U.S. patent application number 16/288911 was filed with the patent office on 2019-06-27 for transdermal therapeutic system for administering the active substance buprenorphine.
This patent application is currently assigned to LTS LOHMANN THERAPIE-SYSTEME AG. The applicant listed for this patent is LTS LOHMANN THERAPIE-SYSTEME AG. Invention is credited to Thomas Hille, Michael Horstmann, Walter Mueller.
Application Number | 20190192506 16/288911 |
Document ID | / |
Family ID | 39326133 |
Filed Date | 2019-06-27 |
![](/patent/app/20190192506/US20190192506A1-20190627-D00001.png)
United States Patent
Application |
20190192506 |
Kind Code |
A1 |
Hille; Thomas ; et
al. |
June 27, 2019 |
TRANSDERMAL THERAPEUTIC SYSTEM FOR ADMINISTERING THE ACTIVE
SUBSTANCE BUPRENORPHINE
Abstract
The invention relates to a transdermal therapeutic system for
administering the active substance buprenorphine. Said system
comprises at least one carboxylic acid that determines the
solubility of buprenorphine in the matrix layer and that can
likewise be absorbed. The transdermal therapeutic system according
to the invention is used in the treatment of pain and characterized
by a considerably increased utilization of the active
substance.
Inventors: |
Hille; Thomas; (Neuwied,
DE) ; Horstmann; Michael; (Neuwied, DE) ;
Mueller; Walter; (Andernach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LTS LOHMANN THERAPIE-SYSTEME AG |
Andernach |
|
DE |
|
|
Assignee: |
LTS LOHMANN THERAPIE-SYSTEME
AG
Andernach
DE
|
Family ID: |
39326133 |
Appl. No.: |
16/288911 |
Filed: |
February 28, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16003855 |
Jun 8, 2018 |
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16288911 |
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15499304 |
Apr 27, 2017 |
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16003855 |
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15053139 |
Feb 25, 2016 |
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15499304 |
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12515848 |
Jan 12, 2010 |
9308202 |
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PCT/EP2007/009622 |
Nov 7, 2007 |
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15053139 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/7053 20130101;
A61K 9/7084 20130101; A61K 31/485 20130101; A61P 25/00 20180101;
A61P 29/00 20180101; A61M 37/00 20130101; A61K 9/7092 20130101;
A61P 25/32 20180101; A61K 9/7069 20130101; A61P 25/04 20180101;
A61K 47/12 20130101; A61P 25/36 20180101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/70 20060101 A61K009/70; A61M 37/00 20060101
A61M037/00; A61K 47/12 20060101 A61K047/12 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 21, 2006 |
DE |
102006054731.4 |
Claims
1. A transdermal therapeutic system for administering buprenorphine
to the skin, comprising: an active-ingredient-impermeable backing
layer; at least one pressure-sensitive adhesive matrix layer
comprising the active ingredient buprenorphine and at least one
carboxylic acid; wherein the matrix layer comprises a polymer
selected from polysiloxanes or polyisobutylene; wherein the
buprenorphine is dissolved in the at least one carboxylic acid to
form a solution and wherein the solution is dispersed, in the form
of droplets, in the matrix layer.
2. The transdermal therapeutic system according to claim 1, wherein
the matrix layer comprises polysiloxane.
3. The transdermal therapeutic system according to claim 1, wherein
the polysiloxane is an amine-resistant dimethylpolysiloxane.
4. The transdermal therapeutic system according to claim 1, wherein
the polysiloxane is a mixture of an amine-resistant and a
non-amine-resistant dimethylpolysiloxane, in which the
non-amine-resistant dimethylpolysiloxane is present at up to 40% by
weight.
5. The transdermal therapeutic system according to claim 1, wherein
the matrix layer comprises polyisobutylene.
6. The transdermal therapeutic system according to claim 1, wherein
the at least one carboxylic acid diffuses into the skin more
quickly than does the active ingredient buprenorphine.
7. The transdermal therapeutic system according to claim 1, wherein
the amount of the dispersed solution is up to 40% by weight.
8. The transdermal therapeutic system according to claim 1, wherein
the at least one carboxylic acid is liquid at skin temperature.
9. The transdermal therapeutic system according to claim 1, wherein
the at least one carboxylic acid is selected from the group
consisting of oleic acid, linoleic acid, linolenic acid or mixtures
thereof.
10. The transdermal therapeutic system according to claim 1,
wherein the buprenorphine and the at least one carboxylic acid are
present in the same weight ratio.
11. The transdermal therapeutic system according to claim 2,
wherein the polysiloxane is a mixture of an amine-resistant and a
non-amine-resistant dimethylpolysiloxane, where the
non-amine-resistant dimethylpolysiloxane is present in the mixture
at up to 40% by weight; wherein the at least one carboxylic acid
diffuses into the skin more quickly than does the active ingredient
buprenorphine and where the at least one carboxylic acid is liquid
at skin temperature; and wherein the amount of the dispersed
solution in the matrix layer is up to 40% by weight.
12. The transdermal therapeutic system according to claim 1,
wherein the matrix layer is in diffusible contact with a layer
based on polyacrylates.
13. The transdermal therapeutic system according to claim 12,
wherein the polyacrylate layer is embodied as a self-adhesive skin
contact layer.
14. The transdermal therapeutic system according to claim 13,
wherein the polyacrylate adhesive possesses no free carboxyl
groups.
15. The transdermal therapeutic system according to claim 1,
wherein active substance utilization under in vivo conditions of at
least 30% is achieved.
16. The transdermal therapeutic system according to claim 1,
wherein active substance utilization under in vivo conditions of at
least 40% is achieved.
17. The transdermal therapeutic system according to claim 1,
wherein active substance utilization under in vivo conditions of at
least 50% is achieved.
18. The transdermal therapeutic system according to claim 1,
wherein the droplets in the matrix layer consist essentially of the
buprenorphine and the at least one carboxylic acid.
19. The transdermal therapeutic system according to claim 1 further
comprising a protective layer to be detached before use.
20. The transdermal therapeutic system according to claim 1,
wherein the buprenorphine and the at least one carboxylic acid are
present in the different weight ratios.
21. The transdermal therapeutic system according to claim 1,
wherein the amount of the at least one carboxylic acid is from 7%
to 9% by weight.
22. A method of treating pain which comprises: administering to a
patient, in need thereof, a transdermal therapeutic system for
administering buprenorphine to the skin, wherein the transdermal
therapeutic system comprises: an active-ingredient-impermeable
backing layer; at least one pressure-sensitive adhesive matrix
layer comprising a therapeutically effective amount of the active
ingredient buprenorphine and at least one carboxylic acid; wherein
the matrix layer comprises a polymer selected from polysiloxanes or
polyisobutylene; wherein the buprenorphine is dissolved in the at
least one carboxylic acid to form a solution; and wherein the
solution is dispersed, in the form of droplets, in the matrix
layer.
23. The method according to claim 22, wherein the matrix layer
comprises polysiloxane.
24. The method according to claim 22, wherein the buprenorphine and
the at least one carboxylic acid are present in the different
weight ratios.
25. The method according to claim 22, wherein the amount of the at
least one carboxylic acid is from 7% to 9% by weight.
26. The method according to claim 22, wherein the matrix layer
comprises polyisobutylene.
27. The method according to claim 22, wherein the amount of the
dispersed solution is up to 40% by weight.
28. The method according to claim 22, wherein the at least one
carboxylic acid is selected from the group consisting of oleic
acid, linoleic acid, linolenic acid or mixtures thereof.
29. The method according to claim 22, wherein active substance
utilization under in vivo conditions of at least 30% is
achieved.
30. The method according to claim 22, wherein active substance
utilization under in vivo conditions of at least 40% is achieved.
Description
[0001] This application claims priority benefit of U.S. application
Ser. No. 12/515,848, filed Jan. 12, 2010, which claims priority
benefit of International Patent Application No. PCT/EP07/09622,
filed Nov. 7, 2007, which claims priority benefit of German
Application No. 10 2006 054 731.4, filed Nov. 21, 2006, the
disclosures of which are herein incorporated by reference in their
entireties
DESCRIPTION
[0002] The present invention relates to a transdermal therapeutic
system with at least one carboxylic acid which determines the
solubility of the buprenorphine in the matrix layer and is likewise
absorbable, for pain therapy, with significantly increased active
ingredient utilization.
[0003] The active ingredient buprenorphine
(17-(cyclopropyl-methyl)-.alpha.-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihy-
dro-3-hydroxy-6-methoxy-.alpha.-methyl-6,14-ethenomorphinan-7-methanol)
is a partially synthetic opiate whose advantage over other
compounds from this class of substance lies in a higher activity.
This means that freedom from pain can be achieved in cancer or
tumour patients with very unfavourable diagnosis, in the final
stage, with daily doses of around 1 mg. A feature of buprenorphine
in this context over the synthetic opioid fentanyl and its
analogues is that the addictive potential of buprenorphine is lower
than that of these compounds. The disadvantage is that, owing to
the high molecular weight of buprenorphine, namely 467.64 daltons,
it is difficult to effect its transdermal absorption.
[0004] In spite of this, transdermal systems containing
buprenorphine (e.g. Transtec.RTM. or Norspan.RTM.) are already
available commercially. German Patent DE 39 39 376 C1 describes
their functioning. The active ingredient is in homogeneous solution
in a polyacrylate matrix, with a carboxylic acid serving as
permeation enhancer and solubilizer.
[0005] Systems in which the active ingredient is in homogeneous
solution are commonly distinguished by low active substance
utilization. The reason for this is that the thermodynamic activity
of the active ingredient, which determines the delivery of active
ingredient, decreases in the course of administration, as a result
of the falling active ingredient loading. Uniform delivery of
active ingredient over the entire administration time is achievable
only through a relatively high active ingredient loading in
comparison to the amount that is to be delivered. The published
data for the Transtec.RTM. 35 product, which is marketed in Europe,
suggest, for example, active ingredient utilization of only 17%
over the administration period. Given that buprenorphine is an
expensive active ingredient, higher active ingredient utilization
would be a substantial advantage from a costs standpoint. A very
low loading of the system with the buprenorphine, which is a
narcotic, and a resultant minimal residual content following
application in the systems used, moreover, is very desirable from
the standpoint of safety.
[0006] It was an object of the present invention, therefore, to
develop a TTS which makes the active ingredient buprenorphine,
whose transdermal absorption is difficult to effect, available to
transdermal administration, with significantly increased active
ingredient utilization.
[0007] This object is achieved in accordance with the invention,
and in a surprising way, by means of a transdermal therapeutic
system for administering buprenorphine to the skin, the TTS
comprising an active-ingredient-impermeable backing layer, at least
one pressure-sensitive adhesive matrix layer, comprising the active
ingredient buprenorphine and at least one carboxylic acid, and, if
desired, a protective layer which is to be detached before use. The
matrix layer is constructed on the basis of polysiloxanes or
polyisobutylene. The buprenorphine is in solution in the carboxylic
acid or the carboxylic acids, and this solution is in dispersion in
the form of droplets in the matrix layer. This is all the more
surprising in view of the fact that buprenorphine, on account of
its known physicochemical properties, more particularly its poor
solubility, its comparatively high melting point of 216.degree. C.,
and, as already mentioned, its high molecular weight, tends readily
towards crystallization. For this reason a solvent with at least
one acidic group is used in order to prevent the buprenorphine
crystallizing during the storage of the pharmaceutical form. Both
buprenorphine itself and carboxylic acids have an extremely low
solubility in polysiloxanes or polyisobutylene. As a consequence of
this it is possible to dissolve buprenorphine in a carboxylic acid
and to disperse this solution in the form of droplets in a matrix
layer prepared on the basis, as base polymer, of polyisobutylene or
of polysiloxanes, preferably amine-resistant
dimethyl-polysiloxanes, more preferably a mixture of an
amine-resistant and a non-amine-resistant dimethylpolysiloxane, the
non-amine-resistant dimethylpolysiloxane being present at not more
than 40% by weight, preferably 2% to 20% by weight. In this case it
is important that the mixture of buprenorphine and carboxylic acid
or carboxylic acids is in liquid form.
[0008] The carboxylic acids employed are typically of sparing
solubility in the organic solvents of the adhesives. Consequently
the liquid mixture of buprenorphine and carboxylic acid can be
dispersed in the solution of the adhesive, with the dispersion
being retained following removal of the solvent. In a matrix layer
of this kind, the solubility of the buprenorphine is dependent
virtually only on the amount of the carboxylic acid or carboxylic
acids. The amount of the dispersed solution can be up to 40% by
weight, it being preferred not to exceed 20% by weight. The droplet
size itself ought preferably not to exceed 50 .mu.m. The preferred
size is dependent, furthermore, on the thickness of the matrix
layer.
[0009] FIG. 1 shows a diagrammatic representation of a one-layer
self-adhesive system of this kind.
[0010] FIG. 2 depicts a system with a skin contact layer;
[0011] FIG. 3 shows a multilayer system with a top patch. In these
figures the meaning of the reference numerals is as follows:
[0012] 1 backing layer [0013] 2 matrix layer based on polysiloxanes
with disperse droplets of a buprenorphine/carboxylic acid solution
[0014] 3 protective layer to be removed before use [0015] 4 skin
contact layer based on a polyacrylate adhesive [0016] 5
pressure-sensitive adhesive layer without buprenorphine [0017] 6
backing layer (e.g. skin-coloured)
[0018] Since carboxylic acids can likewise be absorbed through the
skin, their amount in the system goes down during the time of
application, and hence there is also a reduction in the saturation
solubility of the buprenorphine. As a result of this, the decrease
in the thermodynamic activity of buprenorphine, as is caused by the
delivery, is compensated. The choice of the carboxylic acid is
guided by the absorption through the skin, which is just as quick,
and preferably quicker, as compared with that of buprenorphine. It
is preferred to use carboxylic acids which are liquid at skin
temperature. The carboxylic acid or the carboxylic acids is or are
selected from the group consisting of oleic acid, laevulinic acid,
linoleic acid and linolenic acid. Given an appropriate embodiment
it is possible to achieve supersaturated states during the time of
application. In supersaturated systems the thermodynamic activity
of the active ingredient and hence also the permeation rate per
unit area is increased in accordance with the supersaturation
factor. As a result, advantageously, it is possible to minimize the
delivery area and also the area of the system. During storage, both
buprenorphine and the acid remain in the polymer matrix, so that
during this time the system is not more than saturated, and
recrystallization of the active ingredient is ruled out.
[0019] A further aspect of the invention concerns the effect that
in systems of this kind, if the delivery of the acid is too quick,
the rise in the thermodynamic activity can lead to an excessive
increase in the permeation rate following application. The
consequence is that the TTS becomes prematurely exhausted as a
result of excessively rapid delivery of active ingredient. It has
now been found that this kind of effect is prevented by addition of
a further layer based on polyacrylates. This layer is located
preferably between the polymer matrix layer, containing active
ingredient, and the skin, or else between matrix layer and backing
layer. This additional layer is preferably embodied as a
self-adhesive skin contact layer.
[0020] The solubility of buprenorphine in polyacrylates is
significantly higher than in polysiloxanes or polyisobutylene and,
depending on the precise composition, ranges up to about 10 percent
by weight. Since, as a result, the overall system has a higher
saturation solubility for buprenorphine, the degree of
supersaturation occasioned by the delivery of the acid is reduced
by redistribution of the buprenorphine from the matrix layer into
the polyacrylate layer. As a result of this, the delivery of active
ingredient is more uniform, and premature exhaustion of the system
is prevented. It has been found that, in one preferred embodiment,
with the matrix layer loaded with about 0.4 mg of buprenorphine and
the carboxylic acid used being laevulinic acid, a skin contact
layer with a coating weight of 15-30 g/m.sup.2 is sufficient per
cm.sup.2 in order to achieve the desired effect.
[0021] There are basically no limitations in terms of the monomers
used for producing the polyacrylate adhesive. On the basis of
theoretical considerations, however, preference is given to
adhesives without free carboxyl groups, since they are unable to
immobilize the basic buprenorphine via formation of salts.
[0022] FIG. 2 shows a diagrammatic representation of a system of
this kind; its production is described in Example 1. The thickness
of the matrix layer and skin contact layer must in each case be
optimized as a function of the chosen active ingredient
concentration in the matrix layer and, respectively, the amount of
active ingredient per unit area. The amount or concentration of the
acid in the matrix layer depends on its solvency for buprenorphine.
In the case of the preferred use of laevulinic acid, buprenorphine
and the acid are used in equal proportions by weight. The chosen
concentration of both substances, of 7% to 9% by weight, has proved
to be suitable, but can also be selected differently, taking
appropriate account when selecting the coating weight, without
affecting the performance of the TTS.
[0023] Transdermal therapeutic systems according to Example 1 were
compared in a pharmacokinetics study in humans, with TTS already on
the market, as a reference system. It was found that a 17 cm.sup.2
system according to Example 1 with a buprenorphine content of 6.3
mg corresponds to a 25 cm.sup.2 reference TTS having an active
ingredient content of 20 mg. On the basis of the stated delivery of
the reference product, of 35 .mu.g/h TTS, this gives for the
reference product an active ingredient utilization of 17% and for a
TTS according to Example 1 an active ingredient utilization of 53%.
This clearly shows that, with transdermal systems according to
Example 1, the objective of substantially improved active
ingredient utilization has been achieved. With the TTS of the
invention containing buprenorphine as active ingredient,
accordingly, it is possible to achieve in vivo active ingredient
utilizations of at least 30%, preferably at least 40%, more
preferably at least 50%. A further advantage arising is that these
systems, on account of the higher permeation rate, can be used with
a surface area of approximately 30% less that the reference
systems.
[0024] A particular advantage is that this improved active
ingredient utilization allows the loading of the system with the
narcotic buprenorphine to be reduced further, with a consequent
further minimization in the residual buprenorphine content in the
spent systems after use.
[0025] The transdermal therapeutic systems of the invention can be
provided with different release profiles and in different dose
strengths. As already described above, for example, the active
ingredient release profile can be influenced by means, for example,
of appropriate variation to the layer thickness of the
active-ingredient-containing matrix and/or the skin contact layer,
or by altering the concentration of active ingredient in the
matrix. The dose strength of the TTS of the invention can be
modified, for example, by varying the surface area of the
active-ingredient-containing matrix, while keeping the composition
and layer thickness of the matrix and skin contact layer the same,
in order thus to obtain different dose strengths. In this way it is
possible, preferably, to obtain transdermal therapeutic systems
which have properties comparable with those of transdermal
therapeutic systems already on the market.
[0026] Through the provision of TTS with different dosage levels it
is possible to put a patient individually on the amount of active
ingredient he or she requires. Furthermore, it becomes possible to
set up the delivery of active ingredient to the patient in such a
way that he or she is given the amount of active ingredient he or
she needs, in a way which is known in principle, by means of an
appropriate dosage scheme. In such a scheme, the amount of active
ingredient administered to the patient is increased accordingly by
means, for example, of sequential administration of transdermal
therapeutic systems with different dose strengths. The sequential
increase in the dose of active ingredient allows a further
reduction in the side effects which it is known can possibly arise
in the course of administration of the active ingredient
buprenorphine. Examples of the sequential adaptation of the
delivery of active ingredient to a patient by means of appropriate
dosing schemes are described in, for example, patent applications
WO 2006/030030 A2 and EP 1572167. The present invention hence also
encompasses systems, kits for example, which comprise two or more
TTS of the invention with different dose strengths.
[0027] The form taken by the transdermal therapeutic systems of the
invention may be such as to allow subdivision of the TTS into
different sub-units. Such divisibility likewise allows further
modification of the TTS to the individual active ingredient
requirement of a patient, or the use of the TTS for implementation
of an appropriate dosing scheme. In this case the divisible TTS
advantageously contains a multiplicity of polymer matrix regions
which are separated spatially by regions free of active ingredient.
The TTS can then be divided along the regions free of active
ingredient, by cutting for example, so that one or more polymer
matrix regions are separated off from the rest of the TTS. Examples
of the construction of divisible TTS variants are described in, for
example, patent applications WO 2003/079962 A2 and WO 02/41878
A2.
[0028] The transdermal therapeutic systems of the invention can be
modified and used for different durations of administration. The
TTS of the invention can for example each be applied for at least
12 h or 24 h. With preference, however, the individual TTS of the
invention can also be used over a respective application duration
of at least 72 h, 84 h or 96 h. Longer application durations,
however, are also possible, such as 120 h, 144 h or 168 h, for
example.
[0029] The invention is illustrated by the examples below, but
without thereby restricting the scope of the invention:
Example 1
[0030] A In a stainless steel vessel, 3.65 kg of buprenorphine are
suspended in 3.65 kg of laevulinic acid and 2.6 kg of ethanol. With
stirring, 60.6 kg of a polysiloxane adhesive in the form of a
solution in n-heptane having a solids content of 74% by weight and
9.72 kg of heptane are added. The mixture is stirred until the
buprenorphine base is fully dissolved, to give 80.22 kg of a
buprenorphine-containing adhesive solution with 4.55% of
buprenorphine, with a solids content of 64.8% (adhesive solution
1).
[0031] B For the skin contact layer, a polyacrylate adhesive
prepared from 2-ethylhexyl acrylate, vinyl acetate and
2-hydroxyethyl acrylate is used. 31.87 kg of a solution of this
adhesive, with a solids content of 51% by weight, is admixed with
6.5 kg of ethyl acetate and 1.91 kg of oleic acid, in pure form or
as a mixture with other carboxylic acids, to give, following
homogenization, approximately 40 kg of active-ingredient-free
polyacrylate solution (adhesive solution 2).
[0032] C Auxiliary means known to the person skilled in the art are
used to coat a film, which has been treated so as to be abhesive
for the chosen adhesive, with the buprenorphine-containing adhesive
solution 1. The coating thickness is chosen such that removal of
the solvents results in a coating weight of the matrix layer of 55
g/m.sup.2. The concentration of buprenorphine and laevulinic acid
in this layer is 7% to 9% by weight. The backing layer of the
subsequent system is then laminated onto the "dried" matrix layer.
Adhesive solution 2 is likewise coated onto an abhesively treated
film (the later protective film to be removed before the systems
are used) and the organic solvents are removed. The coating
thickness of the resulting skin contact layer ought to amount,
following removal of the solvents, to approximately 20 g/m.sup.2.
The abhesively treated film is then removed from the matrix layer
produced first, and the matrix layer is laminated onto the skin
contact layer. The individual systems can now be punched from the
resulting total laminate.
[0033] In specific embodiments a TTS as described above can be
provided with an over-plaster of larger surface area, preferably
with rounded corners, comprising a pressure-sensitive adhesive
matrix layer which is free of active ingredient and has a
preferably skin-coloured backing layer. This is of advantage when
the skin contact layer, on the basis of its physical properties
alone, does not adhere sufficiently to the skin and/or when the
buprenorphine-containing matrix layer, for the purpose of avoiding
waste, has pronounced corners (square or rectangular shapes).
Examples 2-5
[0034] Production takes place in the same way as in Example 1, but
with the concentrations and layer thickness of the matrix layer
varied in accordance with Table 1.
Example 6
[0035] As Example 6, the commercial product Transtec.RTM. from
Grunenthal GmbH was used.
TABLE-US-00001 TABLE 1 Composition of the buprenorphine-containing
TTS relative to the active ingredient matrix Laevulinic Weight per
Buprenorphine acid content unit area of content of Buprenorphine
Laminate 1 matrix layer matrix layer content [% by Example
[g/m.sup.2] [% by weight] [mg/cm.sup.2] weight] 1 55 7 0.385 7 2 60
7 0.42 7 3 65 8.4 0.546 8.4 4 80 7 0.56 7
[0036] Using these TTS, in vitro experiments were carried out with
the Franz diffusion cell, which is known to a person skilled in the
art, using epidermis from complete human skin. For this purpose,
diecuts with an area of 2.54 cm.sup.2 were punched from laminates,
and were each tested against diecuts of the commercial product
Transtec.RTM.. Transtec.RTM. is available commercially in three
different dose strengths, which, however, are in proportion to
their surface area. The concentrations of buprenorphine in the
acceptor medium of the Franz cell were measured (Tab. 2).
Additionally, after the experiment, the TTS were analysed for their
buprenorphine and laevulinic acid content. The results of the
analyses of Example 1 are shown in table and graph form alongside
those of the further examples.
TABLE-US-00002 TABLE 2 Average cumulative quantities of
buprenorphine, in micrograms/hour, released to the Franz cell from
the TTS of the invention Example 2 h 4 h 8 h 24 h 32 h 48 h 56 h 72
h 1 <d.l.* 0.015 0.118 1.79 3.40 7.56 13.6 21.1 2 <d.l.*
0.007 0.062 0.87 1.72 5.3 9.63 19.3 3 0.013 0.027 0.076 0.689 1.36
4.7 9.15 21.5 4 0.035 0.071 0.184 1.64 3.27 8.86 12.9 25.9 Transtec
.RTM. n.d. 0.061 0.167 2.35 n.d. 11.4 n.d. 25.4 *<d.l. = below
detection limit
[0037] When the cumulative flux rates from Table 2 are compared
with one another, it is seen that all of the permeation rates of
the TTS according to the invention are situated in the same order
of magnitude as those of the commercial product Transtec.RTM.. Even
if the Franz cell is not a substitute for clinical trials, but is
instead used in order to discriminate between different TTS
formulas, the results presented in Table 2 can be evaluated to show
that, under in vitro conditions, TTS of Example 1 delivers just as
much buprenorphine as Transtec.RTM.. As already described above, a
TTS according to Example 1 was compared, in a pharmacokinetics
study in humans, with this TTS already on the market, as a
reference system, and for the reference product an active
ingredient utilization of 17% TTS was demonstrated, as compared
with active ingredient utilization of 53% for a TTS according to
Example 1.
[0038] After the permeation studies, all of the inventive example
TTS were analysed for their residual laevulinic acid content. The
residual amounts and the relative quantities of laevulinic acid
delivered, as calculated from the residual amounts, are shown in
Table 3.
TABLE-US-00003 TABLE 3 Release of laevulinic acid Laevulinic
Laevulinic Residual laevulinic acid acid content acid in the TTS
released Example [mg/cm.sup.2] [mg/cm.sup.2] [%] 1 0.385 0.025 93.5
2 0.42 0.026 93.8 3 0.546 0.033 94 4 0.56 0.039 93
[0039] Table 3 illustrates that, in accordance with the teaching of
the invention, the TTS become depleted in laevulinic acid during
use, and hence bring about the surprisingly high utilization of the
active ingredient buprenorphine.
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