Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02523734 2005-10-26
WO 2004/096191 PCT/EP2004/004224
Pharmaceutical Composition in the Form of a Hydrogel for Transdermal
Administration of Active Ingredients
The invention relates to a pharnlaceutical composition in the fonn of a
hydrogel, with
whose help active ingredients (pharmaceutical substances), especially steroid
hormones and
their derivatives, can be administered transdermally. In a preferred
embodiment, the hydrogel
contains propylene carbonate, ethanol and 7a-methyl-11(3-fluoro-19-
nortestosterone (eF-
MENT). The invention also relates to a pharnnaceutical composition in the fonn
of a
hydrogel, which has special physical properties, especially increased sweat
resistance, and can
therefore be applied especially well to the skin.
The systemic administration of steroid hormones can be carried out in
principle with
an oral method with the aid of suitable dosage fonns. The bioavailability in
oral
administration is frequently reduced, however, since the active ingredients
are metabolized in
the liver before they pass into the systemic blood circulation (so-called
"first-pass
metabolism"). Also, special requirements are generally set on the dosage forms
in the case of
oral administration, since the release of steroid honnones should be carried
out as unifonnly
as possible over an extended period. To avoid the oral administration of
steroid honnones,
certain steroid derivatives were developed that are suitable in particular for
injection. In this
respect, reference can be made to, for example, the publications WO 99/67270
and WO
99/67271. Another possibility, to administer the steroid hormones continuously
and
bypassing the first-pass effect, consists in the use of suitable implants.
Implants for
administering androgens and their derivatives are disclosed in, for example,
the following
publications: EP-A 970 704, WO 97/30656, WO 99/13883, WO 00/28967, US
5,733,565, K.
Sundarain et al., Annuals of Medicin.e, 1993, 25 (2), 199; R. A. Anderson et
al., J. Clin.
CA 02523734 2005-10-26
Endocrin. &. Metab., 1999, 84(10) 3556 and J. Suvisaai-i et al., Conti-
aception, 1999, 60(5),
299. These implants have the drawback, however, that thev must be inserted in
patients by
an oper-.:.ive intervention by a physician and must be removed again. Such
operative
interventions always entail a certain risk of infection. Also, there exists in
the population a
basic aversion to such dispensing methods, especially if alternative processes
for systemic
administration are available.
To avoid the phai-macological drawbacks of oral administration, on the one
hand, and
the drawbacks of invasive, purely mechanical penetration of the skin with the
aid of medical
instruments (hypodermic needles, scalpels), on the other hand, processes were
developed with
whose aid the active ingredient continuously diffuses through the skin over a
specific time
span and thus enters the systemic blood circulation.
The skin represents the largest organ of the human body with a surface area of
approximately 20,000 cm2 and receives approximately one third of the entire
blood supply in
the organism (cf. Y. W. Cliien, Logics of Transdermal Controlled Drug
Admin.istration. Drug
Dev. Ind. Pharin. 1983, 9, 497). It primarily exerts protective functiolis: it
prevents the
penetration of foreign substances and microorganisms and the loss of essential
endogenic
substances such as water and electrolytes. The skin, however, does not fonn
any fully
impermeable barriers for exogenic substances, such that active ingredients can
be taken up
transcutaneously in the organism via different methods. The percutaneous
permeability is
decisively influenced by the site of administration and by the thickness of
the horny layer,
which represents the main barrier for foreign substances. While hydrocortisone
is taken up as
a model substance on hand surfaces and the soles of the feet to a lesser
extent, the uptake rate
through the skin of the retro-auricular region and the scrotum is increased up
to 40x compared
to the lower arm (cf. H. Asche, Konzept und Aujbau transderfnaler
therapeutischer Systerne
[Concept and Design of Transdermal Th.erapeutic Systenzs]. Schweiz
[Switzerland]. Rundsch.
Med. Prax., 1985, 74, 3).
CA 02523734 2005-10-26
An active ingredient can thus act transdennally, but it must diffuse through
the
epidermis of the skin in an adequate amount and be taken from the blood
circulatioii. In this
case, the epidern-iis exerts an intensive barrier function, which can be
attributed, on the one
hand, to the fact that the relevant active ingredient must pass in succession
through
hydrophilic and lipophilic layers and then again hydrophilic layers, but, on
the otller hand, the
low water content in the stratum corneum also hampers the diffusion of active
ingredients.
The permeation of the hornv laver that is necessary for a systemic action and
also for
the action of the active ingredients to be administered externally in most
cases is carried out in the undamaged skin in a transepidermal manner (in an
intercellular or transcellular manner)
and tlirough pores.(in a transglandular or transfollicular manner) (cf. K.
Karzel et al.,
Mechanisnien transkutaner Resorption - Pharmakologische und biochernische
Aspekte
[Mechanisms of Transcutaneous Resorption - Pharrnacological and Biochemical
Aspects].
Arzneim. -Forsch. Drug Res. 1989, 39, 1487).
Conceptually, the penetration of an active ingredient can be distinguished
from the
permeation of an active ingredient: penetration means that the active
ingredient gets into the
skin, while in the case of permeation, the active ingredient goes through the
skin into the
blood streain. For systemic administration of active ingredients via the blood
circulation, a
penneation is therefore necessary.
For transdermal administration, active ingredient-containing patches were
developed
with whose aid the active ingredients can pass into the systemic blood
circulation. By
diffusion, the active ingredient passes into the tissue that lies beneath the
skin and is released
to the blood vessels, such that it can exert its effectiveness systemically.
Active ingredient-containing patches have the drawback, however, that they are
applied noticeably and visibly to the skin for the period of the
administration of the active
ingredient. Also, the cover film of the patch provides occlusion conditions.
The swelling of
the skin that is produced in this respect can result in altered diffusion
conditions for the active
CA 02523734 2005-10-26
4
ingredient. The active ingredient is incoinpletely released to the skin in
most patch t~pes.
The removal of the patch occasionally causes the patient pain, since the body
hair adheres to
the adhesive surfaces of the patch and thus hair is tom out by the roots when
the patch is
removed. Also, transdermal patches have the drawback that the contact adhesive
that is used
in the patients frequently produces allergies and skin irritations. Also, the
repeated sticking
and tearing-off of the active ingredient-containing patch with repeated use on
the same skin
parts can result in skin reddening and irritation over time.
Ai1 essential drawback of active ingredient-containing patches also consists
in the fact
that they are limited in their contact surface area on the skin. Since,
however, comparatively
high plasma concentrations are necessary for the effectiveness of many active
ingredients, the
latter, however, can be achieved only with large-area administration of the
active ingredient
through the skin; active ingredient-containing patches quickly reach their
limits. This is
especially the case when a specific active ingredient shows an unfavorable
permeation
behavior, which can be compensated only by a corresponding large-area skin
contact. In
general, the assuniption can be made that patches with a size of more than 50
cm2 are only
conditionally suitable for use. Since, in active ingredient-containing
patches, the surface area
of the system is limited, only highly potent active ingredients can be used,
whose active
plasma levels lie in the range of ng/ml. Relative to other details, for
exanlple, reference can
be made to K. H. Bauer et al, Lehrbuch der pharmazeutischen Technologie
[Textbook for
Pharinaceutical Technology], N~issenschaftliche Verlagsgesellschaft mbH
Stuttgart, 1999, 6th
Edition.
As an alternative to the active ingredient-containing patches, active
ingredient-
containing gels were developed that are applied to the skin and dry on the
skin surface within
a short time. The drying is carried out, on the one hand, by evaporating the
solvent,
depending on the type of solvent that is used, but it is also possible that at
least a certain
CA 02523734 2005-10-26
portion of the solvent penetrates selectively from the gel in the skin
directly after the Qel is
applied.
Active ingredient-containing gels, which contain a polymer matrix, are
distinguished
in that after the drying on the skin, a thin film that consists of the
polyiner matrix remains, in
,%NThich the active ingredient and the other non-volatile components of the
2e1 are embedded.
In the dry state, the pol5iner matrix controls the diffusion of the active
ingredient through the
skin and thus makes possible a controlled release to the organism over an
extended time span.
Such a controlled, time-monitored and continuous release of the active
ingredient to the blood
circulation is desirable especially in honnones and hormone derivatives, such
that these active
ingredient-containing gels are especially suitable for administering such
active ingredients.
By bypassing the gastrointestinal tract in the case of transdermal
administration, the
disadvantageous first-pass metabolism is also avoided.
The dosage of the active ingredient can be easily controlled by varying the
amount of
gel and the surface area on which the gel is applied. The duration of action
of active
ingredients with short biological half-lives can be extended in this way. In
the case of active
ingredients with a narrow therapeutic range of action, side effects diminish,
and patient
compliance is also frequently better.
Active ingredient-containing gels represent true one-phase systems. These are
semisolid systems in which liquids are solidified by gel skeleton formers.
Hydrogels and oleo
gels are differentiated depending on whether the liquid that forms the gel is
water or an oil.
The hydrogels consist of an aqueous active ingredient solution that is
solidified into a gel
primarily with macromolecular hydrophilic substances. As gel skeleton formers,
organic
polymers, but also inorganic substances, such as, e.g., bentonite and highly
disperse silicon
dioxide, can be used. Oleo gels are oils that had been stiffened with gel
skeleton formers.
Hydrogels are distinguished from ointments, i.a., in that ointinents are
preparations
that do not contain any aqueous phase. Hydrogels are distinguished from creams
in that they
CA 02523734 2005-10-26
6
do not contain any lipid phase. Relative to further details for limiting the
hydrogels of other
semi-solid dosage forms, reference can be made to, for exainple, K. H. Bauer
et al, Lehrbuch
der ph.arniazeutischen Technologie, U'issenschaftliclze t'eT-lagsgesellsch.af
mbH Stuttgart,
1999, 6`h Edition.
Relative to active ing-redient-containing patches, gels have the advantage
that after
drying on the skin, only a thin film from the components of the gel remains,
which cannot
immediately evaporate or penetrate the skin. By drying, a very close contact
between the
outside skin layer and the gel residue is produced, and pores and extremely
small bumps on
the skin are reached by the fluid gel, which can be achieved only with
difficulty with active
ingredient-containing patches. Stretching of the skin, which is caused by
movements of the
patient, is not a problem because of the elasticity and the adhesion of the
gel residue over the
entire contact surface. Such stretching of the skin in the case of active
ingredient-containing
patches, however, frequently results in an undesirable lateral movement of the
contact surface
of the patch and the outer skin layer. The patient does not feel the active
ingredient being
taken up, and his physical movements are also other-wise in no way unimpaired.
The gels can
also be applied on a large area of the skin, such that active ingredients,
which are unsuitable
for active ingredient-containing patches, can also be administered
transdermally. This is an
essential advantage of the gels compared to the patches. After the release of
active
inb edients is completed, the thin film residue, which remains on the skin,
can be washed off
with water. Skin irritations are generally less than with transdermal patches,
nevertheless they
produce a problem with many hydrogels, especially since these gels have
considerable
amounts (about 70% in hydrogels used at this time) of ethanol to improve the
permeation.
The high ethanol content is necessary to ensure good permeation but results in
skin irritations.
In addition to the compatibility and the good permeation, specific physical
requirements are also set on active ingredient-containing gels. Their
consistencies must be
constituted such that they can be easily applied to the skin and have enough
gel strength that
= CA 02523734 2005-10-26
7
the gel skeleton is maintained, while the volatile components evaporate or are
drawn into the
skin. The amount of gel that must be applied to the skin per dosage unit is
usually 1-5 ml. In
the prior art, polyacrylic acid-based gels are known that experience an
imniediate partial
liquefaction upon skin contact. The reason for this is the deficient
electrolyte tolerance of
these gel systems. Owing to salts in the hydrolipid film on the skin, this
effect causes the
products to quickly run off or drip off. Special problems also arise if the
skin surface contains
large concentrations of salt and is moist because of perspiration. The
application behavior
that is problematical in nature is especially disadvai.tageous against the
backdrop that in the
administration of highly potent steroid hormones, a specific use is necessary
at its destination.
In addition to the effectiveness, in this connection safety (risk of
containination) also plays a
role.
Co7npared to the polyacrylic acid-based gels, the use of cellulose derivatives
as
hydrogel formers that is also known in the prior art has the drawback of
deficient sensory
properties as well as larger amounts of residues of the gel former on the
skin. The
concentrations needed to form a gel skeleton are 2-3x higher compared to
polyacrylates and
produce a so-called "eraser effect" (rippling) after application on the skin.
These residues are
also undesirable for appropriate use of a hydrogel for transdermal
administration of active
ingredients.
US 6,010,716 discloses a pharmaceutical composition for transdermal
adininistration
that comprises a polymer matrix that fonns a flexible film after drying. The
polymer matrix is
selected from cellulose polyiners or cellulose copolyiners or vinyl
pyrrolidone/vinyl acetate
copolymers.
Various requirements are linked to the physical and chemical properties of
active
ingredients that are suitable for a transdennal therapy with the aid of gels.
The molecular
weight should be less than 1000 ginol-I . The substance should be lipid-
soluble, but also
exhibit a certain solubility in aqueous media. As active ingredients that are
suitable in
CA 02523734 2005-10-26
8
principle for transdermal adniinistration because of their physical and
chemical properties,
steroids are especially advantageous from the pharmacological standpoint. In
tllis case, these
are in particular steroids with androgenic action (androgens).
In many cases, the addition of a permeation enhancer is necessary for
achieving the
plasma concentration that is adequate for the action. Many permeation
enhancers were
examined for this purpose, and reference can be made to, for example, E. W.
Smith et al.,
Percutaneous Penetration Enhancers, CRC Press, 1995.
Various compositions for traiisdermal administration of steroid horinones,
i.a., certain
androgens (especially testosterone), are known in the prior art and are
disclosed in, for
exanlple, WO 96/08255, WO 97/03698, WO 97/43989, WO 98/37871, WO 99/13812, WO
00/7113 3, WO 02/066018 and A. W Meikle et al, J. Clin. Endocrin. & Metab.
1992, 74, 623.
A common feature of the coinpositions for transdermal administration that are
described in
the publications above is that the steroid honnone in combination with at
least one permeation
endlancer is administered only to ensure that the active ingredient penneates
through the skin
at all. As examples of known permeation enhancers that are described for
testosterone, fatty
acids, fatty acid esters with simple alcohols, fatty acid monoesters with
multivalent alcohols,
fatty alcohols and teipenes can be mentioned.
There is an essential difference between active-ingredient-containing patches
and
active-ingredient-containing gels, such that it cannot be concluded that a
permeation enhancer
that is suitable for an active ingredient-containing patch is also suitable
for an active-
ingredient-containing gel. This is thus associated with the fact that, i.a.,
active ingredient-
containing gels dry after application on the skin, while in active ingredient-
containing
patches, a back layer that is impermeable to the solvent normally prevents a
drying-out.
Active ingredient-containing patches sometimes contain in their interior a
gelled core
in which the active ingredient and some adjuvants are embedded. In this
connection,
reference can be made to, for example, publication EP-A 208 395. Such gelled
cores of active
CA 02523734 2005-10-26
9
ingredient-containing patches cannot be compared with active ing-redient-
containing gels,
wliich in this respect are intended to be applied to the skin, in their
properties for the above-
mentioned reasons, however.
Currently, in practice oniy those active ingredient-containing gels that
contain large
ainounts of ethanol (70% by weight and more) are used since it is assumed that
with smaller
amounts of ethanol, the necessary permeation rates cannot be reached. Gels
with lower
ethanol contents are described but are not used in practice because of their
low permeation
rates. The problems associated with the high ethanol content, such as
reddening, swelling and
pennanent damage and tears in the skin, are tolerated. In the prior art, a
start is made from the
fact that low-molecular alkyl alcohols, such as, e.g., ethanol, increase the
fluidity of the
liquids in the stratum corneurn or extract lipids from the str=atum corneum
and thus enhance
the pe~-meation of the active ingredient through the skin.
EP-A 811 381 discloses a gel that contains an estrogen and/or a progestin, a
linear
aliphatic primary alcohol with 11-19 carbon atoms, a monoalkyl ether of
diethylene glycol, an
alcohol with 2-4 carbon atoms, glycol, water, a polymer or copolymer that
consists of acrylic
acid and a tertiary amine. Such gels have in particular, however, the drawback
that the
permeation properties for many active ingredients are not completely
satisfactory. The
permeation properties of these formulations can be improved by the water
content being
reduced and the content of alcohol being increased, but this does not
necessarily lead to a
reduced coinpatibility.
A problem that also occurs when using transdennal gels consists of the fact
that
phannaceutical compositions in the form of hydrogels often run off after
application on the
skin, by which the gel skeleton that is necessary for the controlled release
of the active
ingredient is destroyed and possible dripping-off of the product both reduces
patient
compliance and increases the probability of contamination of inappropriate
areas or objects.
This problem occurs in normal skin conditions. It occurs to an especially
great extent if the
CA 02523734 2008-04-14
hydrogels are applied to "sweaty" skin, such that with known and commercially
available
gels, it is required that the skin be basically cleaned before the gel is
applied. A hydrogel
should preferably also remain intact, however, if it is applied to skin that
is not completely
sweat-free.
Treatment with transdermal gels is frequently a long-term therapy, especially
in the
case of the administration of steroids. For the success of such treatments, in
addition to the
effective administration of the active ingredient (a high penneation rate),
patient compliance
is decisive. If a patient breakg off the treatment or does not perform it
regularly, because the
administration of the gel is considered too expensive (e.g., because the skin
must be cleaned
in a special manner or clothing can be soiled) or because intolerance occurs,
the entire success
of treatment is called into question.
For a treatmerit with transdermal gels, in addition to a high permeation rate,
as linear a
permeation as possible is advantageous to maintain as constant an active
ingredient level in
the blood as possible over an extended period.
There is thus a need for pharmaceutical compositions that are suitable for
transdermal
administration of active ingredients and that exhibit advantages compared to
the compositions
of the prior art, especially hydrogels for transdermal administration of
active ingredients (so-
called "transdermal gels") that associate an excellent compatibility with very
good permeation
properties.
According to the invention, a hydrogel is available as it is defined in the
claims and
that combines excellent compatibility with outstanding permeability. In a
preferred
embodiment, the hydrogel can also be applied to the skin with a pronounced
hydrolipid film,
without rapid running-off and dripping-off of the hydrogel resulting.
It was found, surprisingly enough, that with the aid of a pharmaceutical
composition in
the fonn of a hydrogel, which contains a carbonic acid diester, a C2-C4 alkyl
alcohol, an
active ingredient and a polymer matrix, skin irritations and other side
effects can be
CA 02523734 2008-04-14
11
effectively reduced. At the same time, very good results relative to the
permeation behavior
of different active ingredients are achieved with these compositions.
Pharmaceutical compositions that contain carbonic acid diesters, especially
propylene carbonate, are known in the prior art.
WO 98/10742 discloses a single-phase, anhydrous preparation for topical use,
which
contains propylene carbonate, at least one alcohol, glycol, glycerol and a
therapeutically or
cosmetically effective component. The composition is completely anhydrous, and
the active
ingredients can quickly penetrate the skin. A permeation is not provided,
however.
WO 00/41702 discloses a preparation for external use, which contains a 21 -
alkoxy
steroid, propylene carbonate and polyoxyethylene/hardened castor oil. The
composition is
suitable for topical administration of steroids for the purpose of treating
skin diseases, such as,
e.g., chronic or acute eczema, atopic dermatitis, contact dermatitis and
psoriasis.
JP 590 70 612 discloses a gelled ointment base, which contains a carboxyvinyl
polymer, propylene carbonate, propylene glycol, polyethylene glycol and
ethanol. The
ointment base can contain isopropyl adipate to enhance the penetration of the
active
ingredient in the skin. Also here, no permeation is to take place.
JP 91 94 396 discloses a composition that comprises an antihistamine, a
polymer
based on an aminoacrylate, an acid-soluble polymer and a short-chain ester or
ether with a
total of 4-20 carbon atoms, such as, e.g., isopropyl myristate, triacetin-
ethyleneglycol-
mononormalbutyl ether or propylene carbonate. The composition can be used as a
matrix for
a patch.
US 3 924 004 discloses a composition for topical use, which contains a
saturated fatty
alcohol with 16-24 carbon atoms, propylene carbonate, glycol, a surfactant, a
plasticizer, and
water. The composition can be used for topical administration of all types of
active
ingredients, especially anti-inflammatory corticosteroids. The stability of
the composition is
improved if the composition contains no water.
CA 02523734 2008-04-14
12
EP-A 319 555 discloses a transdermal pharmaceutical preparation that has a
therapeutic effect and that can be applied as a spray on the skin. The
preparation contains a
polymer liquid matrix that hardens into a flexible fihn, an active ingredient,
a solvent that
controls the release of the active ingredient, in which the active ingredient
is at least partially
soluble, and a solvent for the matrix that evaporates on the skin. As the
solvent that controls
the release of the active ingredient, sorbitan macrogol laurate andlor paraffm
and/or mid-chain
fatty acid diglycerides and/or triglycerides and/or propylene carbonate are
disclosed. The
preparation is anhydrous.
None of these*publications discloses a phannaceutical composition in the form
of a
hydrogel, which contains a carbonic acid diester, a C2-C4 alkyl alcohol, an
active ingredient
and a polymer matrix. The use of carbonic acid diesters (e.g., of propylene
carbonate) as
permeation enhancers for active ingredients in pharmaceutical compositions in
the form of
hydrogels, which contain a polymer matrix and a C2-C4 alkyl alcohol, is also
not described in
the prior art.
It was found, surprisingly enough, that when using a carbonic acid diester as
a
permeation enhancer for the active ingredient, the content of the C2-C4 alkyl
alcohol in the
composition can be kept relatively low, without in this case having negative
effects on the
permeation behavior. Special importance is given to the carbonic acid diester
within the
composition, since immediately after the pharmaceutical composition is
applied, the water
and the CZ-C4 alkyl alcohol largely evaporate and are drawn into the skin,
while the less
volatile carbonic acid diester remains together with the active ingredient in
the polymer
matrix and thus decisively influences the pharmacokinetic behavior of the
active ingredient.
It was found that carbonic acid diesters are especially compatible and
chemically
stable, normally do not cause any allergic reactions and interact well with
the additional
contents that are contained in the pharmaceutical composition, in particular
with the water and
the C2-C4 alkyl alcohol that are contained in the hydrogel. The proportion by
weight of the
CA 02523734 2008-04-14
13
carbonic acid diester, the water contained in the composition and the C2-C4
alkyl alcohol
can be selected such that the amount of the C2-C4 alkyl alcohol and the side
effects caused by
the latter are mininzized, but simultaneously, nevertheless, very good
permeation efficiency
for the active ingredient is achieved.
The carbonic acid diester according to the invention is a chiral compound,
such that
the latter is preferably in racemic form. It is also possible, however, that
the composition
according to the invention contains the carboxylic acid diester in
concentrated form of an
enantiomer or diastereomer.
The carbonic acid diester preferably exhibits a molecular weight of less than
750
gmol', more preferably less than 500 grnol-', and especially less than 250
gmor'. The
carboxylic acid diester preferably contains no more than 12, but preferably no
more than 10,
and preferably no more than 7, especially no more than 5, carbon atoms.
In a preferred embodiment according to the invention, the carbonic acid
diester is a
compound of general formula (I)
R:ol~o.R 2 lt)
in which either R' and R2, independently of one another, are CI-C6-alkyl, C2-
C6-alkenyl, C2-
C6-alkinyl, C4-C6-cycloalkyl, Cl-C6-heterocycloalkyl, phenyl, Cl-C6-
heteroaryl, phenyl-Cl-
C4-alkyl or CZ-Clo-heteroarylalkyl, whereby the alkyl-, alkenyl- and alkinyl
groups optionally
can be interrupted in each case up to three times by oxygen atoms andlor
sulfur atoms, or R'
and R2, independently of one another, have one of the above-mentioned meanings
and are
connected to one another via a C-C bond. If R' and R2 are connected to one
another via a
C-C bond, the compound of general fonnula (I) is a cyclic carboxylic acid
diester. The Cl-
C6-heterocycloalkyl-, Cl-C6-heteroaryl- and C2-Clo-heteroarylalkyl groups can
contain in the
heterocyclic compound I to 4 heteroatoms, which are selected independently of
one another
from N, 0 and S.
' =" CA 02523734 2005-10-26
14
Preferred radicals Rl and R' (in which the alkyl groups optionally are
interrupted up to
three times by oavaen atoms andior sulfur atoms) are presented below:
C) -C6-Alkyl: -CH3, -CH2CH3, -CHzCHICH,,, -CH(CH;)z, -CH2CH?CH~CH3,
-CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH;)3, -CH2OCH3,
-CH2SCH3, -CH.~CH^OCH3, -CH2CH2SCH3,
-CH2CH2OCHZCH3, -CH~CH2-SCH2CH3 and
-CH2CH?OCH2CHZOCHZCH3;
C2-C6-Alkenyl: -CH=CH2, -CH2CH=CH2, -CH2CH=CHCH3,
-CH(CH3)CH=CH2, and -CH=C(CH3)2;
C2-C6-Alkinyl: -C=CH, -CH2C=CH and -CHZC=CCH3;
Ca-C6-Cycloalkyl: -Cyclopentyl and -cyclohexyl;
Cl -C6-Heterocycloalkyl: -Piperidyl, -morpholinyl, -tetrahydropyranyl and
furanyl;
C1-C6-Heteroaryl: -Pyridyl, -pyrrolyl and -imidazolyl;
Phenyl-C1-C4-alkyl: -CH2-phenyl, -CH2CH,--phenyl, -CH2CH2O-phenyl,
-CH2CH2OCH2-phenyl and -CH2CH2OCH2CH2O-phenyl;
C2-Clo-Heteroarylalkyl: -CH2-Pyridyl, -CH2CH2-pyridyl, -CH2CH2OCH?-pyridyl,
-CH2CH2-imidazolyl, -CHZCH2O-irnidazolyl and
-CHZCHZOCH2-imidazolyl.
As preferred radicals R' and R2, which are connected to one another via a C-C
bond,
the following bivalent groups can be mentioned:
-CH2CH2-, -CH=CH-, -CH(CH3)CH2-, -CH(OCH3)CH2-, -CH(OCH2CH3)CH2-,
-CH(CHi)CH(CH3)-, -CH(OCH3)CH(OCH3)-, -CH-,CHZCH-,-, -CH(CH3)CH2CH2-,
-CH2CH(CH3)CH?-, -CH(CH3)CH2CH(CH3)- and -CHzCH-)OCHzCHz-.
CA 02523734 2008-04-14
As a permeation enhancer, it is especially preferred that the carbonic acid
diester be
a compound of general formula (II)
0
0 0
~ HZ m Rg (II)
N
in which index m is a number from I to 3, and R3 is hydrogen or Cti-C4-alkyl.
According to the invention, a carbonic acid diester of general formula (H), in
which
index m is 1 and R3 is either methyl (propylene carbonate) or hydrogen
(ethylene carbonate),
is especially preferred.
Propylene carbonate [(f)-4-methyl-1,3-dioxolan-2-one] has a molecular weight
of 102
gmol- 1 and a boiling point of 242 C. It occurs in two enantiomeric forms. In
principle, the
composition according to the invention can contain propylene carbonate in the
pure form of
the R-enantiomer or the S-enantiomer or one of the two enantiomers in
concentrated form.
According to the invention, it is preferred that propylene carbonate be
contained in the
composition as a racemate.
The proportion by weight of the carbonic acid diester to the phannaceutical
composition is preferably 1.0-40.0% by weight, more preferably 2.5-30.0% by
weight, even
more preferably 5.0-20.0% by weight, and especially 7.5-12.5% by weight.
Carbonic acid diesters are known in the prior art. - They can be obtained by,
for
example, the reaction of alcohols with phosgene or phosgene derivatives.
Propylene
carbonate can technically be obtained, for example, by reaction of 1,2-
propyleneglycol with
phosgene. Numerous carbonic acid diesters are commercially available.
CA 02523734 2008-04-14
16
According to the invention, the composition preferably contains a C2-C4 alkyl
alcohol
that is selected from the group that consists of ethanol, n-propanol and iso-
propanol. Ethanol
is especially preferred.
The proportion by weight of the C2-C4 alkyl alcohol to the pharmaceutical
composition is preferably 25.0-70.0% by weight, more preferably 30.0-65.0% by
weight,
even more preferably 30.0-60.0% by weight, and especially 40.0-60.0% by
weight.
In a preferred embodiment, the relative ratio by weight between the carbonic
acid
diester and the C2-C4 alkyl alcohol is 0.01-1.50, preferably 0.08-0.80,
especially 0.10-0.30.
In an especially preferred embodiment, the composition according to the
invention
contains ethanol in combination with ethylene carbonate or propylene
carbonate, whereby the
combination of ethanol with propylene carbonate is preferred.
The composition according to the invention is suitable in principle for
transdermal
administration of a wide variety of active ingredients; the composition
preferably contains
steroids as active ingredients.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient a compound of general formula (III)
4
R B R9
R11'
Ra
(III)
R7
A 5
R
R6
in which
R4 is hydrogen, fluorine, chlorine, CI -C3-alkyl or an optionally acetylated
hydroxyl group,
R5, R6, R7, R8, R9, R10 and R11, independently of one another, are hydrogen or
CI -C3-
alkyl,
CA 02523734 2005-10-26
17
the dotted lines, independently of one another, are an optioiial bond, and
A and B, independently of one another, are a carbonyl group or a group
X Y
\ i
/C'--~
in which X is a llydroxyl group or its esters of a carboxylic acid with 1-8
carbon atoms, and Y
is hydrogen or C;-C3-alkyl. According to the invention, compounds of general
formula (III),
in ,vhich R7 , R8 and R9 are hydrogen, are prefen-ed. Compounds of aeneral
fonnula (III) are
known in the prior art. Reference can be made to, for example, the
publications DE 1 182
229, US 3,341,557, US 4,000,273, WO 99/26962, WO 02/48169, Hill et al.,
Dictionaly of
Steroids, Chapinan and Hall, 1991, Fieser & Fieser, Steroide [Steroids], VCH
Weinheiin,
1961, J. F. Griffan et al., Atlas of Steroid Structure, Plenum Pub Coip, 1984
and G. W.A.
Milne, Ashgate Handbook of Endocrine Agents and Steroids, Ashgate Publishing
Company,
2000.
In an especially preferred enlbodiment, the composition according to the
invention
contains as active ingredient a coinpound of general fonnula (IV)
R4 CH3 X
(IV)
O R5
R6
in which X is a hydroxyl group or its esters of a carboxylic acid with 1-4
carbon atoms, R4 is
hydrogen, fluorine or a hydroxyl group, R5 and R6, independently of one
another, are
hydrogen, methyl or ethyl, and the dotted line is an optional bond. The
compounds of general
formula (IV) are 19-nor-androgen derivatives, i.e., the methyl group that is
usually contained
at carbon atom 19 is replaced by hydrogen. These steroids are often
distinguished by a
special pharmacological effectiveness.
CA 02523734 2005-10-26
18
The conipounds of general formula (III) or (IV) can be present in pure form or
as a
mixture of several stereoisoiners. The compounds of general formula (III) or
(IV) are
preferably present in the form of essentially pure stereoisomers, i.e., the ee
or de values are
preferably above 90%, more preferably above 95%, and especially above 99 /'D.
According to the invention, it is especially preferred if the composition
contains as
active ingredient a compound of general formula (V)
R4 CH3 X
H H
= (V)
H H
O ~ "' CH3
in which R4 is fluorine or hydrogen, and X is a hydroxyl group or its acetate.
X is especially
preferably a hydroxyl group.
If R4 is hydrogen and X is a hydroxyl group, the compound is 7a-methyl-19-
nortestosterone (MENT). If R4 is hydrogen, and radical X of the acetate is a
hydroxyl group,
the compound is the corresponding acetate (MENTAc). If R4 is fluorine and X is
a hydroxyl
group, the compound is 7a-methyl-11(3-fluoro-19-nortestosterone (eF-MENT). If
R4 is
fluorine and radical X of the acetate is a hydroxyl group, the compound is the
corresponding
acetate (eF-MENTAc).
These compounds are known in the prior art; reference can be made to Sundaranz
et
al., Annals in Medicine, 1993, 25, 199 and to WO 2002/59139 Al.
The proportion by weight of the compound of general formula (III), (IV) or (V)
to the
phannaceutical composition is preferably 0.001-10.0% by weight, more
preferably 0.01-5.0%
by weight, even more preferably 0.1-2.5% by weight, and especially 0.5-1.0% by
weight.
The relative ratio by weight of the compounds of general formula (III), (IV)
or (V) to
the carboxylic acid diester is preferably 0.0001-10, more preferably 0.005-1,
and especially
0.05-0.1.
CA 02523734 2005-10-26
, ..
i9
In an especiallv preferred embodiment of the invention, the pharnlaceutical
composition contains as active ingredient a compound of general formula (V),
as C2-C4 alkyl
alcohol, ethanol, and as carboxylic acid diester, ethylene carbonate or
propylene carbonate,
whereby the combination of eF-MENT with ethanol and propylene carbonate is
especially
preferred.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient a combination that consists of two or more compounds of
general formula
(III), (IV) or (V).
It is also possible that the composition according to the invention contains
as active
ingredient one or more active ingredients that are different from the
compounds of formula
(III), (IV) or (V). As examples of such active ingredients, androgens,
antiandrogens, 5a-
reductase inhibitors, estrogen receptor modulators, estrogens, antiestrogens,
gestagens,
antigestagens, uterus-active substances, m-cholinoceptor antagonists,
prostaglandins or
prostaglandin derivatives and/or nicotine can be mentioned.
In a preferred embodiment, the composition according to the invention contains
a
combination that consists of one or more active ingredients of general formula
(III), (IV) or
(V) and one or more active ingredients that are different from the compounds
of formula (III),
(IV) or (V). As examples of such active ingredients that are different from
the compounds of
fonnula (III), (IV) or (V), androgens, antiandrogens, 5a-reductase inhibitors,
estrogen
receptor modulators, estrogens, antiestrogens, gestagens, antigestagens,
uterus-active
substances, m-cholinoceptor antagonists, prostaglandins or prostaglandin
derivatives and/or
nicotine can be mentioned.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more androgens. As examples, MENT, MENTAc, eF-MENT,
eF-
MENTAc, testosterone, testosterone propionate, testosterone undecanoate,
testosterone
CA 02523734 2008-04-14
enanthate, mesterolone, nandrolone decanoate, clostebol acetate or metenolone
acetate can be
mentioned.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more antiandrogens, such as, e.g., cyproterone
acetate, flutamide or
bicalutamide.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more 5ct-reductase inhibitors, such as, e.g.,
finasteride or l7a-
estradiol.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more selective estrogen receptor modulators, such as,
e.g., raloxifene.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more estrogens, such as, e.g., estradiol, estradiol
valerate or estriol.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more conjugated estrogens, estrogen si.ilfamates or
antiestrogens, such
as, e.g., clomifene or taxolTM, or partial antiestrogens, such as, e.g.,
raloxifene.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more gestagens, such as, e.g., progesterone,
hydroxyprogesterone
capronate, megestrol acetate, medroxyprogesterone acetate, chlormadinone
acetate,
cyproterone acetate, medrogestone, dydrogesterone, norethisterone,
norethisterone acetate,
norethisterone enanthate, levonorgestrel, gestodene, etonogestrel, dienogest,
danazole,
norgestimate, lynestrenol, desogestrel or drospirenone.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more antigestagens, such as, e.g., mifepristone or
mesoprogestin.
In a preferred embodiment, the composition according to the invention contains
as
active ingredient one or more uterus-active substances, such as, e.g.,
oxytocin.
CA 02523734 2005-10-26
. . , ,
~l
Izi a pr-eferred embodiment, the composition according to the invention
contains as
active ingredient one or more m-cholinoceptor antagonists, such as, e.g.,
scopolamine.
In a preferred embodiment, the coniposition according to the invention
contains as
active ingredient one or more prostaglandins or prostaglandin derivatives,
such as, e.g.,
alprostadil, gemeprost, dinoprostone, sulprostone, dinoprost, latanoprost or
misoprostol.
In a preferred embodiment, the composition according to the invention contains
nicotine as an active ineredient.
Also, a combination of two or more of the active ingredients above is
preferred.
The necessary dosage of androgens, antiandrogens, 5a-reductase iiihibitors,
estrogen
receptor modulators, estrogens, antiestrogens, gestagens, antigestagens,
uterus-active
substances, m-cholinoceptor antagonists, prostaglandins or prostaglandin
derivatives and
nicotine is known to one skilled in the art. In this connection, reference can
be made to, for
example, Mutschler Arzneiinittelwirkungen - Lehrbuch der Phartnakologie und
Toxikologie
[Pharmaceutical Agent Actions - Textbook of Pharmacolo( gy and Toxicology],
2001 and W.
Forth et al., Allgemeine und Spezielle Pharmakologie und Toxikologie [General
and Special
Pharmacology and ToxicologJJ, BI Wissenschaftsverlag [Scientific Press] 1992,
6'h Edition.
In a preferred embodiment, the composition according to the invention contains
a
combination of several active ingredients, selected from the group that
consists of androgens
and/or antiandrogens and/or 5a-reductase inhibitors and/or estrogen receptor
modulators
and/or estrogens and/or antiestrogens and/or gestagens and/or antigestagens
and/or uterus-
active substances and/or m-cholinoceptor antagonists and/or prostaglandins or
prostaglandin
derivatives and/or nicotine and/or compounds of general formula (III), (IV)
and/or (V).
The coinposition according to the invention preferably contains additional
contents as
adjuvants.
In a preferred embodiment, the composition contains as adjuvants
cyclometliicone
" ' =" CA 02523734 2005-10-26
2 2
and/or isopropyl myristate. In the hydrogel, cyclomethicone and isopropyl m~-
Tistate ensure
good spreading on and care of the skin. In a preferred embodiment, the
composition contains
glycerol as an adjuvant. Glycerol serves as a moisturizer for the composition
and the skin.
In a preferred embodiment, the composition contains cycloniethicone, isopropyl
myristate and glycerol as adjuvants. The proportion of water in the
composition and the
adjuvants produce in their combination a better compatibility of the
composition. The
concentration of nurturing adjuvants (cycloinethicone and isopropyl myristate)
as well as the
volatility of the cyclomethicone are important, since residues of the
composition on the skin
should be largely avoided - the latter could otherwise be contaminated by skin
contact of the
patient with another individual.
As additional adjuvants, polyethylene glycol and/or volatile silicone oils,
such as, e.g.,
hexamethylcyclotrisiloxane, octamethylcyclotetrasiloxane and/or
decamethylcyclopenta-
siloxane can be contained in the composition according to the invention. As
adjuvants, in
addition to water and C2-C4 alkyl alcohol, for example, the solvents benzyl
alcohol,
dimethylformamide or dimethyl sulfoxide can also be used. Preferred are also
multivalent
alcohols, such as ethylene glycol, propylene glycol, butylene glycol or
hexylene glycol. To
prevent the composition from drying out, in addition to or instead of
glycerol, sorbitol,
mannitol, polyethylene glycol and/or polypropylene glycol or a copolymer that
consists of
ethylene glycol and propylene glycol can be added. Glycerol has proven
especially suitable.
In addition, the pharmaceutical composition can contain, for example, dyes,
perfumes,
antioxidants, surfactants, bactericides, fungicides, complexing agents,
cyclodextrins,
electrolytes and/or viscosity aids. Such adjuvants are known to one skilled in
the art.
Relative to additional infonnation, reference can be made to, for example,
Fiedler, Lexikon
der Hilfsstoffe [Lexicon of Adjuvants], ECU Aulen.dorf 1996, 4th Edition and
Hunnius
Studienausgabe [Hunnius Textbook Edition], de Gruvter 1993, 7`hEdition.
CA 02523734 2008-04-14
23
The adjuvants improve the compatibility of the composition to the skin. The
relative
proportion of the adjuvants to the pharmaceutical composition is preferably
0.001-15.0% by
weight, more preferably 0.01-10.0% by weight, even more preferably 0.5 to 5.0%
by weight,
especially 1.0 to 4.0% by weight. A proportion of 1.0-2.0% by weight of
cyclomethicone
and/or 0.3-0.8% by weight of isopropyl myristate and/or 0.5-1.5% by weight of
glycerol is
especially preferred.
The pharmaceutical composition according to the invention is a hydrogel. The
water
content of the hydrogel is preferably 5.0-90.0% by weight, more preferably
10.0-70.0% by
weight, even more preferably 20.0-50.0% by weight, especially 25.0-40.0% by
weight.
The relative ratio by weight of the C2-C4 alkyl alcohol to water is preferably
0.1-10.0,
more preferably 0.5-5.0, even more preferably 1.0-3.0, especially 1.8-2.2.
In a preferred embodiment of the invention, as a carbonic acid diester, the
pharmaceutical composition contains either propylene carbonate or ethylene
carbonate, and,
as a C2-C4 alkyl alcohol, the pharmaceutical composition contains ethanol. For
this case, the
pharmaceutical composition preferably contains 29.0-73.0% by weight of ethanol
and 5.0-
50.0% by weight of water, more preferably 34.0-68.0% by weight of ethanol and
10.0-45.0%
by weight of water, even more preferably 39.0-63.0% by weight of ethanol and
15.0-40.0%
by weight of water, especially preferably 44.0-58.0% by weight of ethanol and
20.0-35.0% by
weight of water and especially 54.8-57.5% by weight of ethanol and 27.2-30.8%
by weight of
water.
The pH of the pharmaceutical composition according to the invention is
preferably set at a value between 4.5 and 7.5, more preferably between 5.0 and
7.0, especially
between 5.5 and 6.5. To this end, buffers, such as, e.g., tris-(hydroxymethyl)-
aminomethane,
triethanolamine or bases, such as, e.g., diisopropylamine or potassium
hydroxide, are suitable.
Also, other suitable buffer substances and bases are known to one skilled in
the art. Relative
to further information, reference can be made to, for example, Fiedler,
Lexikon der
CA 02523734 2005-10-26
24
Hilfsstoffe, ECUAulendo7f 1996, 4`h Edition and Hunnius Studienausgabe, de
Gruvter 1993,
Th Edition.
The pharmaceutical composition accordina to the invention also contains a
polymer
matrix. This polymer matrix comprises at least one gel skeleton former and
optionally one or
more thickening agents, by which the rheological properties of the composition
are improved.
By the gel skeleton, patient compliance increases coiisiderably, which is an
essential
advantage of the compositions according to the invention. A balance of gel
properties is
important, which is ensured by the coniposition according to the invention. A
continuous use
of the composition according to the invention is generally carried out by the
patient, which
does not cause any problems, however, especially because it is so easy to
reapply the hydrogel
to the skin.
Suitable gel skeleton formers are known in the prior art. According to the
invention,
as a gel skeleton former, the polyiner matrix preferably comprises an acrylic
polymer. The
acrylic polymer can be a homopolynler or a copolymer.
The acrylic polyiner is a homopolymer, thus the latter is preferably derived
from an
acrylic acid-Cl-C3o-alkyl ester or a methacrylic acid-C1-C3o-alkyl ester.
The acrylic polymer is a copolymer, thus the latter is preferably derived from
acrylic
acid, methacrylic acid, acrylic acid-Cl-C3o-alkyl ester or methacrylic acid-C1
-C30-alkyl ester
in combination with one or more vinyl monomers. The vinyl monomer or monomers
can
either be acrylic acid, methacrylic acid, an acrylic acid-C1-C3o-alkyl ester
or a methacrylic
acid-C1-C30-alkyl ester, but, for example, styrene, ethylene, propylene, vinyl
chloride,
vinylidene chloride, tetrafluoroethylene, vinyl acetate, vinyl ether or vinyl
pyrrolidone can
also be contained in the copolymer.
As acrylic polymers, especially homopolymers or copolymers, which are obtained
by
polymerization of acrylic acid, methacrylic acid, acrylic acid-Cl-C3o-alkyl
ester and/or
methacrylic acid-Cl-C3o-alkyl ester, are preferred.
' =" CA 02523734 2005-10-26
The acrylic polyiners that are contained in the composition according to the
invention
can be uncrosslinked or crosslinked. In a preferred embodiment, the
colnposition according
to the invention contains a crosslinked acrylic polymer.
The acrylic polymer is an uncrosslinked polymer, thus the weight-average
molecular
weight M, of the acrylic polymer preferably lies in the range of 50,000 to
2,500,000 gmol-',
more preferably in the range of 100,000 to 2,000,000 gmol-', especially in the
range of
.
500,000 to 1,500,000 ginol-1
As gel skeleton formers, the composition according to the invention especially
preferably contains acrylic polymers, whicll are copolymers and are derived
from a mixture
that consists of acrylic acid and_acrylic acid-Clo-C30-alkyl esters. In an
especially preferred
embodiment, these copolymers are crosslinked, for example with
allylpentaerythritol. Such
crosslinked polymers are known in the prior art. For example, an acrylate-Clo-
C3o-alkyl
acrylate is commercially available under the designation Pemulen TR1. This is
an
acrylate/C10-30 alkyl acrylate cross polymer. The general chemical structure
of Pemulen
TR1 can be visualized in simplified terms as follows:
- ' *
Co2H m Co2CkH2k+1. n
with k = 10-30.
The proportion by weight of the gel skeleton former to the pharmaceutical
composition is preferably 0.001-20.0% by weight, more preferably 0.005-10.0%
by weight,
even more preferably 0.01-5.0% by weight, especially 0.5-1.0% by weight.
In addition to the gel skeleton fonner, the polymer matrix of the composition
according to the invention can contain additional polymers. The latter can act
as thickening
agents. According to the invention, as thickening agent, the composition
preferably contains
polyacrylic acid. Polyacrylic acid is marketed commercially, for example,
under the
designation Carbopol . According to the invention, Carbopol" 980 is especially
preferred.
= ' = CA 02523734 2005-10-26
26
The proportion bv weight of polyac.rylic acid to the pharmaeeutical
eomposition is
preferably 0-5.0% by weight, more preferably 0.01-2.5% by weight, even more
preferably
0.1-1.0% by weight, especially 0.3-0.5 o by weight. In a preferred embcdiment
of the
invention, the composition does not contain any polyacrylic acid.
In a preferred embodiment of the invention, in addition to the gel skeleton
former, the
polymer matrix contains as a thickening agent a cellulose derivative, but it
is also possible
that no cellulose derivative is present.
As prefei7ed cellulose derivatives, methyl cellulose, ethyl cellulose, propyl
cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose,
hydroxypropylmethyl cellulose, cellulose acetate butyrate, cellulose acetate
propionate,
hydroxypropylmethyl cellulose acetate succinate and methylhydroxypropyl
cellulose
phthalate or mixtures thereof can be mentioned. Ethyl cellulose, hydroxypropyl
cellulose and
hydroxypropylmethyl cellulose are especially preferred, especially ethyl
cellulose and
hydroxypropyl cellulose, whereby hydroxypropyl cellulose is most preferred.
Cellulose derivatives that are preferred according to the invention are
compounds that
have subunits of general formula (VI)
OR12
H2 OR17
O O
jOR13 OR16H (VI)
--O H H O ---
OR14 CHz
OR15
in which R1' R~3, Rla RI', R16 and R17 , in each case independently of one
another, are
hydrogen or a linear or branched C1-C61 alkyl radical, whose carbon chain can
be interrupted
up to 20 times with oxygen atoms and which optionally can be substituted with
1 or 2
hydroxyl groups, carboxyl groups or acyloxy groups, whereby the acyloxy groups
optionally
are derived from a CI -C7 carboxylic acid or C1-C7 dicarboxylic acid. Rlz R13
R'a Rls R16
and R7, in each case independently of one another, are preferably hydrogen or
a linear or
l
=~ CA 02523734 2005-10-26
27
branched C1-C19 alkyl radical, whose carbon chain can be interrupted up to 6x
wifil oxygen
atoms and which optionally can be substituted with 1 or 2 hydroxyl groups.
The individual subunits of general formula (VI) can be substituted in various
ways
within the cellulose derivative. It is thus possible, for example, that in a
first subunit, R12,
R13 R14 R's and R'6 are -CH2CH3, and R17 is -H, while in another subunit, R"
R14 R's R16
and R"' are -CHzCH;, and R 12 is -H.
The cellulose derivatives that are preferred according to the invention
preferably
exhibit a high degree of substitution relative to the hydroxyl groups of
cellulose. The degree
of substitution expressed as molar substitution (MS) is preferably from 2.0 to
6.0, more
preferably 3.0 to 6.0, more preferably 3.0 to 5.0, and especially 3.4 to 4.4.
Especially prefei-red substituents R'` R13, R14 R's, R" and R17 are:
-H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2OH,
-CH2CH(CH3)OH, -[CH)CH(CH3)O],H, -CH2CH(CH3)OCH3 and -[CH2CH(CH3)O],,CH3, in
which x in each case can be a number from 2 to 20, preferably from 2 to 6,
especially 2, 3 or
4.
According to the invention, the subunits of general formula (VI) are
preferably
subunits of hydroxypropyl cellulose, i.e., the radicals R12 R13, R14 R's, R16
and R" are
preferably, independently of one another, -H, -CH2CH(CH3)OH or -
[CH2CH(CH3)O]XH, in
which in each case x can be a number from 2 to 20, preferably from 2 to 6.
Hydroxypropyl
cellulose can be obtained by reaction of alkali metal salts of cellulose with
propylene oxide
and subsequent neutralization of the alkoxy groups. If one of the hydroxyl
groups of the
cellulose in this reaction does not react with propylene oxide, R'2, R13, R14,
R'', R16 or R'7
thus is -H. If one of the hydroxyl groups of the cellulose in this reaction
reacts with one
equivalent of propylene oxide, R", R13 R14 R's R16 or R" thus is CH2CH(CH3)OH.
If one
of the hydroxyl groups of the cellulose in this reaction reacts with one
equivalent of propylene
oxide and the alkoxide that is produced therefrom reacts with another
equivalent of propylene
CA 02523734 2005-10-26
oxide. Ri~, R. R14 Ri~, R16 or R'~ thus is -[CHtCH(CH3)O]7zH. Theoretically in
this case,
index x can be any number depending on how many equivalents oligomerize
propylene oxide.
Index x is preferably a number from 2 to 20, more preferably from 2 to 6,
especiaily 2, 3 or 4.
R" Rl3 R14 RR16 and R 17, in each case independentlyo of one another,
especially
preferably have one of the following meanings: -H, -CH2CH(CH3)OH, -
[CH2CH(CH3)O]2H
or -[CH2CH(CH3)0];H.
According to the invention, a methyl cellulose, a hydroxypropylmethyl
cellulose, an
ethyl cellulose and especially a hydrox}propyl cellulose, in each case with a
nlolar
substitution (MS) of 3.0 to 6.0, more preferably 3.0 to 5.0, especially 3.4 to
4.4, is especially
preferred.
Preferred cellulose derivatives are known to one skilled in the art. Ethyl
cellulose,
hydroxypropyl cellulose and hydroxypropylmethyl cellulose are commercially
available, for
example, under the designations Klueel , Kiuce1 EXF (Aqualont), Lucel HF and
Tylopur
MH 1000. Klucel HF is especially preferred according to the invention.
Relative to other
information, reference can be made to, for example, Fiedler, Lexikon der
Hilfsstoffe, ECU
Aulendorf 1996, 4`h Edition and Hunn.ius Studienausgabe, de Gruyter 1993, 7`h
Edition.
Relative to other information on hydroxypropyl cellulose of the Klucel type,
reference can
be made to Hercules, Aqualon, Klucel - Phvsical and Cheinical Properties,
Produkt-
spezifikation [Product Speeification], Hercules Incorporated 2001.
The weight-average molecular weight Mw of the cellulose derivative preferably
lies in
the range from 50,000 to 2,000,000 ginol-1, more preferably in the range from
300,000 to
1,500,000 gmol-I , even more preferably in the range from 750,000 to 1,250,000
ginol-1,
especially in the range of 850,000 to 1,150,000 gmol-1.
The Brookfield viscosity of the cellulose derivative in water at 25 C at a
concentration
of 1% is preferably 1,000 to 4,000 mPas, more preferably 1,275 to 3 ,500 mPas,
especially
CA 02523734 2005-10-26
"9
1.500 to 3,000 mPas. The measurement is performed with a Brookfield
viscosimeter, Model
LVF with 4 spindles and 4 speeds, with which the range of 0 to 100,000 mPas
can be covered.
The proportion by weight of the cellulose derivative to the phannaceutical
composition is preferably 0-5.0% by weight, more preferably 0.01-2.5% by
weiaht, even
more preferably 0.1-1.5 1o by weight, and especially 0.3-1.0% by weight.
According to the invention, in addition to the acrylic polynier as a gel
skeleton former,
the polynler matrix preferably comprises alternatively as a thickening agent
either polyacrylic
acid or a cellulose derivative. The combination of an acrylic polymer as a gel
skeleton former
with hydroxypropyl cellulose as a thickening agent is especially preferred.
The pharmaceutical compositions according to the invention can contain fatty
acids
with more than 12 carbon atoms or their esters or the fatty alcohols that are
derived from these
fatty acids or primary amines and/or C1-C18-alkyl ethers of mono-, di-, tri-
or tetraethylene
glycol, especially diethylene glycol monoetllyl ether, and/or terpenes. These
compounds are
not necessary components of the pharmaceutical compositions according to the
invention,
however, and the pharmaceutical compositions according to the invention
preferably contain
none of these compounds.
In an especially preferred embodiment, the pharmaceutical composition contains
the
following components in the following proportions by weight:
Table 1:
Component Proportion [%]
by Weight]
eF-MENT 0.01-5.0
Acrylate/C10-30 Alkyl Acrylate 0.1-1.5
Crosspolymer
Polyacrylic Acid 0-1.0
CA 02523734 2005-10-26
Component Proportion. [%]
bv Weight]
Cellulose Derivative 0-2.0
Propylene Carbonate 5.0-20.0 86% Glycerol 0.01-5.0
Cvclomethicone 0.01-5.0
Isopropyl Myristate 0.01-5.0
Purified Water T20.0-50.0
Ethanol 30.0-60.0
Tris-(hydroxymethyl)-aminomethane at pH 5-7
The phanuaceutical coinpositions according to the invention are suitable as
medications. The indication to be treated detennines the active ingredient to
be adn-linistered.
Fonnulations according to the invention that contain steroids can be used, for
example, to
prevent andlor to treat different steroid deficiency symptoms. As exemplary
applications,
androgen replacement therapy, contraception, primary and secondary
hypogonadism,
testicular malfunction, hair loss, aging, loss of bone substance, muscular
atrophy, erectile
dysfunction, benign prostate hypertrophy, and prostate cancer can be
mentioned. In
particular, the compositions according to the invention that contain MENT, eF-
MENT,
MENTAc or eF-MENTAc are suitable for therapy or prevention of primary and
secondary
hypogonadism. Relative to pharmacology, biology and clinical applications of
androgens,
reference can be made to 111utschler Arzneinzittelwirkungen - Lehrbuch der
Pharnzakologie
und Toxikologie, 2001, S. Bhasin et al., Pharmacology, Biology, and Clinical
Applications of
Androgens: Current Status and Future Prospects, John Wiley & Sons, 1 st Ed.,
1996, Ch.
Chawnshang, Androgens and Androgen Receptor: Mechanisms, Functions, and
Clinical
CA 02523734 2008-04-14
31
Applications, Kluwer Academic Publishers, 2002 and M. Carruthers, Androgen
Deficiency in
the Aging Male, CRC Press-Parthenon Publishers, 1 S` Ed., 2002.
The pharmaceutical compositions according to the invention are formulated for
systemic administration of the active ingredient by local application on the
skin. The
compositions can either be applied by hand or a suitable adjuvant, such as,
e.g., a spatula on
the skin by spreading, but it is also possible to apply the compositions in
the form of sprays
on the skin.
The invention also relates to the use of a carbonic acid diester for improving
the
transdermal permeation of an active ingredient in a pharmaceutical composition
in the form of
a hydrogel, whereby the composition in addition preferably comprises a C2-C4
alkyl alcohol,
preferably ethanol, and a polymer matrix. Relative to the preferred components
(i.e., relative
to the active ingredients, the C2-C4 alkyl alcohols, the carboxylic acid
diesters, the polymer
matrix, the adjuvants, the buffer substances, etc.) and relative to the
preferred quantitative
ratios of these components in the pharmaceutical composition, reference can be
made to the
embodiments above. The invention thus relates to the use of a carbonic acid
diester,
preferably a compound of general formula (I), more preferably a compound of
general
formula (II) and especially the use of propylene carbonate for improving the
transdermal
permeation of one or more active ingredients in a pharmaceutical composition
in the form of a
hydrogel, whereby the hydrogel preferably comprises a polymer matrix and a C2-
C4 alkyl
alcohol and preferably is defined as above.
According to the invention, it was also found, surprisingly enough, that a
pharmaceutical composition in the form of a hydrogel, which comprises an
acrylic polymer in
combination with a cellulose derivative, no longer exhibits the problem that
the gel skeleton is
destroyed and the gel runs off if the gel is applied to skin that is wet from
perspiration (sweat-
resistant composition). To acliieve this effect, the presence of a carbonic
acid diester in the
formulation is not necessary.
= ~ CA 02523734 2005-10-26
j7
According to the invention, such a pha?maceutical composition (sweat-resistant
composition) comprises an acrylic polyiner in combination with a cellulose
derivative.
As a cellulose derivative, such a pharmaceutical composition (sweat-resistant
composition) preferably contains a cellulose derivative, as was defined above,
especially a
compound that is selected from the group that consists of ethvl cellulose,
hydroxypropyl
cellulose and hydroxypropylmethyl cellulose. Ethyl cellulose and hydroxypropyl
cellulose
are especially preferred, whereby hydroxypropyl cellulose is more preferred.
The molar
substitution of the cellulose derivative is preferably 2 to 6, more preferably
3 to 6, especially 3
to 5, e.g., 3.4 to 4.4.
As an acrylic polymer, such a phanliaceutical composition (sweat-resistant
composition) preferably contains an acrylic polymer, as it was defined above,
especially a
homopolymer or copolymer, which is derived from acrylic acid, methacrylic
acid, acrylic
acid -C 1 -C io-alkyl ester and/or methacrylic acid-C1-C3o-alkyl ester.
Especially preferred is a
copolymer that is derived from a mixture that consists of acrylic acid and
acrylic acid-Clo-
C3o-alkyl esters. In an especially preferred embodiment, an acrylate/C10-30
alkyl acrylate is a
crosspolymer.
The relative ratio by weight between the acrylic polymer and the cellulose
derivative
in the pharmaceutical composition (sweat-resistant composition) is preferably
0.1-10.0, more
preferably 0.2-5.0, even more preferably 0.5-2.0, and especially 0.75-1.75.
The total proportion of the acrylic polymer and the cellulose derivative to
the
pharmaceutical composition (sweat-resistant composition) is preferably 0.01-
20.0% by
weight, more preferably 0.1-10.0% by weight, even more preferably 0.3-5.0% by
weight, and
especially 1.0-2.0% by weight.
In a preferred embodiment, the pharmaceutical composition (sweat-resistant
composition) contains 0.5-1.0% by weight of an acrylate/C10-30 alkyl acrylate
crosspolymer
in combination with 0.2-0.8% by weight of hydroxypropyl cellulose.
CA 02523734 2008-04-14
33
The pharmaceutical composition according to the invention (sweat-resistant
composition) is preferably a hydrogel. The water content of the hydrogel is
preferably 5.0-
90.0% by weight, more preferably 10.0-70.0% by weight, even more preferably
20.0-50.0%
by weight, and especially 25.0-40.0% by weight.
The pharmaceutical composition according to the invention (sweat-resistant
composition) preferably contains a C2-C4 alkyl alcohol, whereby ethanol is
especially
preferred. For this case, the pharmaceutical composition (sweat-resistant
composition)
preferably contains 29.0-73.0% by weight of ethanol and 5.0-50.0% by weight of
water, more
preferably 34.0-68.0% by weight of ethanol, and 10.0-45.0% by weight of water,
even more
preferably 39.0-63.0% by weight of ethanol and 15.0-40.0% by weight of water,
especially
preferably 44.0-58.0% by weight of ethanol and 20.0-35.0% by weight of water,
and
especially 54.8-57.5% by weight of ethanol and 27.2-30.8% by weight of water.
In addition to the acrylic polymer and the cellulose derivative, the
pharmaceutical
composition (sweat-resistant composition) optionally contains at least one
active ingredient
and additional contents, such as, e.g., skin-care products, adjuvants,
solvents, penneation
enhancers, etc. The active ingredient, the optionally present additional
contents and their
preferred proportions, in percentage, in the composition are as defined above.
The pharmaceutical composition (sweat-resistant composition) in the form of a
hydrogel thus preferably comprises an active ingredient and/or a carbonic acid
diester
and/or a C2-C4 alkyl alcohol and/or a polymer matrix as defined above. Both
the preferred
proportions by weight, in percent, to the composition and relative ratios by
weight of the
individual components below one another and the preferred active ingredients,
preferred
carboxylic acid diesters and preferred C2-C4 alkyl alcohols are as defined
above.
Instead of the carbonic acid diester or supplementing the carbonic acid
diester, the
pharmaceutical composition (sweat-resistant composition) can contain a
permeation enhancer,
which is selected from the group that consists of:
CA 02523734 2005-10-26
34
(i) aliphatic fatty acid esters that contain 10-30 carbon atoms and are
optionally
substituted with 1-2 hydroxyl groups, carboxyl groups or Ci-C4 acyloxy groups;
(ii) aliphatic fatty acid alcohols that contain 10-30 carbon atoms and are
optionally
substituted with 1-2 hydroxyl groups, carboxyl groups or Ci-Ca acyloxy groups;
or
(iii) a compound of general fonnula (VII)
HO-(CHzCHz-O)õ-R' 8 (VII)
in which R'. 8 is Cj-C;?-alkyl, C1-CJralkenyl, C1-C]2-alkanoyl or CI-C12-
alkenoyl, and index n
is a number from 1 to 10.
The pharmaceutical composition (sweat-resistant composition) preferably
contains a
compound of general foi-nlula (VII), in which Rl g is CI -C4-alkyl and index n
is a number from
1 to 3.
Especially preferred compounds of general formula (VII) are: HO-CH2CH2O-CH3,
HO-CH2CHZO-CH2CH3, HO-CH2CHZO-CH2CHZCH3, HO-CHZCH2O-CHZCH2CH2CH3, HO-
(CH2CH2O)2-CH3, HO-(CH2CH2O)2-CH2CH3, HO-(CHzCHzO)z-CHzCHzCH,, HO-
(CH2CH2O)2-CH2CH2CH2CH3, HO-(CH2CHZO)3-CH3, HO-(CHZCH2O)3-CH2CH3, HO-
(CH2CHZO)3-CHZCH2CH3, HO-(CH2CH2O)3-CH2CH2CH2CH3, HO-(CH2CH2O)4-CH3, HO-
(CH2CHzO)4-CH2CH3, HO-(CH2CH2O)4-CH2CH2CH3 and HO-(CH2CHzO)4-
CH2CH2CH,CH3.
For the pharmaceutical composition (sweat-resistant composition), especially
preferred is an embodiment that contains a compound of general formula (VII),
in which R18
is ethyl and index n = 2, i.e., diethylene glycol monoethyl ether.
The following examples are used for further explanation of the invention.
CA 02523734 2005-10-26
~J
E~an~.t~le i:
Two pharmaceutical compositions according to the invention (Types A and B)
were
produced in the usual way. The components of the compositions are presented in
Table 2:
Table 2:
Component Amount [ /a by NVeight]
Type A Type B
Propylene Carbonate 10.0 10.0
Ethanol 55.0 55.0
Purified Water about 30 about 30
eF-MENT 0.8 0.8
Acrylate/C 10-3 0 Alkyl Acrylate 0.8 0.8
Crosspolymer (Pemulen TR-l)
Polyacrylic Acid - 0.4
Hydroxypropyl Cellulose (Klucel HF) 0.35 -
86% Glycerol 1.0 1.0
Cyclomethicone 1.5 1.5
Isopropyl Myristate 0.5 0.5
Tris-(hydroxymethyl)aminomethane at pH 5.8 at pH 5.8
CA 02523734 2005-10-26
36
Example 2 (Best Mode): A pharmaceutical composition (sweat-resistant
coinposition, type C) in the form of a
hydrogel, which comprises an acrylic polymer in combination with a cellulose
derivative, was
produced without an active ingredient. The components of the compositions are
presented in
Table 3:
Table 3:
Component Amount [% by
Weight] of Type C
Propylene Carboiiate 10.0
Ethanol 55.0
Purified Water About 30
Acrylate/C 10-30 Alkyl Acrylate 0.8
Crosspolymer (Pemulen TR-1)
Hydroxypropyl Cellulose (Klucel HF) 0.35
86% Glycerol 1.0
Cyclomethicone 1.5
Isopropyl Myristate 0.5
Tris-(hydroxynnethyl)aminomethane at pH 5.8
(Tromethamine)
CA 02523734 2005-10-26
~~
J!
The following production process was performed:
Pemulen TR-1 and HPC (Klucel HF) were steeped in 96% ethanol. Propylene
carbonate was added and mixed while being stirred. Then, isopropyl myristate
was added,
and it was mixed again. The gel former and the swelling substance began to
swell in the
solvent mixture. The entire mixture was introduced via a hopper in a
mixer/homogenizer
system (Becomix RW 2.5) (drawn into the Becomix RW 2.5) and stirred briefly at
20 rpm.
Then, it was homogenized for 1 minute at 2000-3500 rpm (e.g., with a rotor-
stator
homogenizer). A homogeneous, clear gel with no agglomerates that was still not
completely
steeped was obtained. 86% Glycerol and the entire amount of the purified water
were added
as a streak-free mixture in several partial steps (drawn in), and the gel
again swelled
considerably. It was stirred (about 5 minutes) until a significant clearing-up
of the gel was
visible. With each addition of water/glycerol, the gel skeleton was better
formed and also
became increasingly more clear at the same time. The rpm was 50. Then,
cyclomethicone
was added to the mixture while being stii7ed. A unifonn distribution of the
water/glycerol
mixture as well as the cyclomethicone is thus ensured, and it was homogenized
at the end of
the addition for 1 more minute at 4000 rpm. Then, while being stirred at 50
rpm in 3 partial
sections, a 10% aqueous tromethamine solution was added for neutralization.
The gel in this
case became considerably clearer, and the gel structure built up further. At
the end of the
addition, it was homogenized again for 2 minutes at 2700 rpm.
Example 3:
In a series of tests, 3 different phannaceutical compositions in the form of
hydrogels
were examined with respect to their skin compatibility. The formulations were
as follows:
Comparison fonnulation 1(VB1) (Exainple according to the disclosure of EP-A
817 621):
CA 02523734 2005-10-26
38
70.21/o ethanol, 20% ethylhexyl ethylhexanoate, 1 ro cetearyl octanoate; 1.5%
hydroxypropyl
cellulose; 3.6% water
Comparison formulation 2 (VB2); Androgel (market product):
68.9% ethanol; isopropyl myristate, polyacrylic acid, water, NaOH
Formulation 3 according to the invention (EB3), produced according to the
process of
Example 2:
45% ethanol, 10% propylene carbonate, 2.0% PEG 400, 0.6% acrylic polymer, 4.0%
glycerol,
37.25% water, diisopropylamine q.s.
The local compatibility in rabbits after once-daily dennal application of 0.25
g per
application site over 2 weeks (a total of 14 applicatioiis) on the intact skin
was examined. The
study was caiTied out according to the EMEA Guidelines (CPMP/SWP/2145/00). The
study
was carried out on 6 male animals (white New Zealand/conv.)
As a negative control, tap water was used; as a positive control,
testogel/androgel was
used. The exposure time was 4 hours. Treatment residues were removed with
lukewarm
water. The reading and evaluation of the reaction were carried out in each
case at the end of
the exposure time before the removal of the substance residue. The animals
were sacrificed
and dissected on the day after the last treatment (day 15). The sampling as
well as the
histological working-up were carried out according to the information of SOP
TX ME No.
382.4.
The results are shown in Figure 1, whereby the X-axis indicates the number of
indications, and the formulations are indicated on the Y-axis.
As the comparison tests indicate, the composition according to the invention
is
superior to the commonly used compositions of the prior art. As comparison
formulations 1
CA 02523734 2008-04-14
39
and 2(VB1 and VB2) indicate, gels that have a high ethanol content show
significant side
effects. In this case, it is clear that the side effects are not caused
exclusively by the ethanol
but apparently are also dependent on the type of permeation enhancer that is
used. At an
ethanol content of 70% by weight, the marketed product (androgel) shows
considerably fewer
side effects than comparison formulation 1(VB1), in which ethylhexyl
ethylhexanoate served
as a permeation enhancer (cf. product according to EP-A 817 621).
Example 4:
Rheological characterization of the electrolyte tolerance of gel systems based
on
polyacrylic acid (e.g., carbopol) versus gel systems based on a combination of
hydroxypropyl
cellulose and PemulenTM TR-1 (sweat-resistant composition).
The test set-up simulates the "sweat-resistance" of the described gel systems
on the
skin. To this end, selected electrolyte preparations were added to the
composition, and the
rheological parameters were determined. The electrolyte tolerance is
characterized by
comparison of the untreated sample with the electrolyte-loaded sample.
The preparations were mixed with 0.0 1% NaCI in crystalline form, and the salt
was
added wliile being stirred moderately. Then, the rheological measurement was
carried out
immediately. The measuring apparatus consisted of a rotary viscosimeter RC 20
of the
Europhysics Company with a Peltier thermostat. The measuring temperature was
25 C, and
the preset value of the shear stress (i) was 150 Pascal. The C50-1 measuring
cone was used.
1. Androgel based on polyacrylic acid (Carbopol) (market product androgel)
2. Vehicle according to the invention based on hydroxypropyl cellulose (Klucel
HF)/Pemulen TR-1, hydrogel according to Example 2
The yield points of the androgel dropped because of the electrolyte load to
about 17%
of the starting value. The yield points of the variant according to the
invention based on
' = ~ CA 02523734 2005-10-26
hydroxypropyl cellulose/Pemulen TR-1 were reduced to only about 89% of the
starting value,
however.
Table 4:
Feedstock Yield Points Residual Yield Points
(Pa) (in Percent of the
Starting Value)
Androgel 15.3
without Electrolyte
Androgel 2.5 16.7
with 0.01% NaCI
Vehicle According to the 22.9
Invention withoiAt Electrolyte
Vehicle According to the 20.3 89.5
Invention with
0.01% NaC1
For the system based on hydroxypropyl cellulose/Pemulen TR-1 according to the
invention, the results show a considerably higher electrolyte tolerance. This
behavior
correlates with the real-life application experience. T'he preparation
according to the
invention can be applied without running off and dripping off from the skin.
However, it
results in the market product androgel running off and dripping off, which is
caused by the
strong reduction in yield points.
CA 02523734 2005-10-26
41
Example 5:
The pern-ieation behavior relative to active ingredient eF-MENT of a
composition
according to the invention, which contained 55(11'0 by weight of ethanol and
10% by weight of
propylene carbonate, and had been produced above according to Example 2, was
compared to
the penneation behavior from a composition that corresponded approximately to
the
composition of the market product androgel.
The experiment was performed with the aid of a Franz diffusion cell (c T. J.
Fi-araz,
Invesz. Dermatol. 1975, 64, 191). This model consists of a diffusion cell,
which can be
subdivided into a donor compartment and an acceptor compartment. In this
system, the skin
acts as a barrier between these coinpartments. In this case, the skin is
introduced between the
coinpartments, such that the dermal side is flushed by the solution of the
acceptor
compartment: The acceptor compartment of the diffusion cell is connected to an
HPLC unit,
by which an automatic analysis of aliquots of the solution is possible.
The actual composition of the tested hydrogel according to the invention is
presented
in Table 5:
Table 5:
Component [% by
Weight]
Propylene Carbonate 10.0
Ethanol 55.0
Purified Water -29.0
eF-MENT 0.8
Acrylate/C 10-30 Alkyl Acrylate 0.8
Crosspolymer (Pemulen TR-1)
CA 02523734 2005-10-26
< , .
42
Component [% by
Weight]
Methyl Cellulose ('Tylopur MH 1000, 0.5
Obtainable from the Clariant Company)
86% Glycerol 1.0
Cyclomethicone 1.5
Isopropyl Myristate 0.5
Tris-(hydroxymethyl)aminomethane at pH 5.8
The skin of hairless nude mice (HsdCpb NMRI-nude/nude, Harlan Bioservice,
Walsrode) was examined.
The solution in the acceptor compartment had the following coniposition:
Potassium chloride 0.4 g
Potassium dihydrogen phosphate 0.06 g
Sodium chloride 7.27 g
Sodium hydrogen phosphate dihydrate 0.06 g
HEPES 5.96 g
Gentamicin sulfate 0.05 g
y-Cyclodextrin 5.0 g
Aqua purificata to 1000 g
In the experiments, aliquots of 250 l of the sample were applied on the
surface of the
epidennal side of the skin (45 cm2) with the aid of a syringe. With the
fingertips, which were
protected by gloves, the samples were rubbed lightly on the skin surface. Five
minutes after
the gel was applied, a portion of the skin was introduced into the diffusion
cell. The acceptor
solution of the Franz cell was continuously homogenized. The available
permeation surface
CA 02523734 2005-10-26
43
area was 1.5 cm'`. After specified time intervals (3, 6, 9, 12, 15 and 18
hours), aliquots of the
acceptor solution were removed, injected into the HPLC unit and automatically
analyzed.
The content of eF-MENT in the samples was quantified with the aid of standard
solutions,
whereby the standard solutions were measured in parallel and under the same
HPLC
conditions.
HPLC:
Column: Vertex with precolumn, Nucleosil - 100 C18, 5 m, 125 x 3 min
Mobile Phase: Acetonitrile/water (39/61)
Flow rate: 0.700 ml/min
Temperature: 40 C
Injection volume: 200 l
Detecion wavelength: 244 nin
Retention time: eF-MENT 4.8 minutes.
The results of the studies are illustrated in Figure 2(transdermal gel #09W-
140 is used
as a conlparison exainple; transdermal gel #09W-141 is the example according
to the
invention).
The experiments confirm that the composition according to the invention (#09W-
141),
while having improved compatibility and improved application properties,
exhibits very good
permeation efficiency with respect to the active ingredient that is to be
administered
transdermally.
