermal delivery device of claim 1 onto the skin of a mammal, wherein
the device
decreases the size of the mammary glands in the mammal.
40. A method for treating a patient with a depression disorder, comprising the
step of
adhering the transdermal delivery device of claim 1 onto the skin of the
patient, wherein the
device provides the patient with at least a partial relief from the symptoms
of the depression
disorder for a predetermined period of time.
41. A method for treating a patient with an attention disorder, comprising the
step of
adhering the transdermal delivery device of claim 1 onto the skin of the
patient, wherein the
device provides the patient with at least a partial relief from the symptoms
of the attention
disorder for a predetermined period of time.
42. A method for treating a person for nicotine dependency during smoking
cessation
therapy, comprising the step of adhering the transdermal delivery device of
claim 1 onto the skin
52

of the patient, wherein the device provides the patient with an effective
amount of an ergoline
compound.
43. A method for treating a patient with an eating disorder, comprising the
step of
adhering the transdermal delivery device of claim 1 onto the skin of the
patient, wherein the
device provides the patient with an effective amount of an ergoline compound.
44. A method for treating a patient with a loss of libido, comprising the step
of
adhering the transdermal delivery device of claim 1 onto the skin of the
patient, wherein the
device increases the patient's libido.
45. A method for suppressing bowel movements or diarrhea in a patient with
carcinoid syndrome, comprising the step of adhering the transdermal delivery
device of claim 1
onto the skin of the patient, wherein the device suppresses the patient's
bowel movements or
diarrhea.
46. A method for suppressing bowel movements or diarrhea in a patient with
irritable
bowel syndrome, comprising the step of adhering the transdermal delivery
device of claim 1 onto
the skin of the patient, wherein the device suppresses the patient's bowel
movements or diarrhea.
47. A method for preventing or treating fibrotic cardiac valvulopathy,
comprising the
step of adhering the transdermal delivery device of claim 1 onto the skin of
the carcinoid patient,
wherein the device prevents or treats fibrotic cardiac valvulopathy.
48. A method for obtaining or maintaining a patient's circadian rhythm,
comprising
the step of adhering the transdermal delivery device of claim 1 onto the skin
of the patient,
wherein the device provides the patient with an effective amount of an
ergoline compound.
49. A method for obtaining or maintaining the circadian rhythm of a patient
under
dopamine therapy, comprising the step of adhering the transdermal delivery
device of claim 1
53

onto the skin of the patient, wherein the device provides the patient with an
effective amount of
an ergoline compound, wherein the patient is under dopamine therapy.
50. A method for preventing disturbances in the circadian rhythm of a patient
under
dopamine therapy, comprising the step of adhering the transdermal delivery
device of claim 1
onto the skin of the patient, wherein the device provides the patient with an
effective amount of
an ergoline compound.
51. The transdermal delivery device of claim 1, wherein the lipophilic
antioxidant
reacts with free radicals.
52. The transdermal delivery device of claim 1, wherein the ergoline compound
selected from the group consisting of lisuride, proterguride, physiologically
compatible salts
thereof, and mixtures thereof.
53. The transdermal delivery device of claim 1, wherein the ergoline compound
is
according to Formula I or physiologically compatible salt thereof with an
acid,
<IMG>
wherein ~ is a single or double bond wherein R1 is an H atom or a halogen
atom,
particularly a bromine atom, and wherein R2 is a C1-4 alkyl, for producing an
agent for
obtaining and maintaining the circadian rhythm under a continuous dopamine
therapy.
54

54. The transdermal delivery device of claim 1, wherein the matrix is selected
to
provide a transdermal flux F of the ergoline compound through human skin is in
the range from
about 0.1 to about 5.0 µg/ cm2/h.
55

Description

CA 02502142 2005-03-24
TRANSDERMAL THERAPEUTIC SYSTEM
BACKGROUND
Field of the Invention
[0001] The present invention relates generally to a transdermal therapeutic
device and
system for delivering an ergoline compound. More specifically, the present
invention relates to an extended shelf life transdermal therapeutic device for
delivering an ergoline compound transdermally, over a period of days.
DETAILED DESCRIPTION OF THE INVENTION
(0002] Ergoline Transdermal Therapeutic System With Extended Shelf Life
Description
[0003] The invention relates to a medication for transdermal application
consisting of
an impermeable backing layer, a matrix containing an ergoline compound and
possibly a penetration enhancer, possibly a diffusion barrier covering the
matrix, a
layer of adhesive permeable for these substances and a peel-off protective
cover. The
ergoline derivatives, preferably lisuride, in transdermal therapeutic systems
need to be
stabilized.
[0004] Transdermal therapeutic systems containing ergoline derivatives have
been
used to treat diseases caused by disorders of the dopaminergic system (WO
92/20339,
WO 91/00746). They appear to be especially suited for the treatment of
Parkinson's
disease, Parkinsonism, Restless Legs Syndrome, as prophylaxis for Premenstrual
Syndrome and as a lactation inhibitor (DE 100 43 321). Sometimes they are also
intended for migraine prophylaxis, where a well-tolerated, constant therapy is
desired.
[0005] Transdermal therapeutic systems can, for instance, be structured as so-
called
matrix systems. Matrix systems typically consist of an impermeable backing
layer,
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CA 02502142 2005-03-24
the matrix with the drug formulation imbedded or dissolved and, if the matrix
does
not stick to skin on its own, a layer of adhesive and a peel-off protective
cover.
[0006] To reach a defined, continuous flow, the drug is usually combined with
suitable excipients, such as solvents, penetration enhancers and
crystallization
inhibitors.
(0007] Transdermal therapeutic systems with oxidation sensitive drugs are not
very
stable. Improvement of the stability of these systems is described in DE 100
54 713
A 1. In this description all of the system's formulation components are
selected in a
way that the total of their peroxide numbers (as an indicator of its
oxidizability) is not
more than 20. This means, however, that the contents that can be considered,
are
limited or that it would require elaborate and costly preparatory treatments
of the
individual excipients with sodium hydrogen sulfite solutions to destroy the
existing
peroxides.
[0008] But the problem with preparations containing ergoline derivatives up to
now
has been the instability of the drug itself. Transdermal therapeutic systems
containing
ergoline derivatives after some time show discolorings, typically correlated
with a
decay of the active drug content. This is caused by the rather high oxidation
sensitivity of ergoline derivatives. So lisuride, for instance, is being
oxidized even
without light at the nitrogen in position 6 of the ring system.
[0009] This leads to skin irntation, especially in the case of long-term
application.
Controlled dosing is also not possible anymore due to the unknown reduction of
the
drug content.
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CA 02502142 2005-03-24
[0010] The antioxidants commonly used for stabilizing, such as citric acid,
ascorbic
acid, sodium sulfite, alkyl gallate, ascorbyl palmitate and others, do not
result in any
improvement.
[0011] The aim of the present invention is the creation of a transdermal
therapeutic
system containing an ergoline derivative, which is stable on storage and does
not
allow oxidative degradation of the drug and which can thus remain on the skin
without irritations even over long periods of time.
[0012] According to this invention the task is solved by stabilizing the
ergoline
derivatives in a transdermal therapeutic system through combining at least one
fat-
soluble, radical-trapping antioxidant, preferably Di-tert.-butylmethylphenols,
Di-tert.-
butylmetoxyphenols, tocopherols or ubichinones and a basic polymer.
[0013] Investigations have shown that the presence of one of the above
mentioned
antioxidants alone does not result in a significant improvement of the
stability of the
ergoline derivatives.
[0014] Transdermal therapeutic systems, in which there is also a basic polymer
present, such as butylmethacrylate-(2-dimethyl aminoethyl)methacrylate-methyl
methacrylate-copolymer (Eudragit E 100 by Rohm, Germany), besides the above
mentioned antioxidants, display a surprisingly high stability. In this, the
basic
polymer can be present also in a mixture with the usual other polymers, such
as
neutral polyacrylates. Moreover, the polymer mixture can contain common
adhesiveness enhancers (i.e., resins or polyacrylates) to improve the adhesive
strength.
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CA 02502142 2005-03-24
[0015] The systems according to this invention usually have an area weight of
2 to 10
mg/cm2. This is the sum of all components after drying. The total content of
matrix
forming polymers is 50% to 95% w/w, preferably 60% to 85%. The portion of
other
polymers is 5% to 30% w/w, preferably 10% to 20%. The content of antioxidants
is
between 0.25% and 5% w/w, preferably 0.5% to 1.5%. The portion of the drug is
1%
to 10% w/w, preferably 3% to 6%.
(0016] The combinations according to this invention have an unexpected synergy
effect inhibiting oxidation of ergoline derivatives in transdermal systems.
[0017] The stability of the transdermal therapeutic system comprising an
ergoline
compound is achieved by the presence of at least one fat-soluble or lipophilic
antioxidant and a basic polymer in the matrix containing the ergoline
compound.
Preferably, the ergoline compound is lisuride, the lipophilic antioxidant is
selected
from the group consisting of Di-tert.-butylmethylphenols, Di-tert.-
butylmetoxyphenols, tocopherols and ubichinones and the basic polymer is a
basic
copolymer such as Eudragit.
[0018] Examples of lipophilic antioxidants include, but are not limited to the
following: 2,2,5,7,8-pentamethyl-6-chromanol; 2,2'-Azobis (2-amidino-propane)
dihydrochloride (AAPH); 2,6-di- tert-butyl-4-methylphenol (BHT); ethanolic
BHT;
2-tent-butyl-4-methylphenol; 4-Difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-
3a,4a-
diaza-s-indacene-3-undecanoic acid; A-oryzanol; ascorbyl palmitate; oc-
carotene;
~-carotene; Coenzyme Q 10; Coenzyme Q 1 OH2; coenzyme Q9 (CoQ9H2); copper;
~-Cryptoxanthin; a-lipoic acid; Lutein/zeaxanthin; luteine; lycopene;
malondialdehyde (MDA); meth-6-hydroxy-2,5,7,8-tetramethyl-2-carboxylic acid

CA 02502142 2005-03-24
(Trolox); Nutriene (Tocotrienols); x-Oryzanol; Retinol; R-tocopherol acetate;
R-tocopherol; selenium; x-tocopherol; a -tocopherol acetate; Y-tocopherol;
~-tocopherol; Trolox; ubiquinol; LTbiquinol 10; vitamin E; and zinc.
[0019] The following molecules are examples of hydrophilic antioxidants:
citric acid,
ascorbic acid (vitamin C), sodium sulfite, alkyl gallate, ascorbyl palmitate,
Cysteine,
methionine, glutathione, Sodium hydrogensulfite), uric acid, TBA-RS, and
protein
carbonyls.
[0020] The following are examples of basic polymers and basic polyacrylates:
hydrophilic polyacrylate with basic substituents, GELVA, and Eudragit E100
(dimethyl aminomethyl methacrylate w/neutral methacrylate esters).
Example A - Stability Testing
[0021] Stability investigations are carried out with samples containing
combinations
of different antioxidants and polymers.
[0022] The ergoline compound tested as the drug is lisuride. In addition to
lisuride,
the samples contained additional ingredients for use in transdermal
therapeutic
systems.
[0023] Preparations of the Samples:
[0024] 150g polyvidone and 300g dibutyl sebacate as so$eners and 20g Foral
E105
(hydrated colophonium pentaerthrite ester by Hercules) as tackifier are one
after the
other stirred into 900g of a 50% aqueous solution of polymer adhesive in a
mixture of
2-propanol and acetone at room temperature. Then SOg lisuride and 15g
antioxidant
are pre-suspended in part of the solvent and added to the adhesive mixture,
being
stirred constantly. Once it is completely dissolved, the solution is
replenished with
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CA 02502142 2005-03-24
acetone to achieve the final weight and left sitting for about 24 hours to
remove gas
bubbles. Afterwards the solution is applied to a siliconized polyester film
(Liner
Film) with a suitable coating device (i.e., Knife over Roll), so after
removing the
volatile solvents at 40 to 90°C an even film with an area weight of
about 5 mg/cm2
develops. Then it is concealed with a polyester cover foil. The laminate thus
achieved is cut into single patches with sizes of 10 cm2 each with a suitable
stamping
device and inserted into light proof pouches of aluminum-paper compound
material.
[0025] Table 1: The composition of the samples tested in % w/w.
sample no. #80#81 #82 #83 #84 #85 #86 #87 #88 #90#98
lisuride 3.33.2 4.0 4.0 4.0 4.0 4.0 4.0 4.0 3.03.0
MA24A (1) 44.945.1- 53.052.0
Eudragit E 100 85.085.068.068.060.0-
(2)
Durotac DT 387-2510- 77.077.0- 17.017.015.0-
(3)
Ascorbyl palmitate 2.0
Pocopherol 1.0 1.0 1.0 1.0 1.0 1.0
BHT (4) 0.9 1.0 1.0 1.0
Polyvidon 9.29.3 10.010.010.010.010.010.020.010.010.0
Transcutol (5) 27.027.0- 25.025.0
Eutanol (6) 8.78.6 5.0 5.0 8.08.0
Dimethylacetamide5.95.9
7

CA 02502142 2005-03-24
(1) Polyisobutylene [Adhesive Research, Ireland]
(2) Butyl methacrylate-(2-diaminoethyl)methacrylate-methacrylate-copolymer
(1:2:1)
[Rohm, Germany]
(3) neutral polyacrylate [National Starch, USA]
(4) Butylhydroxytoluene (2,6-di-tert.-butyl-4-methylphenol)
(5) Diethylene glycol monoethylether [Gattefosse, France]
(6) 2-hexyldecanol [Cognis, Germany]
[0026] Storage: The samples are stored under the following conditions:
a) at 4°C
b) at 25°C and 60% humidity
c) at 40°C and 75% humidity
[0027] After one month of storage the concentration of the aminoxide achieved
is
determined through oxidation at the nitrogen in position 6 of the ergoline
ring system
(lisuride-N-oxide).
[0028] Determination of the aminoxide content: The amount of aminoxide is
determined with a HPLC method, showing the following parameters:
[0029] Column: Luna C 18(II), 100 mm x 4.6 mm ID
Pre-column: Phenomenex C 18, 4 mm x 3 mm ID
Column temperature: 35°C
Running time: 30 min
Flow rate: 1.20 ml/min
Mobile phase: A: l OmM TRIS-Buffer, pH 8.7
B: Acetonitrile
Gradient profile: 0 to 25'h minute: 12% B
25'" to 27~' minute: 42% B
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CA 02502142 2005-03-24
28~' to 38th minute: 12% B
Detection: Fluorescence Detector
Preparation of the samples:
[0030] One lisuride patch, produced as described in Example A, is shaken in 50
ml
solvent (2-propanol) for 15 minutes after weighing and removing the liner
film. Then
ml of the solution are diluted with a diluent (acetonitril) to the volume of
20 ml.
About 2 ml of this solution are centrifugated at 5000 rpm for 2 minutes and
the clear
resulting solution is being transferred to a HPLC sample vial.
[0031] Table 2. Creation of aminoxide from lisuride after one month storage
Sample Content
of
lisuride-N-oxide
a) b) 25C c) 40C
4C
#80: 0.51 1.59 2.80
MA24A/Tocopherol
#81: 0.45 1.26 1.86
MA24AlBHT
#82: 0.70 1.21 1.49
Durotac/Tocopherol
#83: 0.71 1.08 1.44
Durotac/BHT
#84: 0 0.11 0.26
Eudragit/Tocopherol
#85: 0.06 0.09 0.22
EudragitBHT
#86: 0 0.14 0.37
Eudragit/Durotac/Tocopherol
#87: 0 0.14 -
Eudragit/Durotac/BHT
9

CA 02502142 2005-03-24
#88: 0.11 0.21 0.44
Eudragit/Durotac/Tocopherol
#90: - - 1.93
MA24A/Tocopherol
#98 0.27 0.58 -
MA24A/Ascorbyl Palmitate
Example B
[0032] Stability investigations are carried out with samples containing
combinations
of different antioxidants with basic polyacrylates. In this process lisuride
is
employed as the drug. In addition to this, the samples contain more
ingredients
usually used in transdermal therapeutic systems.
Preparation of the samples:
[0033] 175g polyvidone and 310g dibutyl sebacate as softeners and 175g
dodecanol
as a co-solvent were consecutively stirred into 1800g of an about 45% aqueous
solution of basic polyacrylate adhesive in acetone at room temperature. Then
80g
lisuride and 17g antioxidants are pre-suspended in part of the solution and
added to
the adhesive solution. Once it is completely dissolved, 35g Focal are added as
a
tackifier. The solution is replenished with acetone to reach the final weight
and is
then left sitting for about 24 hours to remove the gas bubbles. After that,
the solution
is applied to a siliconized polyester sheet (Liner Film) with a suitable
coating device
(i.e. Knife over Roll), so after taking away the volatile solvents at 40 to
90°C an even
film with an area weight of about 5 mg/cm2 develops. Then it is concealed with
a
polyester cover foil. The laminate thus created is cut into single patches
with sizes of

CA 02502142 2005-03-24
cm2 each with a suitable stamping device and put into light proof pouches of
aluminim-paper compound material.
[0034] Table 3. Composition of the samples in % w/w
Sample #. #C005#151 #156#C001 #152
Lisuride 5.0 5.0 5.0 4.0 5.0
Polyvidon 10.0 10.0 10.010.0 10.0
lauryl alcohol 15.0 15.0 15.0 15.0
Foral 1 OS E 2.0 2.0 2.0 2.0
( 1 )
BHT (2) 1.0 0.4
Sodium sulfite 0.1
Eudragit E 100 68.0 68.0 67.085.6 67.9
(3)
(1) hydrated colophonium penta erythritester by Hercules
(2) Butyl hydroxy toluene
(3) Butyl methacrylate-(2-diaminoethyl)methacrylate-methacrylate-copolymer (
1:2:1 )
[Rohm, Germany]
[0035] Storage: The samples are stored at 25°C and 60% humidity and at
40°C and
75% humidity. After one month's and after three months of storage
concentration of
the aminoxide is determined.
[0036) Determination of the aminoxide content: The aminoxide content of the
samples is determined with the HPLC method described in Example A.
11

CA 02502142 2005-03-24
[0037] The results of the stability tests are presented in Table 4.
[0038] Table 4: Creation of aminoxide from lisuride after a one month and a
three
month storage.
Sample content of
lisuride-N-oxide
in % w/w
25C 25C 40C 40C
1 month 3 months 1 month 3 months
#C005: Eudragit0.20 0.50 1.18 3.51
# 151: Eudragit0.21 0.40 0.91 2.43
#153: Eudragit0.21 0.48 0.92 2.00
# 156: 0.14 0.27
EudragitBHT
#C001: 0.10 0.14 0.38 0.44
EudragitBHT
#152: 0.18 0.36 0.82 2.23
Eudragit/Sodium
Sulfite
[0039] Preferably, the transdermal therapeutic device and system of the
present
invention is useful as a medicament in the following conditions: migraine
prophylaxis, menstrual associated migraine, and as an abortive treatment of
migraine
to alleviate the symptoms and shorten the duration of migraine, PMS symptoms,
hyperprolactinemia" gynecomastia, depression, attention deficit disorder
(ADD),
smoking cessation, eating disorders and the loss of libido.
[0040] Additional therapeutic uses of particular embodiments of the
transdermal
therapeutic device and system of the present invention include: (i) to
suppress bowel
movements and diarrhea in carcinoid syndrome and/or irritable bowel syndrome;
(ii)
12

CA 02502142 2005-03-24
to prevent and or treat fibrotic cardiac valvulopathy, which can be drug
induced (e.g.,
by pergolide) and is also the main cause of death in carcinoid patients, and
pulmonary
hypertension; (iii) prophylaxis of migraine attacks (iv) treatment of
migraine; (v)
prevention and/or control of the symptoms of premenstrual syndrome (PMS),
including but not limited to premenstrual migraine, headaches, breast tension
or
mastopathy, and edema. The TTS of the present invention containing a lower
dose
of the ergoline compound is particularly well suited for the therapeutic uses
identified
in (i) - (v).
[0041] One preferred method for preventing and/or treating the symptoms
associated
with PMS is the application of one transdermal therapeutic device of the
present
invention per menstrual cycle. The timing of such application is prior to the
start of
menstruation, such as at about day 24 of the menstrual cycle. This timing can
vary
per individual and the individual and/or the consulting physician are capable
of
determining the day in the individual's menstrual cycle for applying the
device in
order to achieve optimal prevention and/or alleviation of PMS symptoms. In
another
embodiment of the method of the invention, the device of the invention may
also be
used in combination with other prolactin-lowering compounds and/or analgesics.
[0042] The combination of an oral dopamine agonist (lisuride) and levodopa
(approved in some European countries as Restex ~ for RLS). As higher doses of
levodopa (which otherwise is a good treatment which patients like) are linked
to
longterm side effects (so-called augmentation, i.e. more or longer-lasting
involuntary
movements when at rest), a strategy of keeping levodopa low (or even only as
short-
acting rescue medication on top of chronic lisuride patch use) as basic
therapy
13

CA 02502142 2005-03-24
becomes very interesting (analogous to Parkinson's disease, where these
combinations (DA agonists and levodopa) now are the preferred treatment). Many
patients on chronic dialysis for kidney disease suffer from severe RLS (and/or
hormonal disturbances including mild hyperprolactinemia) but cannot tolerate
oral
dopamine agonists. Such dialysis patients may be treated with low dose
lisuride
release from a device of the present invention.
[0043] The TTS of the present invention may also be used as for the purpose of
stabilize or slow progressive neurodegeneration, particularly in Parkinson's
disease.
The TTS of the present invention containing lisuride may also be used to treat
conditions that benefit from continuous administration of a 5-HT1A agonist, a
dopamine agonist, a platelet aggregation inhibitor, an anti-oxidant, a radical
scavenger, and a glutamate antagonist.
Further Inventions
[0044] This invention relates to a transdermal therapeutic system (TTS)
comprising a
pharmaceutical layer containing at least one matrix having an active
ingredient and/or
an active ingredient reservoir; a diffusion barrier that is permeable to said
active
ingredient and arranged on the skin side of the active ingredient reservoir;
and an
ergoline derivative or salt thereof as an active ingredient (a) for producing
an agent
for obtaining and maintaining the circadian rhythm under dopamine therapy and
(b)
to produce an agent for treating restless legs syndrome as well as Periodic
Limb
Movement Disorder (PLMD) or nocturnal myoclonus. The invention also relates to
the use of a means including a transdermal therapeutic system (TTS) containing
a
14

CA 02502142 2005-03-24
dopamine agonist for treating dopaminergic disease states under a special
treatment
plan.
[0045] The term "TTS" mostly denotes percutaneously acting but also
transmucosal
systems. A TTS typically has a sheet-like structure and is attached to an area
of the
skin. A TTS mostly includes a matrix containing an active ingredient (e.g.,in
the
form of a salt) and/or an active ingredient reservoir, and a diffusion barrier
that is
permeable to the active ingredient on the skin side of the active ingredient
reservoir.
The system can optionally be attached to the skin by an additional skin-side
adhesive
that is permeable to the active ingredient. Alternatively, the matrix and/or
diffusion
barrier can itself have adhesive properties. A non-adhesive TTS can be
attached to
the skin using other auxiliary means such as adhesive tapes or bandages. The
matrix
is a material in which the active ingredient is immobilized. An active agent
in an
active ingredient reservoir however is not necessarily immobilized, which is
why the
active ingredient reservoir must be enclosed. The diffusion barrier forms the
skin-side
portion of this shell.
[0046] Importantly, all other parts of the shell should be as impermeable as
possible,
including diffusion paths, to the active ingredient. Immobilized means in this
context
that any uncontrolled active ingredient flow is prevented. However diffusion
of an
active agent in a matrix and/or through a diffusion barrier is not only
possible but
intended. The diffusion coefficients eventually determine the active
ingredient flux
from the TTS into a patient's skin. The dose released into a patient's skin is
in first
approximation a linear function of the active area of the TTS. The active area
is the

CA 02502142 2005-03-24
contact area of those TTS portions that allow active ingredient diffusion.
TTSs can
be used in human and veterinary medicine.
[0047] The flux values obtained using a TTS are considerably lower than the
values
obtain from applying a solution. WO 91/00746 disclosed a device containing
lisuride. The flux values for human skin samples specified therein cannot be
directly
transferred to any achievable in-vivo values.
[0048] Diseases for which a dopamine therapy is indicated such as Parkinson's
disease are severe chronic and disabling diseases from which older and
polymorbid
patients suffer frequently. The state-of the-art practice is oral
administration of a
combination of dopaminergic substances. These generally include various
formulations of levodopa (high initial flux rate, normal or slow release),
levodopa
boosters such as decarboxylase inhibitors as the base and optionally COMT
inhibitors
or MAO-B inhibitors, and various dopamine agonists such as bromocriptine,
lisuride,
cabergoline, pergolide, ropinirole, pramipexole as well as amantadine and,
occasionally, anticholinergic agents. The pharmacokinetics of fast-acting
levodopa is
hard to control for various reasons, and dopamine agonists frequently do not
allow
safe bioavailability and thus efficacy predictions. All these active agents
also can
interact for pharmacological and pharmacokinetic reasons, in addition to their
interaction with other active agents or pharmaceuticals that older patients
with
multiple diseases frequently need.
[0049] TTSs of the design described above are used for various indications
including
Parkinson's disease. When treating Parkinson's disease, the higher doses may
be
required than the doses required to treat other indications described herein.
A
16

CA 02502142 2005-03-24
transdermal therapeutic system also improves compliance, which is of critical
importance for any combinatory treatment of this disease as patients tend to
be older
and have multiple diseases. Improved control and the chance to reach circadian
profiles (e.g. by low stimulation as constantly as possible at night or during
a break)
are particularly important and have not yet been achieved (e.g. to prevent
psychoses
and improve the quality of sleep). The ergoline derivatives of the Formula I,
such as
lisuride, terguride, and bromerguride, have a partially dopamine-agonistic or
partially
antagonistic effect that contributes to preventing the development of
psychoses and
can improve existing psychoses and similar problems.
[0050] Restless legs syndrome (RLS) is a neurological disease that can occur
at all
ages but is more frequent in older people; its main symptoms are cramps and
pain in
the legs due to dysesthesias and paresthesias that trigger an urge to move. As
these
symptoms mostly occur in periods of reduced activity such as when sitting or
resting,
the urge to move results in restlessness during the day and sleep disturbances
at night.
This considerably impairs the quality of life of those affected. Periodic Limb
Movement Disorder (PLMD) or nocturnal myoclonus is associated with RLS and is
the 'kicking' that occurs during sleep in at least 50% of the people that have
RLS.
[0051] In addition, peroral dopaminergic therapies often lead to rebound
problems on
the following day and to so-called augmentations, i.e. hypertonus,
restlessness and an
urge to move.
[0052] It is the technological problem of this invention to provide an agent
for the
treatment of restless legs syndrome, Periodic Limb Movement Disorder (PLMD),
or
nocturnal myoclonus, which is free of side effects or at least shows
considerably
17

CA 02502142 2005-03-24
reduced side effects as compared to oral administrations, that has a slow
initial flux
rate and can be controlled well in terms of quantity administered and
effective time.
(0053] A transdermal therapeutic system according to the invention described
below
can ensure an individually desired and controlled effective time (if required,
by
removing the patch).
[0054] Bioavailability is increased by the TTS as compared to peroral
administration,
which typically reduces the overall dose required to achieve the desired
therapeutic
andlor prophylactic effect.
[0055] A special benefit this invention offers is that--other than with the
common
one-time oral intake per day --a continuous active ingredient flux is
established so
that plasma concentrations can be set as defined and variations can be
controlled. This
mainly prevents the side effects typically observed with one-time oral
administration
such as fatigue, dizziness, vomiting, constipation, etc. These side effects
can be
prevented when the level of active ingredient in the plasma is not subject to
any major
and rapid variation, an automatic occurrence with oral administration, but is
set
slowly and continuously. In addition, the problems encountered with oral
administration such as greatly varying absorption rates and a not too well-
defined
time of maximum concentration in the plasma depending on the type and time of
food
intake are virtually eliminated by this invention. Most of all, it prevents
overdosing
(and thus REM suppression and other disruptions of the sleep pattern).
Furthermore,
administration can easily be canceled by just removing the TTS. Unlike
discontinuing
an orally administered active agent, decomposition in the plasma is fast and
controlled, which also prevents a hangover, rebound, or augmentation effect.
18

CA 02502142 2005-03-24
[0056] In the treatment of Parkinson's disease in which dopamine drugs and
combinations thereof are taken throughout the day, concentrations in the
plasma are
not constant but subject to great variation, and this not only for kinetic
reasons
(highly variable first pass effect depending on the metabolization type) but
also
depending on individual administration conditions (type and times of food
intake,
effect of other drugs on resorption and metabolism, etc.). This is why there
is a risk of
temporary overdosing, which may result in REM suppression and the resulting
sleep
disturbances or psychoses.
[0057] In addition, currently used dopamine therapies frequently have lasting
and
severe side effects. This is where a transdermal therapeutic system according
to the
invention described below can ensure individually dosable, adjustable, and
controlled
action time (if required, by removing the patch) without influencing the
circadian
rhythm that is often disturbed as a result of treating Parkinson's disease and
other
dopaminergic diseases. The dopaminergically treatable disease may be a disease
from the group consisting of Parkinson's disease, parkinsonism, restless legs
syndrome, periodic limb movement disorder or nocturnal myoclonus, and
disturbances of the dopaminergic system.
[0058] It is the technological problem of the invention to provide an agent
for
obtaining and maintaining the circadian rhythm that can be individually dosed
and
adjusted and whose efficacy period can be controlled so that circadian
disturbances
that occur under dopamine therapy when treating dopaminergic diseases, in
particular, when treating patients with Parkinson's disease, are prevented.
The a-
adrenolytic effect of lisuride and the ergoline derivatives of the Formula I
has another
19

CA 02502142 2005-03-24
benefit for this application in that it also noticeably diminishes urinary
urgency at
nighttime and other bladder dysfunctions that are rather common in Parkinson
patients (such as prostatic hyperplasia), which adds to the success of the
therapy.
[0059] The technological problem is solved according to the invention in that
a
transdermal therapeutic system (TTS) is used comprising a pharmaceutical layer
containing at least one matrix having an active ingredient, and/or an active
ingredient
reservoir; a diffusion barrier which is permeable to active ingredients and
which is
arranged on the skin side of the active ingredient reservoir; and an ergoline
derivative
according to Formula I or physiologically compatible salt thereof with an
acid,
N(CZHS)z
-R2
R'
[Formula I]
wherein ------ is a single or double bond wherein Rl is a H atom or a halogen
atom,
particularly a bromine atom, and wherein R2 is a C1-C4 alkyl, particularly
methyl.
Suitable salts of the active ingredients include sulfates, phosphates,
maleates, citrates
and succinates, especially hydrogen maleate.
[0060] The TTS is used as means of obtaining and maintaining the circadian
rhythm
under continuous dopamine therapy. It is further preferred to select the
matrix and/or
diffusion barrier so that the transdermal flux F through human skin measured
as
described in Example 1 is in the range from 0.1 to 5.0 ~,g/ cm2/h, preferably
0.5 to 2.5

CA 02502142 2005-03-24
p,g/ cm2/h. A patch with these specifications is particularly suited for
obtaining
continuous lisuride concentrations in the plasma in the range from 0.05 to 5.0
ng/ml,
preferably 0.1 to 0.5 ng/ml. The use of a TTS comprising a matrix and an
ergoline
derivative of the Formula I or salt thereof as the active ingredient. It is
preferred to
select the flux F and the active surface area for reaching an effective dose
in the range
from 10 p,g to 2 mg of active ingredient (such as lisuride), preferably 50 p,g
to 1 mg,
throughout the day or over 24 hours in the patient's system on the second day
of
application.
[0061] The TTS is also used as an agent for treating restless leg syndrome and
Periodic Limb Movement Disorder. For such a TSS, it is preferred that the
matrix
and/or diffusion barrier are selected so that the transdermal flux F through
human
skin measured as described in Example 1 is in the range from 0.1 to 2.0 pg/
cmzlh. It
is easy to administer exact individual doses by selecting the flux F and/or
the active
surface area. It is preferred to select F and active area so that a dose in
the range from
p,g to 1 mg of active ingredient (for example, lisuride), most preferred 50 to
200
p,g, is built up per day.
[0062] The invention is based on the surprising finding that circadian
disturbances
under dopamine therapies can be prevented using an ergoline derivative of the
Formula I or a salt thereof that is highly effective and has a short half life
(0.5 to 4
hours, particularly 1 to 2 hours). A special benefit this invention offers is
the
establishment of a continuous active ingredient flux so that plasma
concentrations can
be set as defined and variations can be controlled. This mainly prevents the
dopaminergic side effects such as fatigue, dizziness, etc. that are observed
with single
21

CA 02502142 2005-03-24
oral administrations or using a TTS containing an active ingredient with a
long half
life. These side effects can be prevented when the level of active ingredient
in the
plasma is not subject to any major and rapid variation, an automatic
occurrence with
oral administration, but is set slowly and continuously. In addition, the
problems
encountered with oral administration such as greatly varying absorption rates
and a
not too well-defined time of maximum concentration in the plasma depending on
the
type and time of food intake are virtually eliminated by this invention. Most
of all, it
prevents overdosing (and thus REM suppression and other disruptions of the
sleep
pattern). Furthermore, administration can easily be canceled by just removing
the
TTS. The drop in agent concentration in the plasma when removing the TTS is
further accelerated because of the short half life of the suitable agents
according to
the invention. Unlike discontinuing an orally administered active agent or an
active
agent with a long half life, decomposition in the plasma is fast and
controlled, which
also prevents a hangover. Finally it is easy to administer exact individual
doses by
selecting the flux F and/or the active surface area.
[0063] It is preferred to select the flux F and the active surface area for
reaching an
effective dose in the range from 10 ~,g to 1 mg of active ingredient (such as
lisuride),
preferably 50 ~,g to 1 mg, throughout the day or over 24 hours in the
patient's system
on the second day of application. In one embodiment of the present invention,
it is
preferred to select the matrix and/or diffusion barrier so that the
transdermal flux F
through human skin measured as described in Example 1 is in the range from 0.1
to
5.0 pg/ cm2/h, preferably 0.5 to 2.5 fig/ cm2/h. A patch with these
specifications is
particularly suited for obtaining continuous lisuride concentrations in the
plasma in
22

CA 02502142 2005-03-24
the range from 0.05 to 5.0 ng/ml, preferably 0.1 to 0.5 ng/ml. The use of a
TTS
comprising a matrix and an ergoline derivative of the Formula I or salt
thereof as the
active ingredient.
[0064] Restless legs syndrome has been treated with a single oral
administrations of
dopaminergic drugs such as lisuride in the evening reduces the symptoms and
has a
positive influence on the patients quality of life. Unlike the treatment of
Parkinson's
disease where dopaminergic pharmaceuticals and combinations thereof are
administered throughout the day, one-time peroral intake of these drugs for
the
treatment of restless legs syndrome impairs the building of a tolerance
against acute
dopaminergic side effects (due to the initial flux rate); this means that the
known side
effects such as orthostasis, hypotonia, dizziness, nausea, and vomiting may
occur
with each effective dose. Unpredictable and uncontrollable sleep attacks that
have
recently been reported more frequently may also occur. Furthermore, agent
concentration in the plasma is not constant but subject to great variation,
not only for
kinetic reasons but also depending on the conditions of drug intake (type and
time of
food intake, etc.). This is why there is a risk of temporary overdosing, which
may
result in REM suppression and the resulting problems and sleep disturbances.
[0065] The list of ergoline derivatives that can be used includes the
following:
lisuride, bromolisuride (3-(2-bromo-9,10-didehydro-6-methyl-8a-erg- olinyl)-
1,1-
diethyl urea), terguride (3-(6-methyl-8a-ergolinyl)-1,1-- diethyl urea) and
proterguride (3-(6-propyl-8a-ergolinyl)-1,1-diethy-1 urea). However it is
preferred
when the ergoline derivative is lisuride (3-(9,10-didehydro-6-methyl-8a-
ergolinyl)-
l,l-diethyl urea) or a physiologically compatible salt thereof with an acid.
The
23

CA 02502142 2005-03-24
production of lisuride and other suitable ergolines according to the invention
is
described, inter alia, in U.S. Pat. No. 3,953,454, EP 056 358 and U.S. Pat.
No.
4,379,790. Suitable salts of the ergoline derivative include sulfates,
phosphates,
maleates, citrates and succinates, especially hydrogen maleate.
[0066] The TTS can be designed as follows. A covering layer can be arranged on
the
side of the matrix and/or active ingredient reservoir facing away from the
skin. The
covering layer may be formed by films of polyethylene or polyester. It is
typically 10
to 100 microns in thickness. The covering layer may be pigmented and/or metal
plated to ensure sufficient protection from light. Metal plating involves
applying a
very thin layer (typically less than 1 micron, mostly in the 10-100 nm range)
of a
metal such as aluminum to the covering layer. Pigments can be all pigments
commonly used for coating including effect pigments as long as these are
physiologically harmless. A detachable liner such as a siliconized or
fluoropolymer-
coated protective film can be provided on the application side.
(0067] The matrix and/or diffusion barrier may comprise as their main matrix
component a substance selected from the group consisting of polyacrylate,
polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and
mixtures of
these substances as well as copolymers of these polymeric compounds,
preferably
polyacrylate; preferably hydrophilic polyacrylate with basic substituents. A
main
matrix component makes up at least 50 percent by weight, e.g. at least 80-90
percent
by weight of the matrix (matrix to be understood as the finished layer, i.e.
main
matrix components) with adjuvant(s) and active ingredient(s)). The desired
flux is set
by selecting the substance depending on the diffusion coefficient of the
active
24

CA 02502142 2005-03-24
ingredient and, if required, by selecting the layer thickness of the matrix in
orthogonal
direction to the skin surface. Matrix thickness is typically in the range from
10 to S00
microns.
[0068] A preferred polyacrylate adhesive as main matrix component is
commercially
available under the brand name GELVA~multipolymer solution 7881, provided by
Monsanto Deutschland GmbH, Dusseldorf. We expressly refer to the product sold
under this name and its datasheet in the version of Apr. 23, 1996. Eudragit~
E100,
provided by Rohm, Germany, is a copolymerisate from dimethyl aminomethyl
methacrylate with neutral methacrylate esters and particularly well suited for
use.
[0069] The polyacrylate adhesives listed above provide an advantageous non-
trivial
combination of properties, namely optimum flux, good adhesive power, good skin
compatibility, and durability.
[0070] The diffusion barner can alternatively comprise as its main barrier
component
a polymer selected from the group consisting of cellulose ester, cellulose
ether,
silicone, polyolefin and mixtures as well as copolymers of these substances.
What has
been said about the term of the main matrix component above analogously
applies to
the term of the main barrier component. The diffusion barrier can be a film
with a
thickness from 10 to 300 microns; the actual film thickness is selected (in
conjunction
with the diffusion coefficient of the active ingredient in the polymer)
according to the
desired flux.
[0071] The matrix and/or active ingredient reservoir and/or diffusion barrier
can
contain the common adjuvants used in TTSs. It is preferred to use a
penetration-
enhancing agent that is preferably selected from the group consisting of C1-C8

CA 02502142 2005-03-24
aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-
18 fatty
alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and
hydrocarbon
mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools,
dicarboxylic acid dieesters from C4-8 dicarboxylic acids and C 1-6 alkyl
monools, and
mixtures of these substances. Penetration-enhancing agents improve the flux of
the
active ingredient through the skin to which the TTS is attached. Examples of
the
substances listed above are: 1,2-propane diol, menthol, dexpanthenol, benzyl
alcohol,
lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid,
isopalmitic
acid, isostearic acid, oleic acid; methyl ester, ethyl ester, 2-hydroxyethyl
ester,
glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester
or isobutyl
ester of lauric acid, myristic acid, stearic acid, or palmitic acid. Use of
dimethyl
isosorbide, isopropyl myristate and lauryl alcohol is preferred, use of lauryl
alcohol is
most preferred. Other adjuvants are, for example, crystallization inhibitors.
Suitable
crystallization inhibitors are highly dispersed silicon dioxide or
macromolecular
substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines,
dextranes,
sterines, bile acids and, in particular, vinyl pyrrolidone vinylacetate
copolymers and
polyvinyl pyrrolidone vinylacetate copolymers such as Kollidon~ VA 64.
[0072] Suitable crystallization inhibitors are highly dispersed silicon
dioxide or
macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols,
dextrines, dextranes, sterines, bile acids and, in particular, polyvinyl
pyrrolidone
vinylacetate copolymers such as Kollidon~ VA 64.
[0073] It goes without saying that the penetration-enhancing agent has to be
able to
diffuse to a sufficient extent through the matrix or diffusion barrier. If a
matrix and
26

CA 02502142 2005-03-24
lauryl alcohol as an adjuvant are used, it is preferred that the lauryl
alcohol makes up
to 30 percent by weight, most preferred 15 to 20 percent by weight, of the
matrix.
[0074) In addition to the ingredients listed above, sufficient quantities of
sulfur-
containing amino acids such as cysteine, methyl donors such as methionine, or
antioxidants such as glutathione or sodium hydrogensulfite are added to the
matrix as
antioxidants because studies have surprisingly shown that this can prevent or
dramatically reduce the formation of toxic oxidation products of lisuride such
as
lisuride-N-oxide. Antioxidants like glutathione can also have a synergistic
effect on
Parkinson's disease as oxidative stress plays an important part here; even
from early
stages on, there is a glutathione shortage in the dopaminergic substantia
nigra.
Methionine again is particularly desirable as a methyl donor because levodopa
is
mainly decomposed through oxygen methylation (COMT); homoserine levels
increase due to the required levodopa quantities (daily dose up to the gram
range),
which is suspected to be a risk factor for cardial and cerebral events.
[0075] The adjuvants can basically make up from 0 to 50 percent by weight of
the
matrix. The active ingredient can make up 0.2 to 20 percent by weight,
preferably 1 to
10 percent by weight, of the matrix. The sum total of main matrix component,
adjuvants and active ingredients is always 100 percent by weight.
[0076] The active ingredient dose in a human body carrying a TTS is dependent
on
the diffusion-related properties of the TTS mentioned above and also on its
active
surface area on the skin. Active surface area means the area over which the
matrix or
diffusion barrier comes to rest on the skin. Variation in accordance with the
desired
dosage will preferably be in a range from 1 to 100 cm2.
27

CA 02502142 2005-03-24
[0077] Within the scope of this invention, a physician can easily set up
personalized
dose variations for a flux adjusted to the given indication by selecting a
suitable patch
size. Thus the treatment can easily be adjusted to different body weights, age
groups,
etc. It is particularly feasible to equip a TTS comprising a (rather large)
standard area
with subdivision markers for partial doses so that a user can just remove the
protective film from a partial area corresponding to the specified dose. The
respective
subsections can easily be printed on the covering layer.
[0078] The use of lisuride, its salts or derivatives with comparably favorable
properties as active ingredients offers the following therapeutic benefits.
These
substances can be applied at extremely low doses (for lisuride: from 0.075 mg
orally
at a high first pass effect) due to their extraordinarily strong affinity for
dopamine and
other monoamine receptors; thus a TTS with a relatively small application area
can
easily build an effective and well adjustable active ingredient level across
the area
over 24 hours or longer. Unlike long-acting oral active ingredients such as
cabergoline, transdermal dosing of lisuride not only is much improved
(elimination of
the considerable and highly variable first pass effect after oral
administration of
cabergoline or the like), the effects can also easily be discontinued whenever
required
(e.g. when side effects occur) by removing the patch. Then the short half life
of
lisuride in the blood (ca. 2 hrs) comes in useful--a great contrast to oral
dopamine
agonists where side effects last for days once they are administered.
[0079] The combination of these effects has surprisingly resulted in combining
the
benefits of continuous and long-lasting dopaminergic stimulation with the
other
benefits of short-term acting dopaminergic pharmaceuticals in one application.
28

CA 02502142 2005-03-24
Combining these properties enables physicians to tailor the application to a
patient's
individual situation and needs as they can select the application scheme of
two
patches (simultaneous removal and reattachment, overlapping replacement or
replacement at an interval) or, even better, to obtain almost any circadian
rhythm of
dopaminergic therapy by modifying the initial flux rate of the TTS
formulation:
[0080] A Continuous stimulation when the initial flux rate of the patch
matches the
terminal half life after patch removal (tmax-t/2, optionally a short interval,
or when
simultaneously applying a new TTS with a relatively high initial flux rate);
[0081] B A phase with enhanced stimulation (e. g. when adjusting the therapy
or for
bridging a patient's ' off phase) by applying the second patch while the first
is still
attached to the skin or by using patches with a high initial flux rate
(tmax«t/2) or
very low initial elimination rate (e. g. when the application area is small
and the
diffusion of the active ingredient increases with the decrease of the
concentration
gradient); and
[0082] C A phase of reduced dopaminergic stimulation such as reducing time-of
day-specific side effects by either complying with an interval between patch
removal
and attachment of the new patch, or, even simpler, by simultaneously using the
new
patch with a very low initial flux rate (tmax»t/2) at the time of removal.
(0083] In all, we are surprisingly facing the chance of using just one active
ingredient
with suitable receptor affinity, efficacy and kinetics and opening all options
of an
easily applicable and well adjustable dopamine treatment for the patient. As
the side
effects that are almost inevitable when using state-of the-art oral and
transdermal
29

CA 02502142 2005-03-24
therapies are prevented, stronger efficacy and a clearly improved therapeutic
effect
are obtained with simple means.
[0084] This means that levodopa therapy and its long-term complications can be
prevented or delayed or that this or any other oral dopamine therapy has to be
applied
at low doses only and is thus more compatible.
[0085] In this context, the invention also includes a TTS set for obtaining
and
maintaining a continuous receptor stimulation with circadian rhythm,
particularly for
Parkinson's disease, said set containing multiple TTS elements that are set up
for
releasing different doses. The TTS elements can be separated for this purpose,
each
TTS element being configured for a continuously ascending sequence of F
ranging
from 0.1 to 5 p,g/ cm2/h. In addition, or separately, TTS elements can be
equipped
with a continuous sequence of differing active areas. In the latter case it is
possible to
use uniform F values. The TTS elements can be arranged on a big TTS design
showing markings that indicate the areas to be used. An embodiment in which
these
elements are separated is conceivable as well, of course.
[0086] The invention can also be used for other indications. One application
is the
use of a TTS according to the invention to produce an agent for the treatment
or
prevention of the premenstrual syndrome or its symptoms, wherein F preferably
is in
the range from 0.1 to 0.5 p,g/ cm2/h, another one to produce an agent that
inhibits
lactation, wherein F preferably is in the range from 0.1 to 0.5 pg/ cm2~h.
[0087) III. Combination of a transdermal therapeutic system and an oral and/or
parenteral preparation containing dopamine agonists for the treatment of
dopaminergic disease states

CA 02502142 2005-03-24
[0088] Either a continuous or a discontinuous stimulation may be required
depending
on the stage of the disease and the actual status of the patient. A good
foundation is
laid when the level of dopaminergic agents is kept stable across the entire
day.
However patients frequently report that they often need to take a fast-acting
dopaminergic agent at certain times of the day to overcome acute motoric
disturbances, severe and painful dystonia, etc. ("kick"). In extreme cases,
such sudden
"off' states of motoric performance and akinesia (sometimes predictable early
in the
morning or afternoon, but frequently all of the sudden and unexpectedly) can
only be
controlled with injectable active agents such as apomorphine. On the other
hand,
strong and fast efficacy hikes can cause disturbing side effects (e.g. nausea,
emesis,
orthostatic hypotension, narcoleptic attacks). Overdoses due to the narrow
therapeutic
time window of all these dopaminergic agents can result in severe dyskinesia,
dystonia or, especially in older patients, psychoses. The latter severe
problem is
mainly connected with high active agent concentrations in the plasma over
night that
can destroy regular sleeping patterns and prevent the REM sleep phase (with
REM
rebound during daytime as indication of a psychosis).
(0089] Because of the interrelations described, a practical dopamine treatment
is
started at very low doses of one or several active agents with subsequent, for
example, weekly, dose increases until side effects indicate bioavailability.
After a
subsequent and rather arbitrary reduction of the dose or dose stabilization,
the next
active agent is administered and set or dosed ("titrated") accordingly. As a
result,
treatment plans and most of all dosages vary considerably depending on the
severity
of the disease, the patient's individual body constitution and metabolization
type.
31

CA 02502142 2005-03-24
Mostly 3 or more different active agents are administered orally. A typical
patient
would for example start with fast-acting levodopa in the morning, followed by
a dose
of MAO-B inhibitor and, throughout the day, four or five doses of normally
acting
levodopa in combination with a dopamine agonist and, eventually, a slow-acting
preparation containing levodopa (or a low dose of a long-term acting dopamine
agonist) at bedtime ensuring sufficient mobility in the sleep and consequently
a high
relaxation value.
[0090] Such a complicated treatment plan is more often the rule than an
exception
and is not very well compatible, especially not with older patients, is
unstable and
sensitive to interaction with other factors such as other agents administered
or
infection-related diseases as well as dehydration by inadequate fluid intake
or
excessive fluid loss or liver or kidney dysfunctions. This is unsatisfactory
for obvious
reasons for both the physicians and the patients. Patients must therefore
often be
adapted to side effects over several weeks as indoor patients in more or less
specialized hospitals.
[0091] It is the technological problem of the invention to provide an agent
and a
treatment plan for treating dopaminergic disease states while preventing or at
least
reducing disturbing side effects, controlling the initial flux rate of the
active agent and
keeping good control of agent levels in the plasma and effective time.
(0092] The invention solves this technological problem by using a dopamine
agonist
in the form of an agent, comprising at least two discrete compositions, of
which one
is a transdermal therapeutic system (TTS) containing the dopaminergic agent
and
another one containing the same dopaminergic agent and suitable for oral
and/or
32

CA 02502142 2005-03-24
parenteral administration, both suitable for the treatment of dopaminergically
treatable diseases with the following elements: a) the TTS is continuously
applied, b)
within the duration of application in a) the composition for oral or
parenteral dosage
is administered. Phase b) preferably begins 7 days, more preferably 14 days,
most
preferably 28 days after the start of phase a). The invention involves in this
context
the use of a dopamine agonist in the form of an agent consisting of at least
one
spatially discrete composition, of which one is a transdermal therapeutic
system
(TTS) containing the dopaminergic agent for the treatment of dopaminergically
treatable diseases with the following elements: a) the TTS is continuously
applied, b)
within the duration of application in a), no dopaminergic agent is applied
that differs
from the dopamine agonistic agent of the TTS.
[0093) Continuous application means that a new TTS is applied before the agent
level
in the plasma drops disturbingly due to the consumption of the previous TTS,
such as
below the 0.25-fold of the maximum plasma concentration.
[0094] The invention is based on the surprising finding that dopaminergically
treatable diseases, particularly Parkinson's disease, can be treated better
using a single
dopaminergic agent that is highly effective and has a short half life in the
plasma, if
the combination of the invention is optionally carried out using one of the
treatment
plans according to the invention. This means it is important that no other
agent than
the active ingredient of the TTS is used for treating dopaminergic
dysfunctions during
the treatment period. Lasting or continuous dopaminergic stimulation is
achieved
using the TTS. It provides agent concentrations in the plasma that can be well
33

CA 02502142 2005-03-24
controlled or adjusted. The concentration in the plasma can easily be dosed by
varying, for example, the effective surface area of the TTS or its size.
[0095] A transdermal and an oral or parenteral form of application of an
active
ingredient can easily be offered as one kit for a monotherapy of dopaminergic
diseases.
[0096] The invention also relates to a combination of a transdermal
therapeutic
system and an oral and/or parenteral preparation containing one and the same
dopamine agonist with a short half life to produce a pharmaceutical for the
treatment
of dopaminergic diseases.
[0097] Furthermore, a slow increase of the concentration of the active agent
in the
plasma (over days and weeks) can be achieved by applying the TTS; the benefit
is
that initial side effects are prevented. Moreover, daily application at
relatively early
times (e.g. between 6.00 a.m. and 3.00 p.m.), for example, can reliably
prevent
undesirable overstimulation at night and the risk of psychotic states.
[0098] The treatment is supplemented as may be required in advanced stages of
a
disease by administering oral or parenteral preparations with the same
dopaminergic
agent. The tablets comprise a preferred tmax of 15 to 120 minutes,
particularly
preferred of 30 to 60 minutes, and a preferred half life of 0.5 to 4 hours,
particularly
preferred 1 to 2 hours. tmax indicates the period of time between oral
administration
and the buildup of the concentration of the tablet's active agent in the
plasma. Half
life is the period of time during which the concentration in the plasma drops
by half in
the descending portion of the time function. Motoric blockages and akinesia
are
34

CA 02502142 2005-03-24
removed whenever required by such oral administration and the fast extra
action as
needed.
[0099] If oral administrations is started only after starting the continuous
application
of the TTS, considerable tolerance against dopaminergic side effects has built
up and
it is no longer required to carry out tedious titrations (sometimes over
several months)
as would be required for setting up different dopaminergic agents under a
combinatory therapy. This makes the treatment particularly well tolerable.
[00100] Where indicated--for example, because of the severity of an acute
condition
(e.g. akinesia or dystonia in the morning or during off periods at other
times), the
same active agent may be administered parenterally (i.m., i.v.,
subcutaneously, as
contained in the TTS). The same benefits apply in principle as described for
oral
administration. tmax is typically less than 15 minutes, mostly less than 5
minutes.
[00101] Lasting side effects, if unexpected side effects occur, can reliably
be
prevented due to the short half life of the active agent. A short-term drop of
the agent
concentration in the plasma is achieved by just removing the TTS. This is a
particular
advantage over orally administered, long-term acting agents such as pergolide
or
cabergoline the side effects of which after an administration or overdosage
may last
several days.
[00102] The invention facilitates relatively high total absorption quantities
of the
active agent as compared to combinatory therapy where it is highly underdosed
to
prevent side effects resulting from the complex kinetics and interaction of
combining
different substances. Thus the invention considerably increases clinical
efficacy. This
fact combined with better tolerability also allows considerably longer
treatment with

CA 02502142 2005-03-24
the respective active agent and avoids the use of levodopa formulations. This
is
particularly important for younger patients with a high remaining life
expectancy as
levodopa, the gold standard of dopamine therapy) is known to cause long-term
effects
resulting in severe and unpredictable dyskinesia and hyperkinesia, which makes
the
patients eventually dependable on outside help and confines them to bed.
Animal
experiments have also shown that even short-term levodopa treatment, even at
low
doses as are common in combinatory therapies, causes lasting priming or
sensitization
by some kind of inciting mechanism resulting in long-term complications in the
motoric and mental dopamine systems. Things being what they are, most patients
have to rely on levodopa administrations within the first years of the disease
and are
exposed to the detrimental long-term disadvantages of levodopa due to the
underdosage of active agents administered to avoid side effects.
[00103] Despite the relatively high total absorption quantities compared to
the
underdosage practice that is the state of the art, the actual dosage load can
be kept low
(<_10 mg per day, particularly preferred . <5 mg per day) so that the
treatment is
relatively independent of any liver or kidney dysfunctions. Potential
interaction with
other drugs is rather low and predictable as only one active agent is involved
in the
treatment according to the invention; interaction with the common other
Parkinson
agents is completely eliminated.
[00104] The matrix and/or diffusion barrier may be selected so that the
transdermal
flux F through human skin measured as described in Example 1 is in the range
from
0.1 to 5.0 p,g/ cm2/h, preferably 0.1 to 4.0 wg/ cm2/h.
36

CA 02502142 2005-03-24
[00105] It is preferred to arrange a TTS set as part of a means wherein the
set contains
a multitude of TTS elements and wherein said elements are configured for
releasing
different doses. The TTS elements can be separated, each TTS element being
configured for a continuously ascending sequence of F ranging from 0.1 to 5
fig/
cm2/h. It is also conceivable to arrange several TTSs with the same F value in
a
subgroup wherein the F values of the various subgroups form a continuously
ascending sequence and other subgroups comprise constant F values, their value
being the maximum of the sequence mentioned above. It is preferred to select F
and
the active area of the TTS so that a dose in the range from 10 ~g to 2 mg of
active
ingredient (such as lisuride) builds up during the day or within 24 hours as
from the
second day of application, and that this dose subsequently rises in steps. The
TTS
elements can also have a continuous sequence of different active areas. These
may
also be divided into subgroups as described above. Suitable according to the
invention are also other transdermal forms of application known from the state
of the
art.
[00106) The preparation for oral administration can either be in the form of a
tablet, a
powder, a capsule or a solution, is formulated using known state-of the-art
methods
as required for the respective form of application, and as a tablet preferably
contains
25 to 1000 pg of the dopaminergic agent (per tablet), resulting in a dose of
0.075 mg
to 5.0 mg per day for lisuride, for example.
[00107] The preparation for parenteral administration in the form of an
injection or
infusion solution is formulated in accordance with known methods and
preferably
contains 25 to 2000 ~.g of the dopaminergic agent (per ml of solution). For
example,
37

CA 02502142 2005-03-24
the parenteral dose needed to achieve a fast additional effect for lisuride is
up to 5.0
mg with a cozttinuous infusion over 24 or 16 hours and from 25 up to 200 pg in
a
halos injection for a single application.
[001.0$] It is preferred when tho dopamine agonist with a short half life is
an ergoline
derivative of the Formula F or a physiologically tolerable salt thereof with
an acid,
Formula I
whetexn - is a single or double bond wherein Rl is a H atom or a halogen atom,
particularly a bromine atom, and wherein R2 is C1-4 alkyl, particularly
methyl.
[00109] The TTS can be applied at various intervals depending on the kinetics
of
active agent release. It is important that the active agent concentration in
the plasma
does not show any distwrbing variatio~u when the TTS is used continuously. It
is
preferred that the TTS is applied daily.
[00110) The preparation prepared for oral or parenteral adxninistratioz~ is
preferably
administered directly in the event of a dopamine-related malfunction. It may
be
administered preventively if malfunctions are predictable.
[00111) WO 92/20339 discloses a device containing lisuride as the active
ingredient
and its use for treating Parkinson's disease. Propylene glycol lauric acid
increases
flux. WO 91100746 also discloses a TTS containing lisuride, The ergoline
compound
38
** TOTRL PAGE.02 **
1524/03/2005 ~17:i6 X613 235 2508 Oreceiver!

CA 02502142 2005-03-24
itself can be formulated in accordance with pharmaceutical methods known as
the
state of the art.
[00112] It is preferred for the TTS to comprise a pharmaceutical layer
containing at
least one matrix containing the active ingredient and/or an active ingredient
reservoir,
and a diffusion barrier that is permeable to the active ingredient on the skin
side of the
active ingredient reservoir; and an ergoline derivative of the Formula I or a
salt
thereof as an active ingredient.
[00113] The TTS can be designed as follows. A covering layer can be arranged
on the
side of the matrix and/or active ingredient reservoir facing away from the
skin. It may
be formed by films of polyethylene or polyester. It is typically 10 to 100
microns in
thickness. The covering layer may be pigmented, varnished, and/or metal plated
to
ensure sufficient protection from light. Metal plating involves applying a
very thin
layer (typically less than 1 micron, mostly in the 10-100 nm range) of a metal
such as
aluminum to the covering layer. Pigments can be all pigments commonly used for
coating including effect pigments as long as these are physiologically
harmless. A
detachable liner such as a siliconized or fluoropolymer-coated protective film
can be
provided on the application side.
[00114] The matrix and/or diffusion barrier may comprise as their main matrix
component a substance selected from the group consisting of polyacrylate,
polyurethane, cellulose ether, silicone, polyvinyl compounds, polyisobutylene
39

CA 02502142 2005-03-24
compounds, silicate and mixtures of these substances as well as copolymers of
these
polymeric compounds, preferably polyacrylate. A main matrix component makes up
at least 50 percent by weight, e.g. at least 80-90 percent by weight of the
matrix
(matrix to be understood as the finished layer, i.e. main matrix components)
with
adjuvant(s) and active ingredient(s)). The desired flux is set by selecting
the
substance depending on the diffusion coefficient of the active ingredient and,
if
required, by selecting the layer thickness of the matrix in orthogonal
direction to the
skin surface. Matrix thickness is typically in the range from 10 to 500
microns.
[00115] A preferred polyacrylate adhesive as main matrix component is
commercially
available.
[00116] The adjuvants can basically make up from 0 to 50 percent by weight of
the
matrix. The active ingredient can make up 0.5 to 20 percent by weight,
preferably 1 to
percent by weight, of the matrix. The sum total of main matrix component,
adjuvants and active ingredients is always 100 percent by weight.
[00117] The invention will be explained in more detail below based on various
examples.
[00118] EXAMPLE 1 Fux Measurement
FRANZ flow-through diffusion cell is used for flux measurement. The
measured area is 2 cm2 4 cm2 of ventral and dorsal skin of a male hairless
mouse
(MFl hr/hr Ola/Hsd, provided by Harlan Olac, UK) are used as our skin sample
after
carefully removing any subcutaneous fatty tissue. A 2 cm2 TTS is applied to
the skin
sample. The acceptor medium is placed on the opposite side. It is diluted
HHBSS
(Hepes Hanks Balanced Salt Solution) containing 5.96 g/1 of Hepes, 0.35 g/1 of

CA 02502142 2005-03-24
NaHC03 and 0.1 ml/1 l OX of HBSS (provided by Gibco, Eggenstein, DE).
Furthermore, 1000 LU./ml of penicillin (benzylpenicillin potassium salt,
provided by
Fluka, Neu-Ulm, DE) are used.
(00119] The flux is measured as described below. First, the TTS to be measured
is
applied to the skin. The skin is mounted in the diffusion cell immediately
thereafter.
Samples of the acceptor medium are taken at 2-hour intervals between t=0 hrs
and
t=6 hrs and at 8-hour intervals between t=6 hrs and t=54 hrs. 1 ml of acceptor
medium per hour is pumped through the diffusion cell using a peristaltic pump.
The
temperature of the acceptor medium is controlled using a circulating water
bath which
keeps the skin at a temperature of 31 °C with an accuracy of 1
°C.
[00120] 'The active ingredient concentration in the acceptor medium is
determined in
accordance with the following specifications using a radioimmunoassay.
[00121] Calibration Curves: These are constructed using two different methanol
solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1
mg/ml.
These solutions are individually diluted with BSA buffer (0.041 M of
Na2HP02~2H20, 0.026 M of KH2P04, 0.154 M of NaCI, 0.015 M of NaN3, 0.1
(w/v) of BSA, pH 7, supplemented with 0.05% (w/v) of ascorbic acid) to obtain
lisuride-free base concentrations in the range from 1000-3.9 pg/0.1 ml. In
addition, a
sample without active ingredient (0 pg) is used. The calibration samples are
analyzed
three times. The lisuride concentrations are calculated using the
pharmacokinetic PC
program RIO 2.5 (other common software may also be used).
41

CA 02502142 2005-03-24
[00122] Sample Preparation: The acceptor medium is diluted with BSA buffer
prior to the analysis to set the concentrations to an analyzable range of the
calibration
curve. 100 p,l of diluted sample are directly subjected to radioimmunological
analysis.
[00123] Antiserum: The antiserum (rabbit) is obtained by immunizing with
lisuride-1-succinyl-BSA, an immunogen. The antiserum in the assay is diluted
1:12500.
(00124] Tracer: 3H-lisuride hydrogen maleate with a specific activity of 4.3
GBq/mg is used.
[00125] Incubation: 0.1 ml of BSA buffer with active ingredient, 0.1 ml of
tracer solution (ca. 5000 cpm/0.1 ml of BSA buffer) and 0.1 ml of diluted
antiserum
(1:12500) are added to 0.7 ml of BSA buffer and incubated for 18 hours at
4°C.
[00126] Separation: Antibody-bound lisuride is separated from free lisuride by
adding 0.2 ml of charcoal suspension (1.25% (w/v) and 0.125% (w/v) of dextrane
in
BSA buffer) and incubation for 30 minutes at 0°C. The charcoal is
sedimented by
centrifuging for 15 minutes at 3000 g. The supernatant liquid (containing
antibody-
bound active ingredient) is decanted and subjected to radiometric analysis.
[00127] Radiometric Analysis: 4 ml of Atomlight (NEN) scintillation
cocktail are added to the supernatant. The count is carried out using a WALLAC
1409 or 1410 ~-scintillation counter without quench control.
[00128] Analysis: The percutaneous skin flux is calculated as follows:
F=(C ~R)/(A~T),
where F is the percutaneous flux [ng/ cm2/h], C the active ingredient
concentration in
42

CA 02502142 2005-03-24
the acceptor medium [ng/ml], R the acceptor medium flow [ 1 ml/h], A the
measured
area [2 cmz] and T the sample-taking interval [h].
[00129] The maximum transdermal active ingredient flux is obtained directly
from the
data. Mean percutaneous flux values are determined during days 1 and 2 of the
experiment based on the cumulative absorbed dose in time intervals t=0-22 and
t=22-
54.
[00130] Specifications for the Production of TTS
[00131] EXAMPLE 2 Transdermal Therapeutic System / Device "A"
15 mg of Kollidon VA 64 (crystallization inhibitor) are dissolved in 15 mg of
isopropanol. Then 5 mg of lisuride are sprinkled in. 80 mg of polyacrylate
adhesive
(Gelva 7881) are placed in a beaker, and the above suspension is added while
rerinsing with 30 mg of isopropanol. The crystal-free wet mix obtained is
thoroughly
intermixed and spread on a siliconized liner using a 500 micron blade. The
product is
dried at 60°C for 20 minutes, and finally a covering layer is laminated
onto it.
Flux measurements as described in Example 1 showed an F value of 0.43 on day
1,
0.44 on day 2, and a maximum F value of 0.85 (each in ~,g/ cm2/h).
[00132] EXAMPLE 3 Transdermal Therapeutic System / Device "B"
12.5 mg of dimethyl isosorbide are suspended with 2 mg of lisuride in 15 mg of
isopropanol. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a
beaker, and
the above suspension is added while rerinsing with 30 mg of isopropanol. The
crystal-
free wet mix obtained is thoroughly intermixed and spread on a siliconized
liner using
a 500 micron blade. The product is dried at 60°C for 20 minutes, and
finally a
covering layer is laminated onto it. Flux measurements as described in Example
1
43

CA 02502142 2005-03-24
showed an F value of 0.23 on day 1, 0.28 on day 2, and a maximum F value of
0.50
(each in g,g/ cm2/h)
[00133] EXAMPLE 4 Transdermal Therapeutic System / Device "C"
27.2 mg of polyvinyl pyrrolidone (crystallization inhibitor), preferably
Kollidon
VA64, and 16.3 mg of lauryl alcohol are dissolved at 60°C. Then 2 mg of
lisuride
(with or without 0.5 mg of glutathione) is/ are dissolved in this solution at
60°C.
39.38 mg of Eudragit E100, 13.41 mg of Citroflex 4A and 1.71 mg of succinic
acid
are molten at 150-200°C. The lisuride solution is added after the batch
has cooled
down to 80°C. The product is spread at 80°C on a siliconized
liner using a 500
micron blade. Then the product is cooled down to 20°C ; optionally, a
covering layer
may be laminated onto it.
[00134] Flux measurements as described in Example 1 showed an F value of 0.90
on
day 1, 1.6 and 1.76 on day 2, and a maximum F value of 2.4 and 2.53 (each in
~,g/
cm2/h).
[00135] EXAMPLE 5 Making a Preparation for Oral Administration
A tablet base composition containing lactose, microcrystalline cellulose, corn
starch, crosscarmellose and magnesium stearate in the usual quantitative
composition
is intermixed with 2000 wg of lisuride per each gram of tablet basis
composition and
pressed into tablets, each of which containing 200 ~,g of lisuride.
[001,36] EXAMPLE 6 Making a Preparation for Parenteral Administration
An injection base solution containing lactose, NaCI and aqua p.i. in the usual
quantitative composition is intermixed with 50 p,g of lisuride per gram of
injection
44

CA 02502142 2005-03-24
base solution and filled into amber glass ampoules containing 50 ~,g of
lisuride per ml
of solution and preferably lyophilized.
[00137) EXAMPLE 7 Manufacturing of an Agent According to the Invention
A number of TTSs divided into the four groups as described in Example 2 is put
together. The fluxes F of lisuride through human skin of the TTSs of each
group
comprise are 0.25 fig/ cm2/h, 0.5 ~,g/ cm2/h, 0.75 ~,g/ cm2/h and 1.0 fig/
cm2/h. At
least 7 TTSs are to be in the three groups where F is low. 28 or more TTSs are
to be
in the group with the highest F. A multitude of tablets from Example 5 and/or
a
multitude of ampoules from Example 6 is packed with the TTSs compiled in this
way. The compilation is accompanied by an instruction sheet that refers to the
treatment plan according to the invention.
[00138) EXAMPLE 8 Treatment of a Patient with Parkinson's Disease
One TTS from Example 7 per day is applied to a Parkinson's disease patient
over a
period of 28 days. The area of the TTS remains unchanged for seven consecutive
days. The TTSs applied in series of 7 consecutive days increase in area so
that there
will be a four-step increase in lisuride concentration in the plasma (averaged
over a
day). The lisuride flux F of the TTSs applied in four steps is 0.25 p,g/
cm2/h, 0.5 ~,g/
cm2/h, 0.75 ~,g/ cm2/h, and 1.0 ~,g/ cm2/h. The daily application of a TTS
with an F of
1.0 ~,g/ cm2/h after day 28, i.e. there is no further increase of the dose.
Whenever a
new TTS is applied, the old one is removed, of course.
[00139] After day 28, whenever acute conditions such as severe dystonias
occur, a
tablet from Example 7 is administered, or the content of an ampoule from
Example 7

CA 02502142 2005-03-24
is injected i.m. Instead, or in addition, a tablet from Example 7 or the
content of an
ampoule from Example 7 may be administered in the morning for preventive
reasons.
[00140] The patient will at no time during the treatment show any considerable
side
effects. The oral or parenteral administrations because of acute conditions
are
particularly well tolerated, and even after these we did not observe any
noticeable
disruption of the regular REM sleep.
[00141] If against all expectations any disturbing side affects do occur, they
can be
effectively attenuated by removing the TTS without a replacement, which will
soon
result in a reduction of agent concentration in the plasma.
46