PLASTER FOR THE TRANSDERMAL APPLICATION OF PERGOLIDE

EMPLATRE POUR L'UTILISATION TRANSDERMIQUE DE PERGOLIDE

English Abstract

The invention relates to a patch for transdermal application
of pergolid and its pharmaceutically acceptable salts.

French Abstract

L'invention concerne un emplâtre pour l'utilisation transdermique de pergolide et de ses sels pharmaceutiquement acceptables.

Claims

Claims

1. A transdermal therapeutic system comprising an amount of
pergolid as the active agent or one of its
therapeutically acceptable salts and a permeation
promoter selects ed from the group consisting of natural
vitamin E, synthetic vitamin E, a vitamin E derivative
and combinations thereof.

2. The transdermal therapeutic system of Claim l,
characterized in that the pergolid is selected from the
group consisting of a free pergolid base, pergolid
mesylate, pergolid hydrochloride and combinations
thereof.

3. The transdermal therapeutic system of Claim 1 or 2,
further comprising at least one other dopamine coenzyme
as further common active agent.

4. The transdermal therapeutic system of Claim 3,
characterized by pergolid or one of its pharmaceutically
acceptable salts as active agent in two-fold or
three-fold con.bination with other dopamine coenzymes.

5. The transdermal therapeutic system of Claim 3 of 4,
characterized by a further active agent selected from
the group consisting of levodopa, cardidopa, selegeline,
tacrine, physostigmine, galanthamine, 1-hydroxytacrine,
their metabolites and their pharmaceutically acceptable
salts.

6. The transdermal therapeutic system according to any one
of Claims 1 to 5, further comprising a further
permeation promoter selected from the group consisting



8


of an aliphatic, a cycloaliphatic and an
aromatic-aliphatic alcohol, which alcohols are single or
multi-valent and have up to 8 C atoms, an alcohol-water
mixture, a saturated or unsaturated fatty alcohol with 8
to 18 C atoms, and a saturated or unsaturated fatty acid
with 8 to 18 C atoms or an ester of these fatty acids,
and mixtures thereof.

7. The transdermal therapeutic system according to Claim 6,
further comprising a further permeation promoter
selected from the group consisting of ethanol,
1,2-propandiol, dexpanthenol, polyethylene glycol and
mixtures thereof as the further permeation promoter.

8. The transdermal therapeutic system of any one of Claims
1 to 7, further comprising a known stabiliser.

9. The transdermal therapeutic system of any one of Claims
1 to 8, in the form of a patch with an impermeable cover
layer and a removeable protection layer.

10. The transdermal therapeutic system according to Claim 9,
wherein the system is a matrix system or a membrane
system.

11. The transdermal therapeutic system of Claim 9 or 10,
characterized in that the cover layer is comprised of
polyester, polypropylene, polyethylene or polyurethane,
optionally being metallized or provided with pigments.

12. The transdermal therapeutic system of Claim 9, 10, or
11, characterized in that the removeable protection
layer is comprised of polyester, polypropylene or paper
with a silicone or polyethylene coating.




9


13. The transdermal therapeutic system of Claim 9, 10, 11,
or 12, comprising of a matrix system comprising:

- an impermeable cover layer,
an agent-containing self-adhesive matrix layer or
an agent-containing matrix layer coated with an
adhesive,

- removeable protection layer, and

- pergolid or one of its pharmaceutically acceptable
salts as the active agent.

14. The transdermal therapeutic system of Claim 13,
characterized in that the matrix layer is comprised of
polyacrylate, silicone, polyisobutylene, butyl rubber,
styrene/butadiene copolymer or styrene/isoprene
copolymer.

15. The transdermal therapeutic system of Claim 9, 10, 11,
or 12, comprising a membrane system comprising:

- an impermeable cover layer,

- an agent-containing reservoir or an
agent-containing reservoir layer,

- a microporous or semi-permeable membrane,

- a faculative adhesive layer,

- a removeable protection layer and

- pergolid or one of its pharmaceutically acceptable
salts as the active agent.

16. The transdermal therapeutic system of Claim 15, further
comprising a component selected from the group
consisting of known emulsifying agents, known thickening
agents, known membrane system additives and mixtures
thereof.







10


17. The transdermal therapeutic system of Claim 15 or 16,
characterized in that the microporous or semi-permeable
membrane is comprised of an inert polymer.

18. The transdermal therapeutic system of Claim 8 wherein
the known stabiliser is selected from the group
consisting of polyvinylpyrrolidone,
alpha-tocpherolsuccinate, propylgallate, methionine,
cysteine, cysteine hydrochloride and combinations
thereof.

19. The transdermal therapeutic system of Claim 17 wherein
the inert polymer is selected from the group consisting
of polypropylene, polyvinyl acetate and silicone.

20. The transdermal therapeutic system of Claim 17 wherein
the inert polymer is comprised of polypropylene,
polyvinyl acetate or silicone.

Description

CA 02259353 2006-05-17
Plaster for Transdezmal Application of Peraolide
The invention relates to a patch or plaster for transdermal
application of pergolid and its pharmaceutically harmJ.ess
salts.
Fergolid (D~6-n--propyl-8~i-methylmercaptomethylexgoline) is
a dopamine receQtor coenzyme and is administered among
other t.hir~.gs as an anti-parkinsaa ageat (8P-A 0 003 6671 ,
for the treatment of addiction caused by psycho-st~.mulants
(EP-A 0 204 954), and for niCOtirxe addiction (GB~A 2 204
240) .
Various orally admixiist.ered formulations Qf pergolid are
kriowri from EP-A 0 003 667 and fiP-A 0 527 835. The
therapeutically effective daily dose. is 0.01 to 2o mg.
Generally it cari be said that the biological activity pf
drugs administered orally or intravenously is often
unsatisfactory. 'fhe hepatic metabolism of the drug upon
the first passage through the liver can lead to undesired
concentrations and td~ciC by-praduCts, or to the loss of ox
reduction of effect. Compared to oral administration, the
transdermal administration of drugs or agents has various
advantages. The drug supply can be better controlled over
a longer time interval, whereby significant blood plasma
fluctuation is avoided. In addition, the required
therapeutic dosage cata usually be distinctly reduced.
Fuzthermore, a patch is often more preferred by the patient
than one or more tablets to be taken daily.
rn oral application, pergolid has a low bio-activity.
Consequently, it is difficult to achieve a cor~.stant blood


CA 02259353 1998-12-24
2
plasma level over a longer time period, so that three doses
daily are required.
The object of the present invention is to provide a
transdermal system for the systematic application of pergolid
or one of ita pharmaceutically harmless salts where the
drawbacks of oral administration forms are avoided.
The object underlying the invention is now solved with a
1o transdermal therapeutic system with an amount of pexgolid or
one of its pharmaceutically harmless salts.
The agent pergolid can be applied as a free pergolid base,
pergolid mesylate and/or pergolid hydrochloride.
pergolid oz one of its pharmaceutically acceptable salts as
the active agent can also be used in combination with one or
more further known substances, particularly in two-cold or
three-fold combinations. These further known agents can
2o modify, enhance, synergize or alter the potency of the
pezgolid effect. For example, dopamine coenzymes can be
provided.
Particularly suitable further agents include levodopa,
z5 carbidopa, selegeline, tracrine, physostingu~ine,
galanthamirie, 1-hydroxytacrine and/or chemical derivatives
thereof, metabolites thereof and/or pharmaceutically
acceptable salts thereof.
3o Suitable permeation promoters include singly and/or multi-
valent aliphatic, cycloaliphatic and/or aromatic-aliphatic
alcohols with up to 8 C atoms, for example ethanol, 12-
propandiol, dexpanthenol and/or polyethylene glycol;
alcohol/water mixtures; saturated and/or unsaturated fatty
35 alcohols with 8 to 18 carbon atoms: saturated and/or


CA 02259353 1998-12-24
3
unsaturated tatty acids with 8 to 18 carbon atoms; their
esters; natural vitamin E; synthetic vitamin E; and/or
vitamin E derivatives.
Since pergolid is light-sensitive to a certain extent,
stabili2ers can be employed, for example as is known from US-
A 5 114 948 or EP-g 0 314 387. Examples include
polyvinylpyrrolidone, alpha-tocopherolsuccinate,
propylgallate, methionine, cysteine and/or cysteine
xo hydrochloride_
The transdermal therapeutic system according to the invention
can be a patch, particularly with an impermeable cover layer
and removable protection layer, especially a matrix system or
1S a membrane system.
The cover layer can be polyester, polypropylene, polyethylene
or polyurethane, optionally provided with a metallisation or
pigment. The removeable protection layer can be polyester,
2o polypropylene or paper with a silicone and/or polyethylene
coating.
The transdermal therapeutic system according to the invention
may be a matrix patch With
- an impermeable cover layer
- a drug-containing self-adhesive matrix layer or a drug-
containing matrix layer Nhich iS coated with an adhesive,
-- a removeable protection layer and
- pergolid or one of its pharmaceutically acceptable salts
as the active agent (drug),
- optionally with further active agents and/or permeation
promoters and/or stabilisers.
The matrix can be based on polyacrylate, silicone,


CA 02259353 1998-12-24
9
polyisobutylene, butyl rubber, styrene/butadiene copolymer or
styrene/isoprene copolymer. Such matrix materials common in
the medical field are knot~m in the priox art. Examples of
acrylate adhesives include DuroTak adhesives,
A further enubodiment of the invention relates to a membrane
system including
- an impermeable cover layer,
- a drug-containing reservoir or a drug-containing reservoir
layer,
- a semi-permeable membrane,
- s facultative adhesive layer,
- a removeable protection layer and
is - pergolid or one of its pharmaceutically acceptable salts,
- optionally, further active agents and/or permeation
promoters, stabilisers, emulsifying agents, thickening
agents and/or common membrane system or reservoir patch
additives.
The drug-containing reservoir layer can thus be provided in
an intermediate space formed between the covering layer and
the membrane. The reservoir is filled with the active agents
(drug) and facultative additives.
zs
Inert polymers are suitable for the membrane, particularly on
the basis of polypropylene, polyvinylacetate or silicone.
when a membrane is provided, it can have the effect of
so controlling drug re~.ease depending on the pore size.
In the following, the invention is illustrated through
examples.


CA 02259353 1998-12-24
Example 1 (Matrix patch)
The following components are dispersed in a sufficient amount
s of ethyl acetate:
pergolid
g
natural vitamin E 10 g
propylene glycol 15 g
io acrylate adhesive 65 g
(as 35 ~ solution in ethyl acetate
e.g. DuroTak 326-1753)
In a commercial coating machine, the obtained dispersion is
1s applied to a silicone-treated polypropylene foil, which
results in a surface Height of the dried drug-containing
adhesive matrix of 100 g/m2. In a coating station, a 50 ),un
thick polyurethane foil is applied. Thereafter, 20 cmz or
optionally 10, 30, 90 or 50 cm' patches are stamped out of
ao the laminate.
Example 2 (Reservoir TTS)
25 The following components are dispersed in ethanol/water;
pergolid (or a corresponding amount of pergolid salt,
e.g. pergolid mesylate) 5 to 10 ~
optionally, natural vitamin E and/or
so polyvinylpyrrolidone as stabiliser.
For the production of the patches, the following elements are
Loreseen:
35 covering lay~sr of for example polyethylene


CA 02259353 2004-05-27
6
semi-permeable membrane, e.g. CoTan~ 9711 adhesive for
adhesive layer, e.g. Duro-TakTM 326-1753 removeable
protection layer, e.g. GelroflexTM.
In a first step, a laminate is produced in a common machine
with the adhesive, the membrane and the protection layer. In
a second step, an empty TTS is produced from the laminate and
the covering layer. In a third step, the empty TTS is filled
with the active agent dispersion. In a fourth step, the
filled TTS is closed and in a fifth step patches are stamped
out in the desired size.