TRANSDERMAL THERAPEUTIC SYSTEM FOR DISPENSING (S)-3-METHYL-5-(1-METHYL-2-PYRROLIDENYL)-ISOXAZOLE OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE SALTS

SYSTEME THERAPEUTIQUE TRANSDERMIQUE D'ADMINISTRATION DE (S)-3-METHYL-5-(1-METHYL-2-PYRROLIDENYL)-ISOXAZOLE OU D'UN DE SES SELS ACCEPTABLES SUR LE PLAN PHARMACEUTIQUE

English Abstract

An administration form for dispensing (s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazole or one of its pharmaceutically acceptable salts is characterized in that it is a transdermal therapeutic system having the form of a plaster.

French Abstract

L'invention concerne une forme d'administration servant à administrer du (s)-3-méthyl-5-(1-méthyl-2-pyrrolidényl)-isoxazole ou un de ses sels acceptables sur le plan pharmaceutique. Cette forme d'administration se caractérise en ce qu'elle consiste en un système thérapeutique transdermique se présentant sous forme d'emplâtre.

Claims

C L A I M S
1. An administration form for the administration of (s)-3-methyl-5-
(1-methyl-2-pyrrolidenyl)-isoxazole or one of its pharmaceutically
acceptable salts characterized in that it is present as a transdermal
therapeutic system in the form of a patch.
2. The administration form according to claim 1 characterized in
that it comprises a suitable backing layer, an active substance
reservoir laminated thereon, in the absence of other control
mechanisms, a membrane controlling the active substance release, a
pressure-sensitive adhesive device to attach the system to the
skin, and, if required, a protective layer removable prior to
application.
3. The administration form according to claim 1 characterized in
that the backing layer of the system is impermeable to moisture
and active substance.
4. The administration form according to claim 1 characterized in
that the backing layer is permeable to the active substance.
5. The administration form according to one or several of the
preceding claims characterized in that it has a layered structure with
at least one polymer layer.
6. The administration form according to claim 5 characterized in
that the material of the polymer layer is selected from the groups
of polyacrylates and their copolymers, polyisobutylenes, polyterpenes,
ethylene-vinyl-acetate-copolymers, block polymers, synthetic
rubbers, or hot-melt adhesives.
7. The administration form according to claim 5 characterized in
that the polymer layer comprises esters of the hydrogenated

colophony, in particular methyl or glycerol esters of hydrogenated
colophony.
8. The administration form according to one or several of claims 1
- 7 characterized in that it comprises a plasticizer in a
concentration of 0-30%, preferably 5-20%, relative to the total weight of
the matrix.
9. The administration form according to claim 8 characterized in
that the plasticizer comprises at least one component selected
from the groups of hydrocarbons, alcohols, carboxylic acids and
their derivatives, ethers, esters, or amines.
10. The administration form according to claim 8 characterized in
that the plasticizer comprises a natural or partially synthetic
triglyceride or a mixture of these triglycerides in a concentration
ranging from 0- 30%, preferably in the range of 5 - 20%, relative
to the total weight of the matrix.
11. The administration form according to one or several of the
preceding claims characterized in that it comprises a permeation
enhancer in a concentration ranging from 0 - 30%, preferably in
the range of 5 - 20%, relative to the total weight of the matrix.
12. The administration form according to claim 11 characterized in
that the permeation enhancer comprises at least one component
selected from the groups of hydrocarbons, alcohols, carboxylic
acids and their derivatives, ethers, esters, or amines.
13. The administration form according to claim 11 characterized in
that the permeation enhancer comprises at least one component
selected from the group consisting of mono-, di- or
sesquiterpenes.

14. The administration form according to claim 11 characterized in
that the permeation enhancer comprises at least one component
selected from the group consisting of polyoxyethylene derivatives.
15. The administration form according to claim 11 characterized in
that the permeation enhancer comprises a component selected
from the group consisting of nitrogen-containing heterocycles and
their derivatives.
16. The administration form according to claim 11 characterized in
that the permeation enhancer comprises a component selected
from the group consisting of pyrrolidone derivatives.
17. The administration form according to one or several of the
preceding claims characterized in that it has a bag-type active
substance reservoir filled with a liquid or semisolid or thixotropic
matrix.
18. The administration form according to claim 17 characterized in
that a gel former is the base of the semisolid or thixotropic active
substance reservoir.
19. A process for the production of the administration form
according to one or several of the preceding claims characterized in
that (s)-3-methyl-5- (1-methyl-2-pyrrolidenyl)-isoxazole or its
pharmaceutically acceptable salt is applied in solution on a textile
fabric provided on a prefabricated matrix which is optionally provided
with a protective layer, whereupon matrix and active substance
depot are provided with a cover layer.
20. The process according to claim 19 characterized in that
components of a hot-melt adhesive are incorporated, prior to the
addition of the active substance, under heating to preferably
110 - 170°C until a homogeneous melt of 70 to 100°C is obtained.

21. The process according to claim 19 or 20 characterized in that
the homogeneous, active-substance-containing hot-melt adhesive
mass is applied by means of extrusion, casting, roller coating,
knife coating, or by a printing process.

Description

, . CA 02210341 1997-07-14
A transdermal therapeutic system for the administration of
(s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazole or one of
its pharmaceutically acceptable salts
S P E C I F I C A T I O N
The present invention relates to an administration form for the
administration of (s)-3-methyl-5~ methyl-2-pyrrolidenyl)-isoxazole
or one of its pharmaceutically acceptable salts and to a process
for its production.
The active substance (s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-
isoxazole stands out for a highly specific agonistic effect on the
choliIlergic nervous system, in particular on the nicotinic re-
ceptors. Based on recent studies of the Alzheimer's disease ther-
apy, the application of this active substance seems to improve the
cogni~ive abilities of diseased persons to a considerable extent. In
this connection, however, regular and quantitatively constant ad-
ministration of the active substance is an important factor to en-
sure constantly effective blood levels over extended periods. So
far the active substance has been administered exclusively by the
oral route. However, the oral administration of drugs to patients
suffering from dementia imposes unacceptable requirements on
the nursing staff, since the patient - owing to his disease - is not
able lio control the intake on his own.
It is the object of the present invention to provide an administra-
tion form for the administration of the active substance (s)-3-
methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazole to achieve a highly
specific agonistic effect on the cholinergic nervous system of
patielllts suffering from dementia. Replacing the hitherto required
regular oral administration at short intervals, it can achieve a con-
stantly effective blood level and - for the patients' well-being -

CA 02210341 1997-07-14
relieves the nursing staff from the burden and alertness experi-
enced as a disadvantage so far.
To achieve this object the present invention provides a new ad-
ministration form to administer (s)-3-methyl-5- (1-methyl-2-pyr-
rolidenyl)-isoxazole or one of its pharmaceutically acceptable salts,
which consists in the fact that it is present in the form of a patch
as a transdermal therapeutic system (TTS).
Accordingly, the subject matter of the present invention is a TTS
for the administration of (s)-3-methyl-5- (1-methyl-2-pyrrolidenyl)-
isoxazole or one of its pharmaceutically acceptable salts, which is
present in the form of a patch and comprises a suitable backing
layer, an active substance reservoir connected thereto, a mem-
brane controlling the active substance release if other control
mechanisms are absent, a pressure-sensitive adhesive facility to
fix the system to the skin, and, if required, a protective layer re-
movable prior to the application of the system.
The suitable backing layer may consist both of a flexible and in-
flexible material which is impermeable to active substances. Sub-
stances suitable for its production include polymeric sheets or
metallic foils, such as aluminum foils which may be used alone or
coated with a polymeric substrate. In addition, textile fabrics may
also Ibe used if the reservoir cannot penetrate through them owing
to their physical property, or if penetration is prevented by an ade-
quate layer.
The active substance reservoir may have either a layered or a bag-
type structure.
The layered reservoir may optionally consist of a polymeric matrix
and the pure active substance or of a suitable active substance
formulation, wherein the cohesion of the system as such is

, , ~ CA 02210341 1997-07-14
provided by the polymer properties. The reservoir consists of a
base polymer and conventional additives. The choice of the poly-
mer matrix and the base polymer depends on the physicochemical
properties of the active substance on the one hand, and on the
desired release from the system on the other hand. In principle,
any polymer is suitable that is used in the production of pressure-
sensitive adhesives and which is compatible with the active sub-
stance. Examples thereof include: rubber, rubber-like homo-, co-,
or block polymers, polyacrylates and their copolymers. Particularly
preferred are those based on styrene and 1 ,3-dienes, polyisobu-
tylenes and polyterpenes, or polymers based on conventional
acrylate monomers and their derivatives. Among the block poly-
mers based on styrene and 1,3-dienes linear styrene-isoprene-
bloclc-polymers are preferably used. Preferred polymers based on
acrylate are acrylic acid copolymers of 2-ethylhexyl acrylate, vinyl
acetate and acrylic acid with or without cross-linking agents.
Methacrylates are primarily understood as copolymers based on
dime~hylaminomethacrylate and neutral methacrylic acid esters
with or without cross-linking agents.
The klnd and amount of possible additives depends on the polymer
matrix used and on the active substance. According to their func-
tion they may be classified into the following groups: plasticizers,
tackifiers, stabilizers, carrier substances, diffusion and penetration
regulating additives, or fillers. The physiologically acceptable sub-
stances suitable for this purpose are known to pharmacists.
A bag-type reservoir system may consist of the pure active sub-
stance or of a highly viscous or semisolid or thixotropic active
substance preparation. Particularly suitable are oily or aqueous
gels which are dosed into a bag made of suitable sheetings or
membrane materials. In this connection, production of the active
substance preparation may be carried out on the basis of lipo-
philic or hydrophilic bases. In this case, the back of the bag,
which is averted

. ~ CA 02210341 1997-07-14
from the skin,must be impermeable to the active substance, and
the side facing the skin must be permeable to the active sub-
stance. Preferably, a membrane which is permeable to the active
substance can control the active substance release.
In the absence of other control mechanisms, the reservoir may be
combined with a membrane controlling the active substance re-
lease and a pressure-sensitive adhesive device to fix the system to
the skin. A reservoir not sufficiently adhering to the skin repre-
sents a particular case; this is combined with a special pressure-
sensitive adhesive layer ensuring permanent contact of the system
to the skin. In principle, the same materials as those used for the
polymer matrix of the reservoir are suitable for the pressure-sensi-
tive adhesive facility.
The protective layer which, if required, is to be removed prior to
application may consist of the same materials as those used for
the backing layer of the system provided that they have been ren-
dered removable, e.g., by a silicone treatment. However, it is also
possible to use other protective layers, such as paper treated with
polytetrafluoroethylene, cellophane, polyvinyl chloride, polyvinyl-
idene chloride, and the like. If the laminate according to the pres-
ent invention is divided into formats adequate for therapy
(patc,hes) prior to application of the protective layer, the formats
of the protective layer to be applied then may have a projecting
end to make their removal from the patch easier.
In accordance with the layered or bag-type construction of the
transdermal systems described hereinabove, two different produc-
tion processes are described:
a: The active substance is homogeneously mixed with the compo-
nents of the active substance reservoir, optionally in solution or
under heating and cooling, and applied to the cover layer which is

- . CA 02210341 1997-07-14
permeable to the active substances or to a textile fabric Iying
thereon, whereupon the solvent/s is/are removed, if necessary.
Depending on whether the reservoir layer is self-adhesive or not, a
pressure-sensitive adhesive device for permanent attachment to
the skin is introduced between the reservoir and the protective
layer which is removed in case of need.
b~ 'ithin an adequate device, the liquid active substance or the
liquid or semisolid or thixotropic active substance formulation is
dose!d onto a membrane which is permeable to the active sub-
stanoe and covered with a suitable sheeting, avoiding the forma-
tion of voids as far as possible, whereupon the membrane and the
sheeting are tightly sealed to form a bag. Optionally, dosage may
be carried out into a textile fabric which can additionally serve as
a support. It is also possible to dose into preformed bags. The res-
ervoir bag filled with active substance is additionally combined
with a pressure-sensitive adhesive device, which may also have a
multilayered structure and be provided with a control function for
active substance release, and is subsequently covered with a
protective layer which is removed in case of need.