U.S. patent application number 16/388364 was filed with the patent office on 2019-08-08 for transdermal therapeutic system for 5-aminolevulinic acid hydrochloride.
The applicant listed for this patent is LTS Lohmann Therapie-Systeme AG, Photonamic GmbH. Invention is credited to Gerd HOFFMANN, Michael HORSTMANN, Tobias JUNG.
Application Number | 20190240166 16/388364 |
Document ID | / |
Family ID | 46724447 |
Filed Date | 2019-08-08 |
![](/patent/app/20190240166/US20190240166A1-20190808-D00001.png)
United States Patent
Application |
20190240166 |
Kind Code |
A1 |
JUNG; Tobias ; et
al. |
August 8, 2019 |
Transdermal Therapeutic System for 5-Aminolevulinic Acid
Hydrochloride
Abstract
The invention relates to a transdermal therapeutic system that
includes a back layer that is impermeable to an active ingredient;
a polymer matrix containing the active ingredient and a protective
layer that can be pulled off. The active ingredient is
5-aminolevulinic acid hydrochloride and the basic polymer of the
polymer matrix is an adhesive polyacrylate. The inventive
transdermal therapeutic systems are suitable for diagnosing and
treating preliminary stages of skin cancer, such as actinic
keratosis, and oncological skin diseases.
Inventors: |
JUNG; Tobias;
(Efringen-Kirchen, DE) ; HORSTMANN; Michael;
(Neuwied, DE) ; HOFFMANN; Gerd; (Neuwied,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LTS Lohmann Therapie-Systeme AG
Photonamic GmbH |
Andemach |
|
DE |
|
|
Family ID: |
46724447 |
Appl. No.: |
16/388364 |
Filed: |
April 18, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14240810 |
Jun 18, 2014 |
10307382 |
|
|
PCT/EP2012/066541 |
Aug 24, 2012 |
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16388364 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 31/197 20130101; A61P 17/00 20180101; A61K 31/195 20130101;
A61K 9/7061 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/197 20060101 A61K031/197; A61K 31/195 20060101
A61K031/195 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 31, 2011 |
DE |
102011111865.2 |
Claims
1. A transdermal therapeutic system comprising a back layer that is
impermeable to an active ingredient, an active
ingredient-containing polymer matrix and a protective layer that
can be pulled off, wherein the transdermal therapeutic system is a
monolithic active ingredient-in-adhesive system; the active
ingredient is 5-aminolevulinic acid hydrochloride, which is present
in an amount of 10 to 30% by weight based on the polymer matrix;
the polymer matrix contains more than 60% by weight of an adhesive
polyacrylate having a viscosity of 500 to 25,000 mPa-s at
25.degree. C.; the adhesive polyacrylate is based on acrylic acid,
butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate or based on
acrylic acid, 2-ethylhexyl acrylate and methyl acrylate, and the
adhesive polyacrylate does not comprise a cross-linking agent.
2. The transdermal therapeutic system according to claim 1, wherein
the 5-aminolevulinic acid hydrochloride is a crystalline
5-aminolevulinic acid hydrochloride.
3. The transdermal therapeutic system according to claim 2, wherein
50% of the crystals in the crystalline 5-aminolevulinic acid
hydrochloride are larger than the polymer matrix layer
thickness.
4. The transdermal therapeutic system according to claim 2, wherein
more than 99.9% of the crystals of the crystalline 5-aminolevulinic
acid hydrochloride are smaller than about 250 .mu.m.
5. The transdermal therapeutic system according to claim 4, wherein
more than 99.9% of the crystals of the crystalline 5-aminolevulinic
acid hydrochloride have a particle size of 90 to 160 .mu.m.
6. The transdermal therapeutic system according to claim 1, wherein
the polymer matrix contains less than 30% by weight plasticizer,
based on the adhesive polyacrylate.
7. The transdermal therapeutic system according to claim 6, wherein
the polymer matrix contains less than 20% by weight plasticizer,
based on the adhesive polyacrylate.
8. The transdermal therapeutic system according to claim 6, wherein
the polymer matrix contains less than 5% by weight plasticizer,
based on the adhesive polyacrylate.
9. The transdermal therapeutic system according claim 1, wherein
the polyacrylate has acid functionalities.
10. The transdermal therapeutic system according to claim 1,
wherein the polymer matrix contains more than 65% by weight
polyacrylate.
11. The transdermal therapeutic system according to claim 10,
wherein the polymer matrix contains more than 70% by weight
polyacrylate.
12. The transdermal therapeutic system according claim 1, wherein
the viscosity of the adhesive polyacrylate is in the range from
1,500 to 12,000 mPas at 25.degree. C.
13. The transdermal therapeutic system according to claim 1,
wherein the adhesive polyacrylate is based on acrylic acid, butyl
acrylate, 2-ethylhexyl acrylate and vinyl acetate.
14. The transdermal therapeutic system according to claim 13,
wherein the adhesive polyacrylate is produced from a monomer
mixture containing 1 to 10% by weight acrylic acid, 5 to 25% by
weight butyl acrylate, 60 to 80% by weight 2-ethylhexyl acrylate
and 1 to 10% by weight vinyl acetate.
15. The transdermal therapeutic system according to claim 13,
wherein the monomer mixture contains 3 to 7% by weight acrylic
acid, 10 to 20% by weight by weight butyl acrylate, 70 to 78% by
weight 2-ethylhexyl acrylate and 2 to 8% by weight vinyl
acetate.
16. The transdermal therapeutic system according to claim 13,
wherein the monomer mixture contains about 5% by weight acrylic
acid, about 15% by weight butyl acrylate, about 75% by weight
2-ethylhexyl acrylate and about 5% by weight vinyl acetate.
17. The transdermal therapeutic system according to claim 1,
wherein the adhesive polyacrylate is based on acrylic acid,
2-ethylhexyl acrylate and methyl acrylate.
18. The transdermal therapeutic system according to claim 17,
wherein the adhesive polyacrylate is produced from a monomer
mixture which contains 1 to 10% by weight acrylic acid, 50 to 70%
by weight 2-ethylhexyl acrylate and 20 to 40% by weight methyl
acrylate.
19. The transdermal therapeutic system according to claim 17,
wherein the adhesive polyacrylate is produced from a monomer
mixture which contains 2 to 8% by weight acrylic acid, 55 to 65% by
weight 2-ethylhexyl acrylate and 30 to 35% by weight methyl
acrylate.
20. The transdermal therapeutic system according to claim 17,
wherein the adhesive polyacrylate is produced from a monomer
mixture which contains about 5.7% by weight acrylic acid, about
62.2% by weight 2-ethylhexyl acrylate and about 32% by weight
methyl acrylate.
21. The transdermal therapeutic system according to claim 1,
wherein the polymer matrix contains about 28% by weight crystalline
5-aminolevulinic acid hydrochloride and about 72% by weight of
adhesive polyacrylate based on acrylic acid, 2-ethylhexyl acrylate
and methyl acrylate.
22. A cancer treatment comprising the transdermal therapeutic
system according to claim 1.
23. A method of diagnosing and treating skin cancer stages
comprising applying the transdermal therapeutic system according to
claim 1.
24. The method as claimed in claim 23, wherein the skin cancer
stages are actinic keratosis and oncological skin diseases.
25. A method for treating skin cancer, said method comprising:
adhering a transdermal therapeutic system containing
5-aminolevulinic acid hydrochloride in the form of particles less
than 250 .mu.m to skin at a place affected by cancer or
precancerous lesions, allowing said 5-aminolevulinic acid
hydrochloride to dissolve via sweat from the place on the skin
where the transdermal therapeutic system is applied, transdermally
absorbing the dissolved 5-aminolevulinic acid hydrochloride and
enriching the concentration of 5-aminolevulinic acid hydrochloride
in proximity of said cancer or precancerous lesions, allowing said
5-aminolevulinic acid hydrochloride to convert into protoporphyrin
IX, irradiating said cancer or precancerous lesions enriched with
protoporphyrin IX with light of a wavelength selected from the
group consisting of 408 nm, 506 nm, 532 nm, 580 nm and 635 nm,
thereby producing reactive oxygen compounds, and allowing said
reactive oxygen compounds to induce necrosis in said cancer or
precancerous lesions.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This continuation application claims priority to U.S. patent
application Ser. No. 14/240,810, filed Jun. 18, 2014 (allowed),
which claims priority to PCT/EP2012/066541, filed Aug. 24, 2012,
which further claims priority to its parent application, German
Patent Application No. DE 10 2011 111 865.2, filed Aug. 31, 2011.
U.S. patent application Ser. No. 14/240,810, International
Application No. PCT/EP2012/066541, and German Patent Application
No. DE 10 2011 111 865.2 are each hereby incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a transdermal therapeutic
system and a transdermal active ingredient-containing plaster for
5-aminolevulinic acid hydrochloride. It also relates to the use of
a system of this type in photodynamic diagnostics and therapy.
BACKGROUND OF THE INVENTION
[0003] It is noted that citation or identification of any document
in this application is not an admission that such document is
available as prior art to the present invention.
[0004] Transdermal therapeutic systems have become widespread
nowadays as a form of administration for treating numerous
diseases, as they demonstrate certain advantages compared to
conventional forms of administration. Thus, transdermal therapeutic
systems can increase the therapeutic value of an active ingredient
as they ensure a constant dispensing thereof. The advantages of
transdermal therapeutic systems are also that, in comparison to
ointments or creams, they can be applied to the precise area and
therefore at the precise dosage. Furthermore, there is no danger of
inadvertently wiping off the ointment and contaminating other
locations on the skin.
[0005] A transdermal therapeutic system for releasing
5-aminolevulinic acid is known from EP 1 467 706 A1.
5-aminolevulinic acid is selectively absorbed and enriched by tumor
tissue, so it only leads to an increased porphyrin formation and
concentration there, while the healthy tissue remains substantially
uninfluenced. The effect of the 5-aminolevulinic acid is based on
the stimulation of the body's own porphyrin formation. As the
porphyrin strongly fluoresces upon irradiation, the
5-aminolevulinic acid or porphyrin enrichment can be used in
diseased tissue to diagnose precancerous and cancerous lesions and
for the protodynamic therapy thereof. A similar system is also
known from EP 1 303 267 A1. The two systems have the drawback that
the 5-aminolevulinic acid permeates through human skin only
comparatively poorly.
[0006] Actinic keratosis is designated an early form of white skin
cancer, as the latter in 10% of cases can develop within a period
of 10 years into a squamous cell carcinoma of the skin
(spinalioma). It is chronic damage to the horny epidermis caused by
the intensive action of sunlight (UV radiation) over many years. An
important treatment method for actinic keratosis is so-called
photodynamic therapy. An active ingredient is firstly applied here
to the affected skin region and specific light-sensitive
substances, the so-called porphyrins, increasingly form in the
diseased skin cells. As a result, the cells are sensitised to the
subsequent treatment with light and reactive oxygen is produced
(photodynamic effect), which ultimately leads to the death of the
corresponding cells. Good cosmetic results can generally be
achieved using the photodynamic therapy. The photodynamic therapy
can furthermore be repeated virtually as often as desired if the
actinic keratosis occurs again. Apart from the therapeutic effect,
photodynamic therapy also offers a diagnostic use. Using special
light, the regions affected by actinic keratosis and pretreated by
corresponding substances can be made visible in a targeted manner.
It is thus possible to recognise the actinic keratosis early and to
precisely determine the size of the locations affected
(photodynamic diagnostics).
[0007] It is noted that in this disclosure and particularly in the
claims and/or paragraphs, terms such as "comprises", "comprised",
"comprising" and the like can have the meaning attributed to it in
U.S. patent law; e.g. they can mean "includes", "included",
"including", and the like; and that terms such as "consisting
essentially of" and "consists essentially of" have the meaning
ascribed to them in U.S. patent law, e.g. they allow for elements
not explicitly recited, but exclude elements that are found in the
prior art or that affect a basic or novel characteristic of the
invention. Applicants further reserve the right to disclaim, and
hereby disclose a disclaimer of, any previously described product,
method of making the product, or process of using the product.
SUMMARY OF ADVANTAGEOUS EMBODIMENTS OF THE INVENTION
[0008] The aim of the present invention is to provide a transdermal
therapeutic system, which as quickly as possible releases an
adequate quantity of a substance into precancerous and cancerous
lesions in order to then carry out the photodynamic therapy by
means of irradiation. The transdermal therapeutic system should be
well tolerated by the skin, be flexible and adequately sticky, even
on regions that are less well accessible, such as the nasal bone or
the outer ear. Furthermore, the transdermal therapeutic system
should be stable, visually unobtrusive, easy to apply and remove
again.
[0009] The above aim is addressed by a transdermal therapeutic
system or a transdermal active ingredient-containing plaster, which
comprises a back layer that is impermeable to an active ingredient,
an active ingredient-containing polymer matrix and a protective
layer that can be pulled off, and characterised in that
5-aminolevulinic acid hydrochloride is used as the active
ingredient and in that the basic polymer of the polymer matrix is
an adhesive polyacrylate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 graphically illustrates the released quantity of
5-ALA [mg/patch] versus time [h] for several exemplary
embodiments.
DETAILED DESCRIPTION OF ADVANTAGEOUS EMBODIMENTS OF THE
INVENTION
[0011] It is to be understood that the figures and descriptions of
the present invention have been simplified to illustrate elements
that are relevant for a clear understanding of the present
invention, while potentially eliminating, for purposes of clarity,
many other elements which are conventional in this art. Those of
ordinary skill in the art will recognize that other elements may be
desirable for implementing the present invention. However, because
such elements are well known in the art, and because they do not
facilitate a better understanding of the present invention, a
discussion of such elements is not provided herein.
[0012] The present invention will now be described in detail on the
basis of exemplary embodiments.
[0013] The transdermal therapeutic system according to the
invention with 5-aminolevulinic acid hydrochloride as the active
ingredient and an adhesive polyacrylate as the basic polymer of the
polymer matrix is in a position to absorb adequately large
quantities of the suspended pharmaceutical agent, i.e. of the
5-aminolevulinic acid hydrochloride. There is good compatibility
between the adhesive polyacrylate used and the 5-aminolevulinic
acid hydrochloride. The release rate of the 5-aminolevulinic acid
hydrochloride during the application period is extraordinarily
high. Furthermore, the transdermal therapeutic system according to
the invention adheres adequately to the skin but does not irritate
it The transdermal therapeutic system according to the invention
can easily be applied, especially also to small skin regions, such
as the forehead, the outer ear or the nose.
[0014] According to a preferred embodiment, the transdermal
therapeutic system according to the invention is characterised in
that it is capable, within about four hours, preferably within
about an hour and especially preferably within about thirty
minutes, of releasing a quantity of at least 3 mg 5-aminolevulinic
acid hydrochloride (measured as 5-aminolevulinic acid with the
so-called "paddle over disc" method, as described in European
Pharmacopoeia 6.0, 2.9A "dissolution test for transdermal patches",
January 2008: 20904; see also Example 4).
[0015] The transdermal therapeutic system according to the
invention is preferably a monolithic active ingredient-in-adhesive
system (monolithic drug-in-adhesive system). 5-aminolevulinic acid
hydrochloride is suspended or dispersed directly in the polymer
matrix here. The polymer matrix carries out the three functions of
the active ingredient reservoir, the control element and the
adhesive layer in this case. A system of this type consists only of
a back layer that is impermeable to an active ingredient, an active
ingredient-containing polymer matrix and a protective layer that
can be pulled off. The polymer matrix influences the adhesion to
the skin, the storage of the 5-aminolevulinic acid hydrochloride
and its release. A system of this type leads to a plurality of
advantages during the release of hydrophilic substances, such as
5-aminolevulinic acid hydrochloride. Thus, further hydrophilic
matrix materials can be avoided, so the microbiological stability
is improved. The stability of the active ingredient is also
increased as it is chemically inactivated. It is furthermore
possible to control the release of the active ingredient by means
of the particle size.
[0016] The back layer that is impermeable to the active ingredient
is preferably inert and as flexible as possible, so the transdermal
therapeutic system can also be applied to irregular skin regions.
Any suitable material, such as, for example, polyethylene
terephthalate, polyethylene, polybutylene, polyurethane, polyester,
etc., can be used for the back layer. The back layer that is
impermeable to an active ingredient is preferably an optionally
aluminised polyester film, especially preferably a laminate made of
pigmented polyethylene with aluminium vapour-coated polyester,
which (provide) protection against light irradiation and therefore
prevent photosensitisation before the actual photodynamic
therapy.
[0017] The protective layer that can be pulled off can be produced
from various materials, such as, for example, polyethylene
terephthalate, polyethylene or polypropylene and is specially
treated on the side in contact with the active
ingredient-containing polymer matrix in order to make it as easy as
possible to remove therefrom. The protective layer that can be
pulled off is advantageously based on a polyethylene terephthalate
layer.
[0018] In a preferred embodiment, the active ingredient
5-aminolevulinic acid hydrochloride is present as a crystalline
5-aminolevulinic acid hydrochloride. This has the advantage that
the solubility of the active ingredient in the matrix does not have
to be adjusted. Furthermore, an over-saturation and a constant
diffusion pressure are thereby achieved.
[0019] In a preferred embodiment, about 50% of the crystals or
particles of the crystalline 5-aminolevulinic acid hydrochloride
are greater than the layer thickness of the polymer matrix. The
active ingredient projects, so to speak, from the matrix, which has
the advantage that on contact with the skin, especially with sweat,
the projecting crystals very quickly dissolve and can therefore be
easily and quickly transdermally absorbed.
[0020] More than 99.9% of the crystals of the crystalline
5-aminolevulinic acid hydrochloride are preferably smaller than
about 250 .mu.m. Although as the crystal size becomes larger, the
epidermal flow increases, crystals that are too large, i.e. crystal
sizes above about 250 .mu.m, lead to clumping and streak
formation.
[0021] On the other hand, it is preferred for the quantity of
crystals, which are smaller than 90 .mu.m, to make up at most 50%,
and the quantity of crystals, which are smaller than 50 .mu.m, to
make up at most 25%, of the active ingredient mass, as this ensures
a high active ingredient flow.
[0022] A transdermal therapeutic system with 5-aminolevulinic acid
hydrochloride crystals of a particle size of 90 to 160 .mu.m
exhibits a clearly improved transepidermal flow compared with a
system with particles having a particle size of less than 90 .mu.m.
This is probably because more active ingredient is released and is
therefore available for the permeation. Particle sizes in the range
from 90 to 160 .mu.m are therefore especially preferred.
[0023] The polymer matrix of the transdermal therapeutic system
according to the invention preferably contains less than 30% by
weight, preferably less than 20% by weight and especially
preferably less than 5% by weight of plasticiser, for example
citric acid esters, such as acetyl tributyl citrate, in relation to
polyacrylate. The plasticiser content in the transdermal
therapeutic system according to the invention is quite especially
preferably below 5000 ppm.
[0024] So-called enhancers or permeation promoters can also
preferably be dispensed with.
[0025] The adhesive polyacrylate can be obtained with and
advantageously without cross-linking agents (cross-linkers), such
as, for example, aluminium acetylacetonate, polybutyl titanate or
t-amyl peroxy pyrolate, etc.
[0026] The adhesive polyacrylate preferably has acid
functionalities (carboxyl groups), as they are advantageous in
relation to the adhesion. These are especially important when the
crystals of the crystalline 5-aminolevulinic acid hydrochloride are
larger than the layer thickness of the polymer matrix as whole-area
contact between the transdermal therapeutic system and the skin is
not then ensured. The adhesive polyacrylate with acid
functionalities can, for example, be obtained by polymerisation of
a monomer mixture containing an unsaturated carboxylic acid, such
as, for example, acrylic acid, methacrylic acid or maleic acid.
[0027] The monomer mixtures used to produce the adhesive
polyacrylates can also contain acrylic acid derivatives with epoxy
groups, such as, for example, glycidyl (meth)acrylate.
[0028] The polyacrylate is preferably based on acrylic esters, such
as, for example, 2-ethylhexyl acrylate. This is preferably used in
a quantity of more than 50% by weight, especially more than 60% by
weight and especially preferably in a quantity of more than 70% by
weight, based on polyacrylate.
[0029] The viscosity of the polyacrylate is preferably in the range
from 500 to 25,000, especially preferably in the range from 1,000
to 20,000 and quite especially preferably in the range from 1,500
to 12,000 mPas at 25.degree. C.
[0030] In a preferred embodiment, the adhesive polyacrylate is
polyacrylate based on acrylic acid, butyl acrylate, 2-ethylhexyl
acrylate and vinyl acetate, based on 2-ethylhexyl acrylate,
2-hydroxyethyl acrylate and vinyl acetate, based on acrylic acid,
2-ethylhexyl acrylate and methyl acrylate, based on acrylic acid,
2-ethylhexyl acrylate and vinyl acetate, based on 2-ethylhexyl
acrylate, 2-hydroxyethyl acrylate and methyl acrylate, based on
2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and methyl acrylate,
based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, vinyl
acetate, 2-hydroxyethyl acrylate and methyl methacrylate, based on
acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate,
t-octylacrylamide and vinyl acetate and based on 2-ethylhexyl
acrylate and vinyl acetate.
[0031] Adhesive acrylates based on acrylic acid, butyl acrylate,
2-ethylhexyl acrylate and vinyl acetate and adhesive polyacrylates
based on acrylic acid, 2-ethylhexyl acrylate and methyl acrylate,
the latter supplying the best results, are especially
preferred.
[0032] The adhesive polyacrylate mentioned first based on acrylic
acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate is
preferably produced from a monomer mixture, which contains 1 to 10%
by weight, preferably 3 to 7% by weight and especially preferably
about 5% by weight acrylic acid, 5 to 25% by weight, preferably 10
to 20% by weight, and especially preferably about 15% by weight
butyl acrylate, 60 to 80% by weight, preferably 70 to 78% by
weight, and especially preferably about 75% by weight 2-ethylhexyl
acrylate and 1 to 10% by weight, preferably 2 to 8% by weight, and
especially preferably about 5% by weight vinyl acetate.
[0033] The adhesive polyacrylate based on acrylic acid,
2-ethylhexyl acrylate and methyl acrylate are preferably produced
from a monomer mixture, which contains 1 to 10% by weight,
preferably 2 to 8% by weight, and especially preferably about 5.7%
by weight acrylic acid, 50 to 70% by weight, preferably 55 to 65%
by weight, and especially preferably about 62.2% by weight
2-ethylhexyl acrylate and 20 to 40% by weight, preferably 30 to 35%
by weight, and especially preferably about 32% by weight methyl
acrylate. In the case of the latter, small quantities of glycidyl
methacrylate, for example less than 1% by weight, preferably less
than 0.05% by weight, and especially preferably about 0.03% by
weight, glycidyl methacrylate can also be present.
[0034] In a preferred embodiment, the polymer matrix of the
transdermal therapeutic system according to the invention contains
more than 10% by weight and especially preferably more than 20% by
weight 5-aminolevulinic acid hydrochloride. It was experimentally
established that the release of the 5-aminolevulinic acid
hydrochloride increases within the first hour, by increasing the
active ingredient quantity from 20% by weight to 30% by weight, by
about a factor of 6.
[0035] On the other hand quantities of 5-aminolevulinic acid
hydrochloride that are too large lead to a deterioration in the
ability to adhere to the skin and to problems in the coating. It is
therefore preferred if less than 35% by weight and especially less
than 30% by weight 5-aminolevulinic acid hydrochloride is present.
The range between 25 and 30% by weight is optimal.
[0036] The quantity of the polyacrylate used in the transdermal
therapeutic system according to the invention is preferably more
than 60% by weight and especially preferably more than 70% by
weight.
[0037] In a preferred embodiment, the transdermal therapeutic
system is a monolithic active ingredient-in-adhesive system, more
than 99.9% of the crystals of the crystalline 5-aminolevulinic acid
hydrochloride are smaller than 250 .mu.m, the adhesive polyacrylate
is based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and
vinyl acetate and especially preferably on acrylic acid,
2-ethylhexyl acrylate and methyl acrylate, and the polymer matrix
contains 25 to 30% by weight, preferably about 28% by weight,
5-aminolevulinic acid hydrochloride and 70 or more % by weight,
preferably about 72% by weight, polyacrylate. A system of this type
exhibits a very rapid release of a large quantity of active
ingredient and the processability is excellent.
[0038] The transdermal therapeutic system according to the
invention is produced in a known manner. An active
ingredient-containing adhesive mass based on an adhesive
polyacrylate is firstly produced. Ethanol, ethyl acetate, heptane,
hexane, isopropyl alcohol, methanol, toluene, 2,4-pentandiene and
mixtures thereof are preferably possible solvents. Ethyl acetate
and hexane are especially preferred. Conventional coating, drying
and laminating methods and cutting follow. The solvent is almost
completely removed during the drying process. Perforation and
packaging finally follow.
[0039] The present invention also relates to the use of the
transdermal therapeutic system according to the invention for the
diagnosis and therapy of preliminary skin cancer stages, such as
actinic keratosis, and of skin cancer and oncological skin
diseases. The external application of the transdermal therapeutic
system leads to the penetration and enrichment of the active
ingredient in the diseased tissue. 5-aminolevulinic acid
hydrochloride is an endogenous compound and a precursor substance
in the biosynthesis of porphyrins, which are constituents, for
example, of the haemoglobin and the cytochrome cycle.
5-aminolevulinic acid hydrochloride is converted into the actual
photosensitiser, the protoporphyrin IX (PPlX). After the
enrichment, an irradiation takes place with adequate light, for
example with light of various wavelengths, such as, for example,
408 mm, 506 mm, 532 mm, 580 mm and 635 mm. In this case, reactive
oxygen compounds are produced, which make the target tissue visible
during the diagnosis or lead to an apoptosis and necrosis thereof
during the therapy.
[0040] The present invention also relates to a transdermal
therapeutic system, as described above, as a therapeutic agent.
[0041] Furthermore, the present invention relates to a transdermal
therapeutic system, as described above, for treating preliminary
skin cancer stages, such as, for example, actinic keratosis, and
oncological skin diseases. The transdermal therapeutic system is
preferably used to treat actinic keratosis.
OPERATIVE EXAMPLES
[0042] The subject matter of the present invention is elucidated in
more detail below, using examples and a figure, without any
intention that the subject matter of the invention should be
confined to these exemplary embodiments or figure.
Example 1
[0043] The transdermal therapeutic system produced contains the
following constituents:
TABLE-US-00001 % (% by weight/ % by weight) mg/Plaster Active
ingredient: 5-aminolevulinic 19.7 10.2 acid hydrochloride
Polymer.sup.a): DURO-TAK 49.6 25.8 387-2353 Back layer: 3M
SCOTCHPAK .TM. 30.7 16.0 1109 Protective layer: polyethylene
.sup.b) 59.0.sup.c) terephthalate layer siliconised on one side (75
.mu.m) .sup.a)in ethyl acetate and hexane, which are both virtually
completely removed during the drying process .sup.b)is removed
before application .sup.c)estimated
[0044] In relation to the polymer matrix, 28% by weight
5-aminolevulinic acid hydrochloride and 72% by weight DURO-TAK
387-2353 (polyacrylate without cross-linking agent) are accordingly
present.
Example 2
[0045] The composition of this example corresponds to Example 1,
except that instead of DURO-TAK 387-2353, the same quantity of
DURO-TAK 387-2052 (polyacrylate with cross-linking agent) was
used.
Comparative Example 3
[0046] The composition of this example corresponds to Example 1,
except that instead of DURO-TAK 387-2353, the same quantity of
Bio-PSA 4301 (a silicone polymer) was used.
Example 4
[0047] The release rate was measured using the so-called "paddle
over disc" method, as described in European Pharmacopoeia 6.0,
2.9.4. "dissolution test for transdermal patches", January 2008:
20904, under the following conditions:
Apparatus used: paddle over disc Release medium: citrate buffer pH
3.0 Volume of the release medium: 300 ml
Temperature: 32.degree. C..+-.0.5.degree. C.
[0048] Rotation frequency: 50 min.sup.-1 Sample removal time: 0.5
h, 2 h and 7 h Sample volume: 10.0 ml
[0049] The results are shown in FIG. 1. Specifically, FIG. 1 is a
graph showing released quantity 5-ALA [mg/patch] versus time [h]
for Examples 1, 2, and 3. Example 1 is acrylate (non cross-linked),
Example 2 is acrylate (cross-linked), and Example 3 is silicone
(comparative).
[0050] The release rate of a transdermal therapeutic system
according to Example 1 is higher than that according to Example 2.
Both Example 1 and Example 2 exhibit a clearly faster release
compared to comparative Example 3. Furthermore, the stability of
the 5-aminolevulinic acid hydrochloride according to Example 1
after one and three months is higher than that of the
5-aminolevulinic acid hydrochloride according to Example 2, which
is degraded more quickly.
[0051] While this invention has been described in conjunction with
the specific embodiments outlined above, it is evident that many
alternatives, modifications, and variations will be apparent to
those skilled in the art. Accordingly, the preferred embodiments of
the invention as set forth above are intended to be illustrative,
but not limiting. Various changes may be made without departing
from the spirit and scope of the inventions as defined in the
following claims.
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