Note: Descriptions are shown in the official language in which they were submitted.
2030178
DESCRIPTION
The present invention relates to a transdermal thera-
peutic system (TTS) which contains as active component
buprenorphine (17-(cyclopropylmethyl)-a-(1,1-dimethyl-
ethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-a-
methyl-6,14-ethenomorphinane-7-methanol).
Buprenorphine is a partially synthetic opiate. Com-
pared to other compounds of this class of substances,
the advantage of buprenorphine is higher effective-
ness. This means that patients suffering from cancer
or a tumor with unfavorable diagnosis in final stage
can be relieved from pain with daily doses of about 1
mg. However, buprenorphine does not solve two major
problems occuring in connection with opiates, i.e.,
the danger of habit formation and the low bioavaila-
bility of these substances in case of oral administra-
tion. For example, the bioavailability from the gas-
trointestinal tract amounts to only about 10%, and in
case of sublingual application only about 50%.
When buprenorphine was introduced as analgesic, it was
regarded as non-habit-forming. However, this initial
assumption has been corrected. In the meantime, bupre-
2 2030178
norphine is subject to the German narcotics act, afterit had been increasingly abused by addicts.
However, since quite recently, experts are of the
opinion that it is the form of administration of a
medicinal drug which contributes to the risk of ad-
diction. This can easily be understood in case of
high-potency analgesics in the therapy of extreme
paln.
Immediately after application the blood level of the
analgesic is higher than therapeutically required and
causes euphoria, however, then drastically decreases
and rapidly effects blood levels which do no longer
treat the pain successfully. Due to his pain, the pa-
tient starts to long for the next dosage - an iatro-
genic addiction is created.
In case of buprenorphine and other highly effective
opiates continuous infusion would therefore be the
most suitable kind of administration to avoid said
iatrogenic habit formation by means of constant blood
levels.
However, continuous infusion cannot be applied and
controlled without any aid of a physician during domi-
3 2~3~17~
ciliary care; inflammations frequently result at theplace where the cannula is inserted.
Even an oral depot preparation cannot be the suitable
form to administer buprenorphine, since the low bio-
availability in case of oral application requires ap-
proximately ten times the amount of active substance
compared to the required intravenous dosage. In this
connection, buprenorphine, as partial opiate antago-
nist, involves great problems, since a respiratory
depression caused by an overdosage of the active sub-
stance cannot be treated by the administration of an
antagonist, such as nalorphine which is the suitable
antidote in case of poisonings caused by opiates. Al-
though the oral bioavailability for buprenorphine is
stated to be 10%, overdosages may nevertheless occur,
since buprenorphine shall also be administered to pa-
tients with the probability of liver function disturb-
ances so that quite more than 10% of buprenorphine may
survive the first liver passage without having been
subjected to metabolism.
In addition, the development on the market for medici-
nal agents during the last years has shown that oral
depot preparations are not always suitable. Generics
having the same in-vitro-release as preparations of
2030178
the original suppliers do not have the same effective-
ness as those original preparations. This means that
overdosages and underdosages may arise due to uncon-
trolled release in vivo. Both cases are disastrous in
case of buprenorphine. In case of underdosage, the
patient suffers from intense pain. In case of over-
dosage, fatal respiratory depressions which cannot be
treated with nalorphine could be the most severe con-
sequence.
In addition, it has been left out of consideration
until now, that an oral depot preparation which became
damaged and thus does not retard buprenorphine, but
releases it at one blow (called "dosedumping" among
experts) cannot immediately be removed from the human
body.
The reservations with respect to forms of administra-
tion which release buprenorphine in a retarded manner
are avoided by the merits of the transdermal thera-
peutic systems, since the medicinal agent need not be
administered to the human body via cannulae so that it
can be applied even by nonprofessionals. At the same
time, active substance supply according to O.order is
safeguarded; the supply may be interrupted at any time
by tearing the system off. Thus, transdermal therapeu-
2030178
tic systems seem to be the most suitable form to ad-
minister buprenorphine.
However, one has to consider the objection that bupre-
norphine only badly penetrates through the human skin.
This is due to its high molecular weight (m.w. 468)
and - above all - its high melting point and very
slight solubility in conventional organic solvents and
water, and diffusion which is the precondition for
penetration through human skin requires dissolved sub-
stances.
On the other hand, the solubility must not be increas-
ed by salt formation, since bases in ionized form are
not absorbed.
Until today, all attempts failed to bring buprenor-
phine on a transdermal basis to a resorption in the
required amount, although - for the reasons described
above - a TTS is the most suitable form of administra-
tion for this active substance.
It is accordingly the object of the present invention
to provide buprenorphine or one of the pharmaceutical-
ly compatible salts thereof in the form of a transder-
mal therapeutic system which releases buprenorphine or
the pharmaceutically acceptable salt thereof over a
period of at least 24 hours in a controlled manner and
20~0178
ensures that the buprenorphine does not notably decom-
pose when the prefabricated transdermal therapeutic
system is stored, and which further ensures that bu-
prenorphine, which insufficiently passes through skin,
in vivo penetrates through the skin at the required
amount.
According to the present invention this object is
achieved in a surprising manner by a transdermal ther-
apeutic system for the administration of buprenorphine
to the skin. The system comprises a backing layer
which is impermeable to the active substance, a pres-
sure-sensitive adhesive reservoir layer, and, option-
ally, a removable protective layer, and is character-
ized in that the reservoir layer comprises 20 to
90%-wt polymeric material, 0.1 to 30%-wt softener, 0.1
to 20%-wt buprenorphine base or one of the pharmaceu-
tically acceptable salts thereof, and 0.1 to 30%-wt
solvent for the active substance base.
This solution is surprising all the more since bupre-
norphine has a bioavailability of only 50% when admin-
istered sublingually. Since the first liver passage is
evaded by this mode of application, the low bioavaila-
bility can only be due to insufficient absorbability
of the substance by the oral mucosa. However, a sub-
7 203~1 7~
stance which only hardly passes the mucosa of themouth, will be absorbed by the human skin even harder.
The backing layer which is impermeable to the active
substance may consist of flexible or inflexible mate-
rial. Substances suitable for the production of the
backing layer are polymeric foils and metal foils,
such as aluminum foil which may be used alone or
coated with a polymeric substrate. Textile fabrics may
be used too, if the components of the reservoir cannot
penetrate the fabric due to their physical properties.
In a preferred embodiment of the present invention the
backing layer is a composite material of an aluminized
foil.
The reservoir layer consists of a polymeric matrix and
the active substance, whereby the polymeric matrix en-
sures the coherence of the system. The polymeric mat-
rix consists of a basic polymer and, optionally, con-
ventional additives. The selection of the basic poly-
mer depends on the chemical and physical properties of
the buprenorphine. Examples of polymers are rubber,
rubber-like synthetic homo-, co- or blockpolymers,
polyacrylic esters and the copolymers thereof, poly-
urethanes and silicones. In principle all polymers are
suitable which can be used in the production of pres-
8 203~I78
sure-sensitive adhesives and which are physiologically
acceptable. Particularly preferred are those consist-
ing of block copolymers based on styrene and 1,3-
dienes, polyisobutylenes, polymers based on acrylate
and/or methacrylate.
Amongst the blockcopolymers based on styrene and 1,3-
dienes, linear styrene-isoprene-blockcopolymers or
styrene-butadiene-blockcopolymers are particularly
used.
Self cross-linking acrylate copolymers of 2-ethyl
hexyl acrylate, vinyl acetate, and acrylic acid with
titanium chelate ester, or non-self-cross-linking ac-
rylate copolymers without titanium chelate ester are
preferred for the use as acrylate-based polymers.
Suitable polymers which are added to the basic polymer
are polymethacrylates, esters of hydrogenated colopho-
ny, and polyvinyls.
Copolymers based on dimethylaminoethyl methacrylates
and on neutral methacrylic esters are preferably used
as methacrylates. The methylesters and glycerol esters
of hydrogenated colophony are particularly preferred
for the use as esters of hydrogenated colophony. Poly-
203~78
vinylpyrrolidones and polyvinyl alcohols are prefer-
ably used as polyvinyls.
The kind of common additives depends on the polymer
used: According to their function they can be divided,
e.g.l in tackifiers, stabilizers, carrier substances,
and fillers. The physiologically acceptable substances
suitable for this purpose are known to the skilled ar-
tisan.
According to the present invention it turned out that
a softening agent combined with a solvent for bupre-
norphine is required to permit transdermal application
of buprenorphine.
The choice of softener depends on the polymer. Higher
alcohols, such as dodecanol, undecanol, octanol, the
esters of carboxylic acids whereby the alcohol compo-
nent may also be a polyethoxylated alcohol, diesters
of dicarboxylic acids, such as di-n-butyladipate and
triglycerides, particularly medium-chain triglycerides
of the caprylic/capric acids of coconut oil, have
proved to be particularly suitable. Further examples
of suitable softeners are multivalent alcohols, for
example, glycerol and 1,2-propanediol, which can also
be etherified by polyethylene glycols.
203~78
- -
The significance of the buprenorphine solvent is
proved by the examples. The examples show that the
solvent is an indispensable component of the formula-
tion. The combination softener/solvent according to
the teaching of the present invention builds the pre-
condition for the penetration of the buprenorphine
base through the skin.
Suitable solvents for buprenorphine within the matrix
are those with at least one acidic group. Particularly
suitable are the monoesters of dicarboxylic acids,
such as monomethyl glutarate and monomethyl adipate.
In principle all acids are suitable which dissolve bu-
prenorphine to a sufficient extent thereby avoiding
complete salt formation. In the latter case, penetra-
tion through the skin can no longer be expected.
Permanent contact to the skin is ensured by a suffi-
cient self-adhesiveness of the reservoir layer.
The removable protective layer which is in contact
with the reservoir layer and removed prior to appli-
cation, for example, consists of the same materials as
used for the production of the backing layer provided
that they are rendered removable, for example, by a
11 ~o~al7s
silicone treatment. Other removable protective layers,
for example, are polytetrafluoroethylene, treated pa-
per, cellophane, polyvinyl chloride, and the like. If
the laminate according to the present invention is
divided into formats suitable for the therapeutical
purpose (plasters) prior to application, the dimen-
sions of the protective layers to be applied thereto
may have a projecting end with the help of which the
protective layer can be removed from the plaster more
easily.
The transdermal therapeutic system according to the
present invention is produced by mixing homogeneously
the active substance together with the components of
the pressure-sensitive adhesive reservoir layer, op-
tionally in solution, and spreading it on the backing
layer, which is impermeable to the active substance,
whereupon the solvent/s is/are removed, if necessary.
Subsequently, the adhesive layer is provided with an
adequate protective layer.
In principle, the reverse way is possible too, i.e.,
that the adhesive solution is spread on the protective
layer. The solvents are removed too, and it is covered
with the backing layer.
12 2030178
The invention is illustrated by the following exam-
ples:
ExamPle I:
10.0 9 each of glutaric acid monomethyl ester, methan-
ol, and butanone, and 15.0 9 1-dodecanol are mixed
under stirring. Subsequently, 10.0 9 buprenorphine
base are added; it is stirred until the solid sub-
stance is completely dissolved (approximately 30 min.,
visual control). Then 133.0 9 of a self cross-linking
acrylate copolymer of 2-ethyl hexyl acrylate, vinyl
acetate, and acrylic acid 46% in a solvent mixture
(ethyl acetate : heptane : isopropanol : toluene: ace-
tylacetone 37 : 26 : 26 : 4 : 1) are added under stir-
ring; homogenization follows. Subsequently, 1.3 9 alu-
minum acetylacetonate are additionally added, and it
is stirred at room temperature for 3 hours. The evapo-
ration loss is compensated.
189.3 9 52.8%-wt of active substance-containing adhe-
sive solution are obt~ined which is spread on an alu-
minzed and siliconized polyethylene foil by means of a
350 ~m coating bar. After the solvents have been re-
moved by drying to 60C for 30 min., the adhesive film
is covered with a polyester foil of 15 ~m thickness.
An area of 16 cm2 is punched by means of suitable cut-
_ 13 203a~7~
ting tools, the edges are separated off. The releaseof this example and that of the other examples are
shown in the table. The table shows both the control-
led release into physiological saline and through
excised rodent skin.
All further examples are carried out according to the
pattern given in Example I. At first the liquid compo-
nents are mixed, then the buprenorphine base is added.
After dissolution of the buprenorphine base, optional-
ly a methacrylate copolymer based on dimethylamino-
ethyl methacrylate and neutral methacrylic esters is
added, and, after dissolution thereof, the adhesive
solution is added. The following table shows the com-
ponents of the formulation after drying. Their mean-
ings are as follows:
Acrylate: Acrylate copolymer of 2-ethyl hexyl
acrylate, vinyl acetate and acrylic
acid
Semi-ester: Monomethylester of glutaric acid (in-
dicated by G) or adipic acid (indicated
by A)
G.L.: Polyethoxylated glycerol with C8 /Ct O -
ethoxy groups
polymeric b: copolymer with basic character based
_ 14 2~30~7Y
additives: on dimethylaminoethyl methacrylate and
neutral methacrylic esters;
n: copolymer with neutral character
based on methacrylic methylester and
methacrylic butyl ester;
PVP: polyvinylpyrrolidone
The in-vitro-release was determined in a shaking-wa-
ter-bath at 37C. The acceptor medium was 100 ml phys-
iological saline which was completely renewed after 2,
4, and 8 hours. The concentration was determined by
HPLC after 2, 4, and 8, and 24 hours. The penetration
through the mice skin was measured on the basis of
Franz' diffusion cells.
The release curves according to Example 1 are illus-
trated in Figure 1 and 2.
2030 1 78
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INTERPRETATION OF THE IN-VITRO-RESULTS
Examples VII, XIV, and XVII prove the necessity of in-
corporating into the transdermal systems a solubilizer
with at least one acidic group, since the in-vitro-
penetration apparently decreases drastically, if such
a solubilizer is not present. In these examples the
in-vitro-penetration amounts to 0.l mg/2.54 cm2 x h.
At the same time, Examples I and XXI demonstrate that
it is nearly of no importance whether glutaric acid-
or adipic acid monomethylester is used. Example XII
proves that a softener has to be added to the solubil-
izer, since in the absence of a softener the in-vitro-
penetration amounts to 0.22 mg/2.54 cm2 x 24 h, and
thus is only slightly above the systems without sol-
ubilizer.
Examples XIV, XIII, XX, and XVIII serve to examine the
influence of the quantity of the semi-esters on the
in-vitro-penetration; the semi-ester portion was in-
creased (succession of Examples as stated above) from
0% over 2.5% and 5% to 10%. Due to this, the in-vitro-
penetration at the mice skin increased from 0.1 over
0.48 and 0.64 to 0.84 mg/2.54 cm2 x 24 h. When semi-
esters are added, the increase of the in-vitro-pen-
203~8
_ 17
etration is nearly linear. This is illustrated by the.following Figure 3.
The comparison of Examples X and XI shows that 1-dode-
canol is preferably used as softener. The other Exam-
ples show the influence of the polymeric additives on
the in-vitro-penetration - the use of these substances
is necessary to ensure film formation, adhesiveness,
adherence, and coherence.
It is understood that the specification and examples
are illustrative but not limitative of the present in-
vention and that other embodiments within the spirit
and scope of the invention will suggest themselves to
those skilled in the art.
