UTILISATION DE POLYMERES FILMOGENES DE SOINS CAPILLAIRES A PARTIR DU GROUPE DES POLYURETHANES ET PREPARATIONS PHARMACEUTIQUES ET PANSEMENTS ADHESIFS CONTENANT CES POLYMERES

USE OF FILM-FORMING HAIR-CARE POLYMERS FROM THE GROUP OF POLYURETHANES AND PHARMACEUTICAL PREPARATIONS AND PLASTERS CONTAINING SAID POLYMERS

Abrégé français

L'invention concerne l'utilisation de polyuréthanes filmogènes trouvant une application dans les produits de soins capillaires ou de mélanges de ces polyuréthanes avec d'autres polymères dans des préparations pharmaceutiques destinées à l'application dermique ou transdermique de principes actifs. L'invention concerne également des pansements adhésifs et des préparations pharmaceutiques contenant ces polyuréthanes destinés aux soins capillaires.

Abrégé anglais

The present invention relates to the use of film-forming polyurethanes which
are used in hair-care products or the
use of mixtures of said polyurethanes and other polymers in pharmaceutical
preparations for dermal or transdermal application of
active agents, as well as to plasters and pharmaceutical preparations
containing said hair-care polyurethanes.

Revendications

31
Claims:
1 . Use of one or more film-forming polyurethane(s) used in hair care
agents or a
mixture thereof in a pharmaceutical preparation for dermal or transdermal
administration of
one or more active ingredient(s), wherein the one or more film-forming
polyurethane(s) is a
neutralized, completely reacted carboxylated linear polyurethane, comprising a
reaction
product from reaction of
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula I, in which R means hydrogen or C1-C20-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,
<IMG>
(2) 10 - 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic

32
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).
2. Use of
one or more film-forming polyurethane(s) used in hair care agents or a
mixture thereof in the manufacture of a pharmaceutical preparation for dermal
or transdermal
administration of one or more active ingredient(s), wherein the one or more
film-forming
polyurethane(s) is a neutralized, completely reacted carboxylated linear
polyurethane,
comprising a reaction product from reaction of
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula I, in which R means hydrogen or C1-C20-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,
<IMG>
(2) 10 - 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and

33
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).
3. Use of
one or more film-forming polyurethane(s) used in hair care agents or a
mixture thereof, further mixed with one or more other polymers or copolymers
of urethanes
and other monomers, in a pharmaceutical preparation for dermal or transdermal
administration of one or more active ingredient(s), wherein the one or more
film-forming
polyurethane(s) is a neutralized, completely reacted carboxylated linear
polyurethane,
comprising a reaction product from reaction of
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula I, in which R means hydrogen or C1-C20-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,
<IMG>
(2) 10 ¨ 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional

34
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).
4. Use of
one or more film-forming polyurethane(s) used in hair care agents or a
mixture thereof, further mixed with one or more other polymers or copolymers
of urethanes
and other monomers, in the manufacture of a pharmaceutical preparation for
dermal or
transdermal administration of one or more active ingredient(s), wherein the
one or more film-
forming polyurethane(s) is a neutralized, completely reacted carboxylated
linear
polyurethane, comprising a reaction product from reaction of
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula 1, in which R means hydrogen or C1-C20-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,
<IMG>

35
(2) 10 ¨ 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).
5. The use according to any one of claims 1 to 4, wherein the film-forming
polyurethane is a polyurethane-14-AMP-acrylate copolymer.
6. The use according to any one of claims 1 to 5, wherein the film-forming
polyurethane is the polyurethane-14-AMP-acrylate-copolymer Dynam®.
7. The use according to any one of claims 1 to 6, wherein the film-forming
polyurethane has a concentration in solution of 0.01-40% (w/w).
8. The use according to any one of claims 1 to 6, wherein the film-forming
polyurethane has a concentration in solution of 5-30% (w/w).

36
9. A dermal or transdermal pharmaceutical preparation comprising the film-
forming polyurethane as defined in any one of claims 1 to 8, and one or more
active
ingredients.
10. The dermal or transdermal pharmaceutical preparation according to claim
9,
wherein the one or more active ingredients are selected from the group
consisting of:
.circle. androgens selected from the group consisting of testosterone and
its esters,
testosterone dipropionate, 7-methyl-11-fluoro-19-nortestosterone and 7-methyl-
19-
nortestosterone;
.circle. estrogens selected from the group consisting of ethinyl estradiol,
mestranol,
quinestranol, estradiol, estrone, estrane, estriol, estetrol and conjugated
equine
estrogens;
.circle. gestagens selected from the group consisting of progesterone,
hydroprogesterone
caproate, levonorgestrel, norgestimate, norethisterone, drospirenone,
dydrogesterone,
norelgestromin, levonorgestrel, dienogest, danazol, lynestrenol, etonogestrel,
medrogestone, nestorone and cyproterone acetate;
.circle. m-cholinoceptor antagonists selected from the group consisting of
scopolamine,
trospium chloride, tiotropium and homatropine;
.circle. prostaglandins selected from the group consisting of dinoprost,
misoprostol,
sulprostone, and gemeprost;
.circle. finasteride, raloxifene, nicotine, oxytocin, nitroglycerin,
fentanyl, naloxone,
bupropion, clonidine, propranolol, metoprolol, diltiazem, nicardipine,
captopril,
isosorbide dinitrate, dimethyl isosorbide, talinolol, lidocaine, propipocaine,
diazepam,

37
midazolam, methyl phenidate, parathormone, rotigotine, insulin, heparin,
oxybutynin,
sulfaguanidine and zidovudine; and
their chiral forms and pharmaceutically acceptable salts.
11. The dermal or transdermal pharmaceutical preparation according to claim
10,
wherein the one or more active ingredients comprises testosterone.
12. The dermal or transdermal pharmaceutical preparation according to claim
9,
wherein the one or more active ingredients are selected from the group
consisting of:
.circle. oligomers of catechins that are included in tanning materials,
oligomers of
gallotannins with flavan derivatives, phenocarboxylic acids, gallic acid and
esterified
sugars of its derivatives;
.circle. antiseptic agents selected from the group consisting of
chlorhexidine, triclosan and
ethacridine;
.circle. antibiotics selected from the group consisting of fusidic acid,
erythromycin,
roxithromycin, clarithromycin, spiramycin, minocycline, clindamycin, neomycin
B,
kanamycin, gentamycin, amikacin, tobramycin, netilmicin metronidazole,
nimorazole,
tinidazole polymyxin B, colistin, tyrothricin, bacitracin, mupirocin and
cephalexin;
.circle. antifungal agents selected from the group consisting of
ketoconazole, itraconazole,
amphotericin B, griseofulvin, fluconazole, amorolfine, flucytosine,
terbinafine,
naftifine, ciclopirox, natamycin, nystatin, undecenoic acid and isoconazole;
.circle. topical corticosteroids selected from the group consisting of
methylprednisolone
aceponate, clobetasol propionate, mometasone fuorate, hydrocortisone,

38
betamethasone-17-benzoate, prednicarbate, diflucortolone valerate,
triamcinilone
acetonide, amcinonide, desoxymethasone, fluocortolone and fluticasone;
.circle. topical macrolide immunomodulators selected from the group
consisting of
tacrolimus and pimecrolimus;
.circle. antihistamines selected from the group consisting of azelastine,
fexofenadine,
levocabastine, loratadine, mizolastine, clemastine, bamipine, cetirizine,
dimetidine,
ketotifen, and emedastine;
.circle. immunosuppressive agents selected from the group consisting of
cyclosporin,
azathioprine and mycophenolate mofetil;
.circle. anthralins selected from the group consisting of cignolin and
dithranol;
.circle. vitamin D3 analogs selected from the group consisting of
calcipotriol and tacalcitol;
.circle. topical retinoids selected from the group consisting of tretinoin,
isotretinoin, acitretin,
adapalene and tazarotene;
.circle. cytostatic agents selected from the group consisting of
methotrexate, 5-fluorouracil, 5-
hydroxytamoxifen, zinc-pyrithione and fludarabin;
.circle. UV-protective stilbene derivatives;
.circle. plant extracts selected from the group consisting of green tea
extract, Centella asiatica
extract, willow bark extract, birch extract, tea tree oil, olive leaf extract,
aloe vera
extract, marigold extract, passion blossom extract, witch hazel extract,
chamomile
extract, bearberry leaf extract and licorice root extract, ZN combination of
18.beta.-
glycyrrhetic acid, and mixtures thereof; and
.circle. urea, lactic acid, fumaric acid ester, azelaic acid, hydroquinone,
benzoyl peroxide,
benzyl benzoate, ketoprofen, ibuprofen, salicylate, naproxen, diclofenac-Na
and salts,
ketorolac, indomethacin, piroxicam, nicotinamide, dipropyl phthalate,
aminopyrine,

39
flufenamic acid, ketotifen, polidocanol, oligonucleotides, si-RNA and
ribozymes,
RNA decoy nucleotides, aciclovir, penciclovir, idoxuridine, trifluridine,
vidarabine,
tromantadine, 5-aminolävulinic acid, lidocaine, procaine and cinchocaine; and
their chiral forms and pharmaceutically acceptable salts.
13. The dermal or transdermal pharmaceutical preparation according to claim
12,
wherein the one or more active ingredients comprises terbinafine.
14. The dermal or transdermal pharmaceutical preparation according to claim
12,
wherein the one or more active ingredients comprises 5-aminolävulinic acid.
15. The dermal or transdermal pharmaceutical preparation according to claim
12,
wherein the one or more active ingredients comprises urea.
16. The dermal or transdermal pharmaceutical preparation according to claim
12,
wherein the one or more active ingredients comprises hydrocortisone.
17. The dermal or transdermal pharmaceutical preparation according to claim
12,
wherein the one or more active ingredients comprises diclofenac or a
pharmaceutically
acceptable salt thereof.
18. The dermal or transdermal pharmaceutical preparation according to claim
12,
wherein the one or more active ingredients comprises a vitamin D3 analog
selected from the
group consisting of calcipotriol and tacalcitol.

40
19. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 9 to 18, comprising one or more solvents.
20. The dermal or transdermal pharmaceutical preparation according to claim
19,
comprising:
.circle. 0.01 - 30 % (w/w) of the one or more active ingredients, and
.circle. 0.01 - 99.98% (w/w) of the one or more solvents.
21. The dermal or transdermal pharmaceutical preparation according to claim
19
or 20, wherein the one or more solvents are compatible with skin and are
volatile.
22. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 19 to 21, wherein the one or more solvents are selected from the group
consisting of:
.circle. ethanol,
.circle. isopropanol,
.circle. ethyl acetate,
.circle. volatile silicones,
.circle. acetone, and
.circle. water.
23. The dermal or transdermal pharmaceutical preparation according to
any one of
claims 19 to 22, whereby the one or more solvents is an aqueous solvent
mixture whose
proportion of water is below 50% (w/w).

41
24. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 9 to 23, further comprising:
.circle. 0.01 - 20% (w/w) of one or more softeners,
.circle. 0.01 - 10% (w/w) of one or more moisturizers,
.circle. 0.01 - 10% (w/w) of one or more emulsifiers and/or
.circle. 0.01 - 15% (w/w) of one or more permeation enhancers.
25. The dermal or transdermal pharmaceutical preparation according to claim
24
wherein the one or more softeners are selected from the group:
.circle. triethyl citrate,
.circle. tributyl citrate,
.circle. acetyl triethyl citrate,
.circle. acetyl tributyl citrate,
.circle. triacetin,
.circle. dibutyl phthalate,
.circle. dibutyl sebacate,
.circle. diethyl phthalate,
.circle. propylene glycol,
.circle. polyethylene glycol,
.circle. glycerol, and
.circle. castor oil.

42
26. The dermal or transdermal pharmaceutical preparation according to claim
24
or 25, wherein the one or more moisturizers are selected from the group
consisting of:
.circle. glycerol,
.circle. sorbitol,
.circle. propylene glycol,
.circle. polyethylene glycol, and
.circle. polyvinyl pyrrolidone.
27. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 24 to 26, wherein the one or more emulsifiers are selected from the
group consisting
of:
.circle. Na-lauryl sulfate,
.circle. Na-cetyl stearyl sulfate,
.circle. glycerol fatty acid ester,
.circle. lecithin,
.circle. fatty alcohols,
.circle. cholesterol,
.circle. sorbitan fatty acid ester,
.circle. polyoxyethylene fatty acid ester,
.circle. polyoxyethylene fatty acid glycerides, and
.circle. polyoxyethylene fatty alcohol ether.

43
28. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 24 to 27, wherein the one or more permeation enhancers are selected
from the group
consisting of:
.circle. laurocaprams,
.circle. sulfoxides,
.circle. terpenes or ethereal oil,
.circle. oleic acid,
.circle. oleyl alcohol,
.circle. lauryl acid,
.circle. propylene glycol,
.circle. propylene carbonate,
.circle. N-methyl-pyrrolidone, and
.circle. isopropyl myristate.
29. The dermal or transdermal pharmaceutical preparation according to claim
28,
wherein the one or more permeation enhancers are selected from the group
consisting of:
.circle. oleic acid,
.circle. R-(+)-limonene,
.circle. isopropyl myristate,
.circle. combination of oleic acid with propylene glycol,
.circle. R-(+)-limonene with propylene glycol, and
.circle. isopropyl myristate with propylene glycol.

44
30. The dermal or transdermal pharmaceutical preparation according to claim
29,
wherein the isopropyl myristate is mono-isopropyl myristate.
31. The dermal or transdermal pharmaceutical preparation according to claim
29,
wherein the combination of oleic acid with propylene glycol is in a 1:1 ratio.
32. The dermal or transdermal pharmaceutical preparation according to claim
29,
wherein the R-(+)-limonene with propylene glycol is in a 1:1 ratio.
33. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 24 to 32, comprising polyurethane-14-AMP-acrylate-copolymer
DynamX®, isopropyl
myristate, isopropanol, triethyl citrate, ethanol and water.
34. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 24 to 32, comprising polyurethane-14-AMP-acrylate-copolymer
DynamX®, triethyl
citrate, oleic acid, propylene glycol, ethanol and water.
35. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 24 to 32, comprising polyurethane-14-AMP-acrylate-copolymer
DynamX®, triethyl
citrate, ethanol and water.
36. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 24 to 32, comprising polyurethane-14-AMP-acrylate-copolymer
DynamX®, triethyl
citrate and ethanol.

45
37. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 24 to 32, comprising polyurethane-14-AMP-acrylate-copolymer
DynamX®, isopropyl
myristate, isopropanol, triethyl citrate, propylene glycol, ethanol and water.
38. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 9 to 37 in the form of a solution, emulsion or suspension.
39. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 9 to 38 which can be sprayed.
40. The dermal or transdermal pharmaceutical preparation according to claim
39,
further comprising a propellant.
41. The dermal or transdermal pharmaceutical preparation according to any
one of
claims 9 to 40 for use for dermal or transdermal administration of the one or
more active
ingredients.
42. Applicator that contains a dermal or transdermal pharmaceutical
preparation
according to any one of claims 9 to 41.
43. The applicator according to claim 42, in the form of a roller, a pump
sprayer, a
sprayer, a tube, a brush bottle or a pipette bottle.

46
44. Flexible, readily adhesive, non-sticky, cosmetically inconspicuous
patch for
dermal or transdermal administration of an active ingredient obtained by
applying a dermal or
transdermal pharmaceutical preparation according to any one of claims 9 to 39
on the skin
and subsequent evaporation of the solvent.
45. The patch according to claim 44, wherein the water vapor permeability
is
above 0.05 g*cm-2*24 h-1.

Description

CA 02633599 2008-06-17
Use of Film-Forming Hair Care Polymers from the Group of Polyurethanes and
Pharmaceutical Preparations and Plasters Containing Said Polymers
The invention relates to the use of film-forming hair care polymers from the
group
of polyurethanes and pharmaceutical preparations that contain these hair care
polymers for
dermal or transdermal administration of active ingredients. The pharmaceutical
preparations are applied on the skin in liquid form. By evaporation of the
likewise
contained solvent, they form there a flexible, cosmetically inconspicuous,
readily
adhering, non-sticky film, from which a controlled release of active
ingredient into the
skin or through the skin in the systemic circuit is carried out.
The human skin as a target organ of the pharmaceutical substance
administration is
currently used in two respects. On the one hand, active ingredients are
administered
locally for treatment of various dermal diseases such as psoriasis or
neurodermatitis. On
the other hand, active ingredients can be administered transdermally for
treatment of
systemic diseases and for hormone substitution.
In the case of local administration, semisolid preparations, such as
ointments,
creams or gels, are predominant. In most cases, the transdermal administration
takes place
via transdermal therapeutic systems, such as matrix or reservoir patches. In
recent years,
semi-solid products (hydroalcoholic gels, such as, for example, Testogel )
have also been
used for transdermal administration.
In the gel formulations for transdermal administration that are found on the
market,
the active ingredients that are to permeate as alcoholic solution are present.
They are
thickened by means of a polymer (for example polyacrylic acid) and applied
once daily on
the skin in the form of a hydro alcoholic gel.

CA 02633599 2008-06-17
2
Since alcohols evaporate quickly, the active ingredients also have only a
short time
to get into the epidermis. More than 90% of the active ingredient therefore
does not get
into the blood, but rather for the most part remains on the surface of the
skin. The quick
loss of the solvent results in a supersaturation, which frequently results in
active
ingredients crystallizing out. A penetration is then considerably hampered
since the active
ingredient can diffuse into the skin only in dissolved form.
Active ingredient residues that are not fixed to the skin involve the danger
of a
dose loss as well as a contamination of clothing or other people.
In particular in the transdermal administration, very frequently large
application
surface areas are required to transport the necessary amounts of active
ingredient through
the skin. This requires high gel volumes of several milliliters per single
dose. The
patients consider this to be impractical and unpleasant in the handling.
Finally, control of
the release of active ingredient over an extended period with standard gel
preparations is
not possible.
In contrast to this, a controlled release of active ingredient in the
transdermal
therapeutic systems is possible, but generally the number of offered dosages
is limited for
reasons of marketing logistics. An individual, patient-related dosage is
therefore possible
only to a limited extent. Also, with respect to the contact surface area of
the transdermal
therapeutic system on the skin, limits are placed on the dosage range. Patches
larger than
20 cm2 are uncomfortable to wear owing to the large area of skin to which they
are fixed.
Other drawbacks are skin irritations that are caused by the adhesive layer of
the patch, as
well as cosmetic impairments. In addition, the production of transdermal
patches requires
expensive devices and procedures.

CA 02633599 2014-03-06
3
For many of the above-mentioned drawbacks, solutions were already offered in
the
past. Thus, in EP1150661B1, a topical spray that contains a film-forming
composition and
one or more active ingredients is claimed. This spray contains, i.a., film-
forming polymers.
Applied on the skin, it produces a flexible, readily adhering, breathing film.
This invention may provide alternative pharmaceutical preparations that ¨
applied on
the skin ¨ form a film that is improved relative to the active ingredient
permeation compared
to known preparations.
The invention uses a film-forming polyurethane that is usually used in hair
care
agents or a mixture of this polyurethane with various other polymers in
pharmaceutical
preparations for dermal or transdermal administration of active ingredients.
In one aspect, the present invention provides use of one or more film-forming
polyurethane(s) used in hair care agents or a mixture thereof in a
pharmaceutical preparation
for dermal or transdermal administration of one or more active ingredient(s),
wherein the one
or more film-forming polyurethane(s) is a neutralized, completely reacted
carboxylated linear
polyurethane, comprising a reaction product from reaction of
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula I, in which R means hydrogen or CI-Cm-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,

CA 02633599 2014-03-06
3a
OH
R COOH
HO
Formel I
[Formula I]
(2) 10 ¨ 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).
In another aspect, the present invention provides use of one or more film-
forming
polyurethane(s) used in hair care agents or a mixture thereof in the
manufacture of a
pharmaceutical preparation for dermal or transdermal administration of one or
more active
ingredient(s), wherein the one or more film-forming polyurethane(s) is a
neutralized,
completely reacted carboxylated linear polyurethane, comprising a reaction
product from
reaction of

CA 02633599 2014-03-06
3b
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula I, in which R means hydrogen or CI-Cm-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,
OH
RCOOH
HO
Forme! I
[Formula I]
(2) 10 ¨ 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).
In another aspect, the present invention provides use of one or more film-
forming
polyurethane(s) used in hair care agents or a mixture thereof, further mixed
with one or more
other polymers or copolymers of urethanes and other monomers, in a
pharmaceutical

CA 02633599 2014-03-06
3c
preparation for dermal or transdermal administration of one or more active
ingredient(s),
wherein the one or more film-forming polyurethane(s) is a neutralized,
completely reacted
carboxylated linear polyurethane, comprising a reaction product from reaction
of
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula I, in which R means hydrogen or Ci-C20-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,
OH
R.COOH
HO
Formel I
[Formula I]
(2) 10¨ 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).

CA 02633599 2014-03-06
3d
In another aspect, the present invention provides use of one or more film-
forming
polyurethane(s) used in hair care agents or a mixture thereof, further mixed
with one or more
other polymers or copolymers of urethanes and other monomers, in the
manufacture of a
pharmaceutical preparation for dermal or transdermal administration of one or
more active
ingredient(s), wherein the one or more film-forming polyurethane(s) is a
neutralized,
completely reacted carboxylated linear polyurethane, comprising a reaction
product from
reaction of
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), represented
by
formula I, in which R means hydrogen or Ci-C20-alkyl, present in an amount by
weight that is
sufficient to produce 0.35-2.25 milliequivalents of carboxyl functional group
per gram of
polyurethane,
OH
R COOH
HO
Formel I
[Formula I]
(2) 10¨ 90% by weight, relative to the weight of polyurethane, of one or more
organic
compound(s), each of said one or more organic compound(s) not having more than
two active
hydrogen atoms and being selected from the group consisting of linear
bifunctional
polyethylene glycols, linear bifunctional polypropylene glycols, polyether
diols, polyester
diols, polyacetal diols, polyamide diols, polyesters, polyester polyamide
diols, poly(alkylene
ether) diols, polythioether diols and polycarbonate diols, and

CA 02633599 2014-03-06
3e
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to react
with the active hydrogen atoms of the one or more 2,2-hydroxymethyl-
substituted carboxylic
acid(s) and the one or more organic compound(s), with the exception of
hydrogen at the
carboxylate of the one or more 2,2-hydroxymethyl-substituted carboxylic
acid(s).
In another aspect, the present invention provides a dermal or transdermal
pharmaceutical preparation comprising the film-forming polyurethane according
to the
present invention, and one or more active ingredients.
In another aspect, the present invention provides dermal or transdermal
pharmaceutical preparation according to the invention for use for dermal or
transdermal
administration of the one or more active ingredients.
In another aspect, the present invention provides an applicator that contains
a dermal
or transdermal pharmaceutical preparation according to the invention.
In another aspect, the present invention provides flexible, readily adhesive,
non-
sticky, cosmetically inconspicuous patch for dermal or transdermal
administration of an
active ingredient obtained by applying a dermal or transdermal pharmaceutical
preparation
according to the invention on the skin and subsequent evaporation of the
solvent.
It was found, surprisingly enough, that the polyurethanes used in hair care
agents
exhibit good properties with respect to flexibility, stability on the skin and
breathing activity,
similar to preparations with known polymers (such as, for example, Eudragit )
in the case of
clearly elevated active ingredient permeation.
To this end, the film-forming polyurethanes are dissolved or suspended
together with
one or more active ingredients in a suitable solvent and with the addition of
some adjuvants,
and the thus formed pharmaceutical preparation is applied in liquid form on
the skin.

CA 02633599 2014-03-06
3f
The application of the thus formed pharmaceutical preparation on the nail, for
example for treating nail psoriasis or nail mycoses (onychomycosis), is also
possible.
After the solvent evaporates on the skin, the pharmaceutical preparation forms
a thin,
flexible invisible film. From the film that is formed, one or more active
ingredients can be
directed onto the skin via the polymer reservoir that is produced or can be
released

CA 02633599 2008-06-17
4
through the skin into the systemic circuit. The administration method that is
proposed
here is distinguished by a simple administration, for example by spraying or
brushing the
pharmaceutical preparation, a flexible dosage and a controllable release of
active
ingredient over an extended period. The film that is produced shows good
adhesion on the
skin with low irritation potential and an inconspicuous appearance. By the
fixing of the
active ingredient in film on the skin, a loss of active ingredient by contact
with clothing or
a contamination of other people is avoided. Another advantage of this
invention is that
unlike in the production of transdermal patches, no expensive devices or
procedures are
required. The various components are dissolved only in the solvent or
suspended and
decanted. The application of the solution can be carried out independently of
the skin
condition. In contrast to the patch, which should be applied to a hairless,
smooth location,
existing hair or wrinkles do not produce any problems.
During the evaporation of the solvent, no recrystallization of the active
ingredients
that are used takes place. Rather, a supersaturated solution, which shows a
high
thermodynamic activity, is produced. As a result, the permeation of the active
ingredient
in the skin is enhanced on a permanent basis. Also, in dried film, the active
ingredient
does not crystallize out, but rather is present in dissolved form. This allows
diffusion
within the film, so that the active ingredient can also diffuse to the
interface after the film
is dried and can be released to the skin. In the formulations, either an
individual active
ingredient can be added, or several active ingredients (for example estrogens
such as
ethinylestradiol in combination with gestagens such as levonorgestrel) can be
added,
which then are transported together or in parallel through the skin. By the
hair care
polyurethanes, the recrystallization of the active ingredient is avoided and
simultaneously
its absorption through the skin is promoted thermodynamically.

CA 02633599 2008-06-17
Hair care polymers that are suitable for use in pharmaceutical preparations
according to the invention belong to the group of polyurethanes. The
polyurethanes that
are used in hair care products, alone or in combination with other polymers,
such as, for
example, acrylates, are especially well suited for this application, since the
films that are
formed have a high flexibility with simultaneously greater strength. Examples
of suitable
polyurethanes can be found in the following list. In the list, polyurethanes
are cited
according to their trade names. Within the corresponding parentheses, the
designation of
the polyurethane and the respective current manufacturer are indicated.
- Luviset P.U.R. (polyurethane-1, BASF),
- DynamX (polyurethane-14 and AMP-acrylate copolymer, National Starch and
Chemical),
- Avalure UR 405, Avalure UR 425 (polyurethane-2, Noveon),
- Avalure UR 445 (polyurethane-4, Noveon),
- Avalure UR 450 (polypropyleneglycol-17/isophorone diisocyanate/
dimethylpropionic acid copolymer, Noveon)
- AquamereTTM A/H (polyvinylpyrrolidone/polycarbamyl/polyglycol ester)
- Aquamere TM C
(polyvinylpyrrolidone/dimethylaminoethylmethacrylate/polycarbamyl/poly-
glycol ester)
- AquamereTM S
(polyvinylpyrrolidone/dimethiconylacrylate/polycarbamyl/polyglycol ester)
The use of an optionally neutralized, completely reacted, carboxylated linear
polyurethane, comprising the reaction product that consists of

CA 02633599 2008-06-17
6
(1) one or more 2,2-hydroxymethyl-substituted carboxylic acid(s), produced by
the
formula I, in which R means hydrogen or C i-C20-alkyl, present in an amount by
weight
that is sufficient to produce 0.35-2.25 milliequivalents of carboxyl
functionality per gram
of polyurethane,
OH
RCOOH
HO/
Formel I
[Formula I]
(2) 10 ¨ 90% by weight, relative to the weight of polyurethane, of one or more
organic compound(s), which in each case do not have more than two active
hydrogen
atoms, and
(3) one or more organic diisocyanate(s), present in an amount that is
sufficient to
react with the active hydrogen atoms of the 2,2-hydroxymethyl-substituted
carboxylic acid
and the organic compounds, with the exception of hydrogen at the carboxylate
of the 2,2-
hydroxymethyl-substituted carboxylic acid,
is preferred.
The 2,2-hydroxymethyl-substituted carboxylic acids are produced by the formula
I
OH
RCOOH
HO/
Formel I
[Formula I]

CA 02633599 2008-06-17
7
in which R means hydrogen or CI-C20-alkyl, preferably CI-Cs-alkyl. Special
examples
comprise 2,2-di-(hydroxymethyl)acetic acid, 2,2-di(hydroxymethyl)propionic
acid, 2,2-
di(hydroxymethyl)butyric acid, 2,2-di(hydroxymethyl)pentanoic acid, etc. The
preferred
acid is 2,2-di(hydroxymethyl)propionic acid. The 2,2-hydroxymethyl-substituted
carboxylic acids are present in an amount that yields 0.35-2.25, preferably
0.5-1.85,
milliequivalents of carboxyl functionality per gram of polyurethane, and in
general this is
about 5-30% by weight of the polyurethane polymer.
The organic compounds, which react with isocyanate and can be used for the
production of the polyurethane polymers according to the invention, have no
more than
two active hydrogen atoms (determined according to the Zerewitinoff method).
The active
hydrogen atoms are normally bonded to oxygen, nitrogen or sulfur atoms. These
compounds have a molecular weight of about 300 to 20,000, preferably about 500
to
8,000. The compounds are preferably linear to avoid gelling during the
polymerization,
but small amounts of non-linear compounds can be used with the proviso that
their use
does not lead to any gelling. The organic compounds are present in an amount
of 10-90%
by weight, preferably in an amount of 15-70% by weight, of the polyurethane.
The preferred organic compounds with two active hydrogen atoms are the linear
bifunctional polyethylene and polypropylene glycols, in particular those that
are
commercially available and are produced by reaction of ethylene oxide (or
propylene
oxide) with water, ethylene glycol (or propylene glycol) or diethylene glycol
(or
dipropylene glycol) in the presence of sodium hydroxide as a catalyst. These
polyglycols
have molecular weights of about 600 to 20,000, preferably about 1,000 to
8,000.
Polyglycols with homogeneous molecular weight or a mixture of glycols with
different

CA 02633599 2008-06-17
8
molecular weights can be used. It is also possible to incorporate small
amounts of
additional alkylene oxides by copolymerization into the polyglycol.
Other suitable organic compounds with two active hydrogen atoms are those that
have hydroxyl, carboxyl, amino or mercapto groups. Among them, polyhydroxy
compounds, such as polyether diols, polyester diols, polyacetal diols,
polyamide diols,
polyester polyamide diols, poly(alkylene ether) diols, polythioether diols and
polycarbonate diols are preferred. Compounds with two or more different groups
within
these classes, for example amino alcohols and amino alcohols with two amino
groups and
one hydroxyl group, can also be used. Bifunctional compounds are preferably
used,
although small amounts of tri- (and multi-) functional compounds can also be
used.
Suitable polyether diols are, for example, the condensation products that
consist of
ethylene oxide, propylene oxide, butylene oxide or tetrahydrofuran and their
co-, graft or
block polymerization products, such as mixed ethylene oxide, propylene oxide
condensates and the graft polymerization products from the reaction of olefins
that are
under high pressure with the mentioned alkylene oxide condensates. Suitable
polyethers
are produced by condensation of the above-mentioned alkylene oxides with
multivalent
alcohols, such as ethylene glycol, 1,2-propylene glycol and 1,4-butanediol.
Suitable polyester diols, polyester amide diols, and polyamide diols are
preferably
saturated and are obtained by, for example, reaction of saturated or
unsaturated
polycarboxylic acids with saturated or unsaturated multivalent alcohols,
diamines or
polyamines. For the production of these compounds, suitable carboxylic acids
comprise,
for example, adipic acid, succinic acid, phthalic acid, terephthalic acid, and
maleic acid.
For the production of polyesters, suitable multivalent alcohols comprise, for
example,
ethylene glycol, 1,2-propylene glycol, 1,4-butanediol, neopentyl glycol and
hexanediol.

CA 02633599 2008-06-17
9
Amino alcohols, such as ethanolamine, are also suitable. For the production of
polyester
amides and polyamides, suitable diamines are, for example, ethylenediamine and
hexamethylenediamine.
Suitable polyacetals can be produced from, for example, 1,4-butanediol or
hexanediol and formaldehyde. Suitable polythio ethers can be produced by, for
example,
condensation of thiodiglycol alone or combined with other glycols, such as
ethylene
glycol, 1,2-propenylene glycol, or with other polyhydroxy compounds, as
previously
disclosed. Polyhydroxy compounds, which already contain urea or urethane
groups, and
natural, multivalent alcohols, which can be further modified, for example
castor oil and
carbohydrates, can also be used.
In the production of the polyurethane polymer, it may be desirable to subject
the
polymer, in addition to the organic compound, with not more than two active
hydrogen
atoms, which in many cases has a high molecular weight, with use of an organic
compound with a lower molecular weight, preferably of less than about 300 and
more than
60, to a chain lengthening. Typical chain-lengthening agents comprise
saturated or
unsaturated glycols, such as ethylene glycol, diethylene glycol, triethylene
glycol, etc.;
amino alcohols, such as ethanolamine, propanolamine, butanolamine, etc.; mono-
and di-
alkoxylated aliphatic, cycloaliphatic, aromatic and heterocyclic primary
amines, such as
N-methyl diethanolamine, N-oleyldiethanolamine, N-
cyclohexyldiisopropanolamine, N,N-
dihydroxyethyl-p-toluidine, N,N-dihydroxypropylnaphthylamine, etc.; diamines,
such as
ethylenediamine, piperazine, N,N-bis-gamma-aminopropyl-N-methylamine, etc.;
carboxylic acids, including aliphatic, cycloaliphatic, aromatic and
heterocyclic
dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, glutaric
acid, adipic
acid, sebacic acid, terephthalic acid, naphthalene-1,5-dicarboyxlic acid,
maleic acid,

CA 02633599 2008-06-17
fumaric acid, diglycolic acid, quinolinic acid, lutidinic acid, etc.;
aminocarboxylic acids,
such as glycine, alpha- and beta-alanine, 6-aminocaproic acid, 4-aminobutyric
acid, p-
aminobenzoic acid, and 5-aminonaphthoic acid, etc. The preferred chain-
lengthening
agents are aliphatic diols.
The organic polyisocyanates or mixtures of polyisocyanates, which can be
reacted
with the organic compound, are aliphatic or aromatic polyisocyanates or
mixtures thereof.
The polyisocyanates are preferably diisocyanates, thus a linear polymer is
produced,
although small amounts of trifunctional isocyanates together with the
diisocyanates can be
used. The isocyanate is present in an amount that is sufficient to react with
the active
hydrogen atoms of the 2,2-hydroxymethyl-substituted carboxylic acid and the
organic
compounds, with the exception of hydrogen at the carboxylate of 2,2-
hydroxymethyl-
substituted carboxylic acid. This amount varies, based on the amount of
carboxylic acid
and organic compounds.
Examples of diisocyanates comprise, without, however, being limited thereto,
methylenedi-p-phenyldiisocyanate, methylene-bis(4-cyclohexylisocyanate),
isophorone
diisocyanate, toluene diisocyanate, 1,5-naphthalene diisocyanate, 4,4'-
diphenylmethane
diisocyanate, 2,2'-dimethy1-4,4'-diphenylmethane diisocyanate, 4,4'-dibenzyl
diisocyanate,
1,3-phenylene diisocyanate, 1,4-phenylene diisocyanate, mixtures of 2,4-and
2,6-toluene
diisocyanate, 2,2'-dichloro-4,4'-diphenylmethane diisocyanate, 2,4-dibromo-1,5-
naphthalene diisocyanate, butane-1,4-diisocyanate, hexane-1,6-diisocyanate,
and
cyclohexane-1,4-diisocyanate.
If it is not desired to lengthen the polymer chain, the reaction of the
diisocyanate
with the organic compound, which contains two active hydrogen atoms, is
brought to a
halt by adding a monofunctional compound that contains active hydrogen in
order to

CA 02633599 2008-06-17
11
consume any residual isocyanate functionality. Examples of these chain
stoppers are well
known in this area of expertise; for this system, the preferred chain stopper
is ethanol.
The polymerization of urethanes is performed in the reaction medium with or
without, typically, catalysts for the urethane reaction that are known in the
area of
expertise. Suitable catalysts comprise dibutyltin-dilaurate, tin(II) salts of
carboxylic acids
with 2 to 18 carbon atoms, such as tin(II) laurate, tin(II) stearate, tin(II)
acetate, tin(II)
butyrate, tin(II) octoate, etc., as well as mixtures thereof. The other
suitable catalysts
include dibutyltin oxide, dibutyltin sulfide, lead resinate, lead benzoate,
lead salicylate,
lead-2-ethyl hexoate, lead oleate, iron acetyl acetonate, cobalt benzoate,
tetra(2-
ethylhexyl)-titanate, tetrabutyl titanate, etc. Many other compounds
accelerate the
reaction of a hydroxyl group or another group with an isocyanate rather than
certain other
reactions of the isocyanate group, and any of these compounds can be used. The
experts
are to select a special catalyst to impart desirable characteristic features
to the individual
urethane reactions. The existing special compounds are the preferred compounds
and are
mentioned as explanatory and not limiting. In addition, any suitable tertiary
amine, for
example triethylenediamine, N-ethylmorpholine, N-methylmorpholine or 4-
dimethylamino-ethylpiperazine, can be used either alone or together with the
metal
catalyst.
As far as the ratio of the co-reactants is concerned, it should be selected
such that
the molecular ratio of the isocyanate groups to the active hydrogen atoms is
as close as
possible to 1:1. Certainly, this exact ratio cannot always be achieved in
practice;
therefore, a ratio of between about 0.7:1 and 1.3:1 and preferably between
about 0.9:1 and
1.2:1 should be sought, and any excess diisocyanate can, as previously
discussed, be
suppressed with the monofunctional compound that contains active hydrogen.

CA 02633599 2008-06-17
12
The polymerization is performed according to known polymerization processes
for
the production of polyurethane that are well known to the experts. By way of
example,
polymerization processes and reaction conditions are indicated in the examples
of
DE69401230T2.
The use of the polyurethane-14-AMP-acrylate copolymer (DynamX ) is especially
preferred.
The hair care polymers from the group of polyurethanes that are listed above
form
cosmetically inconspicuous and flexible films on the skin. Cosmetically
inconspicuous
and flexible films are then always present if the formed film is transparent
and is barely or
only moderately fixed to the skin. A strong attachment to the skin would
result in
undesirable wrinkling. The wearing comfort and the cosmetic attractiveness
would be
reduced. During a wearing time of at least 24 hours, the films show a
sufficient adhesion
(i.e., no peeling off or detaching) and have so high a flexibility that during
this time, no
visible cracks form. An extended wearing period of 72-84 hours ¨ this
corresponded to a
twice-weekly administration ¨ is also conceivable.
The pharmaceutical composition according to the invention in this case
combines a
simple administration and a flexible dosage. It is quick-drying, non-sticky
and readily
adhesive. The release of active ingredients can be controlled over an extended
period. For
hormones, a higher active ingredient permeation through the human epidermis
than in the
hormone patches that are usual in the market or from ethanolic hormone
solutions of the
same concentration is reached in this case. There is no contamination of
clothing or other
people.
For viscosity and cosmetic reasons, the concentration of the film-forming hair
care
polyurethane in the pharmaceutical preparations must move only within specific
limits.

CA 02633599 2008-06-17
13
An excessive polymer proportion results in a considerable increase in
viscosity. An
administration, for example by spraying, would thus be hampered. Another
result would
be the formation of films that are too thick, which in turn would cause a
strong fixing to
the skin and thus an undesirable wrinkling. The thickness of the polymer films
thus
formed by application of the pharmaceutical preparation on the skin is above 1
pm and
must not exceed 100 pm. Preferred film thicknesses are between 5 m and 50
urn.
Since the amount of the polyurethane that is contained, however, also has an
influence on the active ingredient loading capacity, a concentration range can
be set
individually for each polyurethane that produces a film that is based on the
properties of
the polymer and the active ingredient, and said film makes possible an
adequate active
ingredient permeation over the desired period and at the same time corresponds
to the
cosmetic requirements (no wrinkling). The polyurethane concentration in the
liquid
pharmaceutical preparation (without propellants) can in this case take on
values of
between 0.01 to 40% (w/w), preferably from 5 to 30%.
The polyurethane films, moreover, show only a low occlusivity, i.e., a water
vapor
permeability of greater than 0.05 g * cm-2 * 24111 (determination according to
Ph. Brit
1993 Appendix XXJ). They are thus also suitable for extended periods of use.
In addition to one or more of the above-mentioned polyurethanes, optionally as
a
mixture of additional polymers, the pharmaceutical preparation according to
the invention
also contains at least one suitable solvent as well as at least one active
ingredient.
As active ingredients, all pharmaceutically active substances are suitable
that can
be incorporated into the polyurethane solutions and allow a dermal or
transdermal
administration in corresponding indications. Also, the administration of
active ingredients
for therapy of dermal diseases, such as for example, of mycoses, is
conceivable by means

CA 02633599 2008-06-17
14
of the pharmaceutical preparation according to the invention. Thus, skin
lesions can be
treated specifically, for example by spraying with the polyurethane solution.
For the
treatment of injured skin, attention must be paid especially to the
compatibility of the
solvent.
The following list names active ingredients that are suitable for
administration with
the pharmaceutical preparations according to the invention:
For the transdermal administration, the following are suitable:
- Androgens, such as testosterone and its esters (such as, for example,
testosterone dipropionate), 7-methyl-11-fluoro-19-nortestosterone or 7-methyl-
19-nortestosterone
- Estrogens, such as ethinyl estradiol, mestranol, quinestranol, estradiol,
estrone,
estrane, estriol, estetrol and conjugated equine estrogens,
- Gestagens, such as progesterone, hydroprogesterone caproate,
levonorgestrel,
norgestimate, norethisterone, drospirenone, dydrogesterone, norelgestromin,
levonorgestrel, dienogest, lynestrenol, etonogestrel, medrogestone, nestorone
and cyproterone acetate
- m-Cholinoceptor antagonists, such as scopolamine, trospium chloride,
tiotropium and homatropine
- Prostaglandins, such as dinoprost, misoprostol, sulprostone, and
gemeprost;
- As well as danazol, finasteride, raloxifene, nicotine, oxytocin,
nitroglycerin,
fentanyl, naloxone, bupropion, clonidine, propranolol, metoprolol, diltiazem,
nicardipine, captopril, isosorbide dinitrate, isosorbide mononitrate, dimethyl
isosorbide, talinolol, lidocaine, propipocaine, diazepam, midazolam, methyl

CA 02633599 2008-06-17
phenidate, parathormone, rotigotine, insulin, heparin, oxybutynin,
sulfaguanidine and/or zidovudine,
including their chiral forms and pharmaceutically acceptable salts.
For the dermal application, the following are suitable:
- The oligomers of catechins that are included in the tanning materials,
oligomers of gallotannins with flavan derivatives, phenocarboxylic acids,
gallic
acid and esterified sugars of its derivatives
- Antiseptic agents, such as chlorhexidine, triclosan and ethacridine
- Antibiotics, such as fusidic acid, erythromycin, roxithromycin,
clarithromycin,
spiramycin, minocycline, clindamycin, neomycin B, kanamycin, gentamycin,
amikacin, tobramycin, netilmicin metronidazole, nimorazole, tinidazole
polymyxin B, colistin, tyrothricin, bacitracin, mupirocin and cephalexin
- Antifungal agents, such as ketoconazole, itraconazole, amphotericin B,
griseofulvin, fluconazole, amorolfine, flucytosine, terbinafine, naftifine,
ciclopirox, natamycin, nystatin, undecenoic acid and isoconazole
- Topical corticosteroids, such as methylprednisolone aceponate, clobetasol
propionate, mometasone fuorate, hydrocortisone, betamethasone-17-benzoate,
prednicarbate, diflucortolone valerate, triamcinilone acetonide, amcinonide,
desoxymethasone, fluocortolone and fluticasone
- Topical immunomodulators (macrolides), such as tacrolimus and
pimecrolimus, but also epothilones
- The antihistamines azelastine, fexofenadine, levocabastine, loratadine,
mizolastine, clemastine, bamipine, cetirizine, dimetidine, ketotifen, and
emedastine

CA 02633599 2008-06-17
16
- The immunosuppressive agents cyclosporin, azathioprine and mycophenolate
mofetil
- The anthralins cignolin and dithranol
- The vitamin D3 analogs calcipotriol and tacalcitol
- The topical retinoids tretinoin, isotretinoin, acitretin, adapalene and
tazarotene
- The cytostatic agents methotrexate, 5-fluorouracil, 5-hydroxytamoxifen,
zinc-
pyrithione and fludarabin
- The UV-protective stilbene derivatives
- The plant extracts green tea extract, Centella asiatica extract, willow
bark
extract, birch extract, tea tree oil, olive leaf extract, aloe vera extract,
marigold
extract, passion blossom extract, witch hazel extract, chamomile extract,
bearberry leaf extract and licorice root extract, for example as 18B-
glycyrrhetic
acid (Zn combination) or mixtures thereof, as well as
- Urea, lactic acid, fumaric acid ester, azelaic acid, hydroquinone,
benzoyl
peroxide, benzyl benzoate, ketoprofen, ibuprofen, salicylate, naproxen,
diclofenac-Na and salts, ketorolac, indomethacin, piroxicam, nicotinamide,
dipropyl phthalate, aminopyrine, flufenamic acid, ketotifen, polidocanol,
oligonucleotides, si-RNA and ribozymes, RNA decoy nucleotides, aciclovir,
penciclovir, idoxuridine, trifluridine, vidarabine, tromantadine, 5-
aminolavulinic acid, lidocaine, procaine and cinchocaine,
including their chiral forms and pharmaceutically acceptable salts.
In this case, the active ingredient can be present both in dissolved form and
as an
emulsion or suspension.

CA 02633599 2008-06-17
17
The concentration of the active ingredient in the polymer film that is
produced
from the pharmaceutical preparation depends on the active ingredient level to
be achieved.
It is dependent on the skin permeation of the active ingredient and optionally
on the
presence of permeation enhancers in the formulation. In solutions, the amount
of active
ingredient to be incorporated is limited by the saturation solubility of the
active ingredient
in the solution. If the latter is exceeded, the active ingredient is present
in partially
dissolved and partially suspended form. The amount of the active ingredients
contained in
the pharmaceutical preparation according to the invention is between 0.01 and
30% (w/w),
preferably between 0.01 and 15% (w/w).
The polyurethane films according to the invention are very thin systems with
limited loading capacity. Therefore, active ingredients are preferably
suitable for
administration by this system that either have structurally produced a good
skin
permeation, can be transported very efficiently through the skin by the
polymer system per
se or a permeation-promoting addition or are highly potent and therefore must
be
administered only in small doses. In this connection, hormones, primarily
estrogens,
gestagens, and androgens, especially ethinyl estradiol and levonorgestrel, are
especially
suitable.
To avoid long waiting periods when the preparation is dried, which can impair
the
patient compliance, skin-compatible, slightly volatile solvents are used.
These are
preferably ethanol, isopropanol, ethyl acetate, volatile silicones, acetone
and water. The
solvent can be used alone or combined with one another. In the case of aqueous
solvent
mixtures, the proportion of water is preferably below 50% (w/w) based on the
otherwise
extended drying period.

CA 02633599 2008-06-17
18
One or more softeners optionally can be added to the pharmaceutical
preparations.
Preferred softeners are triethyl citrate, tributyl citrate, acetyl triethyl
citrate, acetyl tributyl
citrate, triacetin, dibutyl phthalate, tributyl sebacate, diethyl phthalate,
propylene glycol,
polyethylene glycol, glycerol or castor oil. In this case, the softener
content must be
adapted to the polyurethane and its concentration, since in the case of a
softener content
that is too high, the film is sticky. In the case of a softener content that
is too low,
however, the adhesiveness and flexibility decrease. The film would then flake
off or
become cracked after a certain time. The proportion of softeners optionally to
be added in
the pharmaceutical composition according to the invention is preferably
between 0.01 and
20% (w/w). The softeners can be used alone or in combination with one another.
In addition, optionally still other pharmaceutically compatible substances
such as
moisturizers and emulsifiers can be added to the pharmaceutical compositions
according
to the invention.
As moisturizers, preferably glycerol, sorbitol, propylene glycol, polyethylene
glycol or polyvinyl pyrrolidone as well as combinations thereof are suitable.
The
proportion of the pharmaceutical preparation thereof is preferably between
0.01 and 10%
(w/w).
Emulsifiers that are preferred according to the invention are Na-cetylstearyl
sulfate, glycerol fatty acid ester, lecithin, fatty alcohols, cholesterol,
sorbitan fatty acid
ester, polyoxyethylene(POE)-fatty acid ester, POE-fatty acid glycerides, or
POE-fatty
alcohol ethers. The latter can be added to the pharmaceutical preparation
preferably at a
proportion of between 0.01 and 10% (w/w).
A control of the transport of the active ingredient from the polymer system
over
the skin can be carried out both via the selection of a special permeation-
promoter or a

CA 02633599 2008-06-17
19
combination of various substances and via the amount of the substance or
substances to be
added.
Preferred permeation enhancers that optionally are to be added are selected
from
the group of laurocaprams, sulfoxides, terpenes or ethereal oils, oleic acid,
oleyl alcohol,
lauryl acid, propylene glycol, propylene carbonate, N-methyl-pyrrolidone or
isopropyl
myristate. In this case, the permeation promoters can be used both
individually and in
combinations. Especially preferred are oleic acid, the terpene R-(+)-limonene
and
isopropyl myristate. Quite especially preferred are mono-isopropyl myristate
and
combinations of oleic acid, R-(+)-limonene or isopropyl myristate with
propylene glycol,
preferably in a 1:1 ratio.
For example, R-(+)-limonene, oleic acid and isopropyl myristate, primarily in
combination with propylene glycol, are especially advantageous for the active
ingredient
ethinyl estradiol. Their proportion of the pharmaceutical preparation is
preferably
between 0.01 and 15% (w/w).
In addition to the permeation enhancers, the basic solvents, such as, for
example,
ethanol, ethyl acetate or isopropanol, can also contribute to promoting
permeation.
However, the active ingredient permeation that consists of a polymer film that
is produced
from an ethanolic polymer solution is clearly superior to that from an
ethanolic active
ingredient solution without a polymer. The presence of the organic solvent
alone thus
does not cause the increased permeation of the active ingredient through the
human
epidermis. The polymer plays an important role in this process. This
observation is also
supported in that different amounts of active ingredient from preparations
with different
polymers are transported through the human epidermis.
In the case of incorporating large amounts of active ingredients or in the
addition

CA 02633599 2008-06-17
of pharmaceutical adjuvants to a large extent, the formulation is to be
adapted, for
example, by increasing the softener content, since the film properties can
change, for
example, with respect to the adhesiveness by the added substances.
The pharmaceutical preparations according to the invention can be decanted
into
commercially available applicators and are applied to the skin with their
help. In this
connection, rollers, pump spray bottles, sprayers, tubes, brush bottles or
pipette bottles are
especially suitable. In the case of decanting in one sprayer, there is a need
for the
additional admixing of a propellant. As a propellant, for example, dimethyl
ether or
combinations of propane and butane can be used. In this case, the dosage of
the active
ingredients is carried out by means of devices or processes that are known to
one skilled in
the art.
For ethinyl estradiol and levonorgestrel, it was possible to show that with
the new
pharmaceutical preparations both with and without permeation enhancers, more
active
ingredient can be transported through the human epidermis than from an
ethanolic solution
of the same concentration. The new polymer systems are superior to simple
ethanolic
solutions of the same active ingredient concentration with respect to the
amount of active
ingredient that is permeated within 24 hours.
From the pharmaceutical preparation according to the invention, it was
possible
with and without the addition of permeation enhancers for significantly more
ethinyl
estradiol per unit of surface area to be transported through the human
epidermis within 24
hours than from a commercially available contraceptive patch (EVRA ; active
ingredients: ethinyl estradiol and norelgestromin). With the addition of
permeation
enhancers, just as much levonorgestrel per unit of surface area is permeated
within 24
hours through the human epidermis from the pharmaceutical preparation
according to the

CA 02633599 2008-06-17
21
invention as from a commercially available patch for hormone replacement
therapy
(Fem7 Combi, Phase II; active ingredients: estradiol and levonorgestrel).
Example 1: Pharmaceutical Preparation without Permeation Enhancers
To find a pharmaceutical preparation without permeation enhancers that dries
on
the skin in flexible, cosmetically inconspicuous films, an active ingredient
to be
administered optionally was dissolved while being heated generally in 96%
ethanol. After
the active ingredient was dissolved, a polymer was added, and the preparation
was stirred
on the magnetic stirrer until the polymer was completely dissolved. After a
clear solution
was obtained, optionally crosslinking agents or softeners were added, and the
solution was
stirred for another 24 hours. The storage of the polymer solution was carried
out in glass
vessels that were tightly sealed with a siliconized rubber plug and an
aluminum flange cap.
Polymers, polymer content, softeners and softener content were varied in these
formulation tests.
The thus obtained preparations were rated as described below based on the
criteria
of viscosity, drying time, stickiness of the outside, cosmetic attractiveness
and durability
on the skin. To this end, about 50 mg (corresponding to 10 mg/cm2) of the thus
obtained
preparations were applied on the skin with the help of a metal template.
Five minutes after the preparation was applied on the skin, the drying of the
film
was examined by putting a glass slide without pressure on the film. The film
was regarded
as dry if no liquid residues could be detected on the slide after the film was
lifted. To
ensure good patient compliance, only films that can be considered to be dry
after 5
minutes are to be selected.

CA 02633599 2008-06-17
22
To examine the stickiness of the outside of the film, a wad of cotton was
applied
with slight pressure to the dry film. The evaluation was carried out based on
the amount
of cotton fibers held back by the film.
The cosmetic attractiveness of the film was evaluated visually with the naked
eye
with respect to the thickness, transparency, and degree of skin attached to
the film.
After being in place for 24 hours, the durability of the film on the skin was
visually
evaluated with a magnifier with a 10x magnification. The fewer cracks and gaps
of the
film (flaking), the better its quality.
The viscosity of the solutions was evaluated visually in the storage vessel
with the
purpose of selecting low- to moderately viscous preparations that can be
administered by
spraying.
A preparation was then regarded as successful if in all of the above-mentioned
criteria, the best evaluation (low to medium viscosity, drying after 5
minutes, little or no
stickiness of the outside of the film, small thickness, good transparency and
only slight
attachment to the skin as well as little or no formation of cracks or gaps
after 24 hours)
was achieved. Any change in the pharmaceutical preparations according to the
invention
with respect to their contents and their concentration has the result of a
change in the film
properties, which can lead to a change in the evaluation of the above-
mentioned criteria.
Within certain limits, these changes are acceptable, so that concentration
spans for the
individual components can be indicated. Strong deviations, however, result in
polymer
films on the skin that no longer have the desired properties described and
thus are no
longer suitable for the planned use.

CA 02633599 2008-06-17
23
The table below contains data on the quantity ranges within which the
pharmaceutical preparations form a flexible, readily adhering, non-sticky and
cosmetically
inconspicuous film on the skin.
Quantity range Example 1
_
DynamX 0.1 ¨ 40% (w/w) 10% (w/w)
_
Triethyl Citrate 0.1 ¨ 18% (w/w) 1% (w/w)
Water 0.1-50% (w/w) 16% (w/w)
Ethanol 32 ¨ 99.7 % (w/w) 68% (w/w)
Active Ingredient 0.1 ¨ 30% (w/w) 5% (w/w)
A pharmaceutical composition that consists of 10% (w/w) DynamX , 1% (w/w)
triethyl citrate, 16% water, 68% (w/w) ethanol and 5% (w/w) active ingredient
forms an
especially suitable film.
Example 2: Pharmaceutical Preparation with Permeation Enhancers
To increase the transport of the active ingredient through the skin, the
permeation¨
promoting substances can be added to the formulations that are evaluated
positively with
respect to the above-mentioned criteria.

CA 02633599 2008-06-17
24
Quantity Range A B C D E F
DynamX 0.1 ¨ 40 % 10% 10% 10% 10% 10% 10%
Triethyl Citrate 0.1 ¨ 18 % 1 % 1 % 1 % 1 % 1 %
1 %
Oleic Acid 0.1 ¨ 10 % 5% 2.5% 1.5%
R-(+)-Limonene 0.1 ¨ 10 % 51)/0 2.5 %
IsopropylMyristate 0.1 ¨ 10 % 5 %
Propylene Glycol 0.1 ¨ 10 % 2.5 % 1.5 % 2.5 %
Ethanol 22 ¨ 99.8 % 62.2 % 62.2 % 62.2 % 62.2 % 62.2 %
62.2 %
Water 0.1-50 % 16.8 % 16.8 % 16.8 % 16.8 % 16.8 % 16.8 %
Active Ingredient 0.1 ¨30 % 5 % 5 % 5 % 5 % 5 %
5 %
%-Data = means % (w/w)
Example 3: Ethinyl Estradiol - Permeation Comparison with Ethanolic Solution
For skin permeation tests, human abdominal skin from plastic surgery
operations
was used. The skin was freed from the underlying fatty tissue and stored
frozen until
used. For preparation, round samples from the skin pieces were punched out,
and the
epidermis was separated by heat separation from the other skin components
(Kligman, A.
M., Christophers, E., Preparation of Isolated Sheets of Human Stratum Corneum.
Archives of Dermatology, 1963. 88: pp. 702-705). The epidermis was clamped
together
with a suitable supporting membrane in vertical Franz diffusion cells. As an
acceptor
medium, more neutral phosphate buffer with 0.5% y-cyclodextrin was used as a
solubilizer. During the entire test, the cells were tempered to 32 C, and the
acceptor
medium was continuously thoroughly mixed in the cells with a magnetic stirring
rod.
After the respective formulation was applied on the epidermis (in each case
four cells per
formulation), a sample was removed at defined times from each cell, and the
volume was

CA 02633599 2008-06-17
replaced by fresh acceptor medium. The active ingredient content of the
samples was
determined without further working-up by HPLC.
The permeation of ethinyl estradiol was determined from the polymer system
according to the invention (DynamX 10% (w/w); ethinyl estradiol content 5%
(w/w))
with and without permeation enhancers (oleic acid 2.5 % (w/w); propylene
glycol 2.5%,
(w/w)) by a heat-separated human epidermis and compared to the permeation from
an
ethanolic solution (5% (w/w) ethinyl estradiol). The results of the permeation
tests are
shown graphically in Figure 1/8.
Example 4: Ethinyl Estradiol - Permeation Comparison with Patches
The permeation of ethinyl estradiol from the polymer system according to the
invention (DynamX 10% (w/w); ethinyl estradiol content 5% (w/w)) with and
without
enhancers (oleic acid 2.5% (w/w); propylene glycol 2.5 %, (w/w)) was
determined by a
heat-separated human epidermis and compared to the permeation of ethinyl
estradiol from
a commercially available contraceptive patch (EVRA ). The results of the
permeation
tests are shown graphically in Figure 2/8.
Example 5: Ethinyl Estradiol - Permeation Comparison of Different Polymer
Solutions
The permeation of ethinyl estradiol from the polymer system according to the
invention (DynamX 10% (w/w); ethinyl estradiol content 5% (w/w)) was
determined by a
heat-separated human epidermis and compared to the permeation of ethinyl
estradiol from
polymer solutions with other polymers and the same ethinyl estradiol content
(5% (w/w))

CA 02633599 2008-06-17
26
and with an ethanolic solution (5% (w/w) ethinyl estradiol). The compositions
of the
tested formulations are cited in the following table:
Formulation EUD DYN KLU SIL REF
Eudragit
Polymer DynamX Klucel LF SGM 36 -
RL PO
Polymer
rid 20.0 10.0 5.0 10.0 -
Content
Triethyl
[%] 6.0 1.0 1.0 - -
Citrate
Ethanol ryd 69.0 67.2 89.0 25.0 95.0
Water [%] - 16.8 -
Q7-9180 [%] - - 51.5 -
193 Fluid [%] - - - 8.5
Ethinyl
[%] 5.0 5.0 5.0 5.0 5.0
Estradiol
In this case, Eudragit RL PO is an ammonium methacrylate copolymer, SGM 36
is a silicone rubber, and Klucel LF is a hydroxypropyl cellulose. In
addition, Q7-9180
means: Dow Corning Q7-9180 Silicone Fluid 0.65 cst (a mixture that consists of
hexamethyldisiloxane and octamethyltrisiloxane) and 193 fluid: Dow Corning 193
fluid
(PEG-12 dimethicone). The results of the permeation tests are shown
graphically in
Figure 3/8.

CA 02633599 2008-06-17
27
Example 6: Levonorgestrel ¨ Permeation Comparison with Ethanolic Solution
The permeation of levonorgestrel from the polymer system according to the
invention (DynamX 10%; levonorgestrel content 0.3% (w/w)) with and without
enhancers
(oleic acid 2.5%; propylene glycol 2.5%, (w/w)) was determined by a heat-
separated
human epidermis and compared to the peinieation of levonorgestrel from an
ethanolic
solution (0.3% w/w levonorgestrel). The results of the permeation tests are
shown
graphically in Figure 4/8.
Example 7: Levonorgestrel ¨ Permeation Comparison with Patches
The permeation of levonorgestrel from the polymer system according to the
invention (DynamX 10%; levonorgestrel content 0.3% (w/w)) with enhancer (oleic
acid
5.0%; propylene glycol 5.0%, (w/w)) was determined by a heat-separated human
epidermis and compared to the permeation of levonorgestrel from a commercially
available patch (Fem7 Combi, Phase II). The results of the permeation tests
are depicted
graphically in Figure 5/8.
Example 8: Determination of the Ethinyl Estradiol Plasma Levels in Pigs After
One-
Time Administration of a Transdermal Patch or a Film-Forming Polymer Solution
The test was performed with 8 female pigs (German landrace, age 3-4 months) in
accordance with the German Animal Protection law and after authorization from
the
responsible office. The animals were divided into two groups with four animals
each.
The division was carried out randomly according to weight, so that two groups
with
similar mean body weight were produced (23.5 kg 0.5 kg). On the day before
the
experiment, the test area on the back of the animal was shaved without
injuring the skin.

CA 02633599 2008-06-17
28
Before the test medication was administered, the skin was carefully cleaned
with alcohol.
One EVRA patch (20 cm2, 0.03 mg of EE/cm2) each was administered to the
animals of
one group. In the case of the patch detaching during the test (skin contact <
90%), the
patch was removed and replaced by a new patch on another skin site. 300 IA of
the film-
forming preparation (composition: 10.0% DynamX , 1.0% triethyl citrate, 67.2%
ethanol,
16.8% water, 5.0% ethinyl estradiol) was administered on 20 cm2 to the animals
of the
second group. Both preparations were administered in each case once at the
beginning of
the test. The condition of the medication was observed over the period of the
test (7 days)
and possible skin reactions were documented. Starting from the time of
administration,
blood samples were taken after 6 hours, 12 hours, 24 hours, 48 hours, 72
hours, 144 hours
and 168 hours, and the plasma per GC-MS on ethinyl estradiol was analyzed.
The ethinyl estradiol-plasma levels can be seen in Figures 6/8 ¨ 8/8. The
surface
area below the concentration-time curve (AUC o-los hours) as well as the times
of the
maximum plasma level (tmax) are found in the following table.
EVRA Patch Film-Forming Polymer Solution
Animal No. tmax AUC0-1 6 8 hours Animal No. tmax AUC0-168
hours
[hours] pg*ml-l*h] [hours]
[pg*ml-l*h]
1 48 146 5 72 1353
2 48 111 6 24 10572
3- - 7 6 555
4 48 659 8 - 279
Both pharmaceutical products showed adequate skin contact over the test
period.
After administration, the polymer solution formed a clear, bright film on the
skin, which

CA 02633599 2008-06-17
29
after 24 hours began to show cracks. The film could no longer be seen after
three to six
days. Skin reactions were not observed. Only one animal in the patch group
showed a
reddening of the skin, which presumably could be attributed, however, to the
removal of
the patch to be detached. The ethinyl estradiol-plasma levels in both groups
showed
considerable fluctuations. In the group with the film-forming preparations,
moreover, the
maximum plasma level was achieved at different times. The calculated surface
area under
the concentration-time curve was, however, on a higher level in the group with
the film-
forming preparation than in the patch group. With the aid of the film-forming
polymer
solution, measurable ethinyl estradiol-plasma levels in vivo could thus be
produced in
pigs, and said levels had a tendency to be higher than the plasma levels
achieved in the
patch group.
List of Figures:
Figure 1/8 [Example 3] shows the results of the comparison tests for active
ingredient permeation (ethinyl estradiol) from the pharmaceutical preparation
according to
the invention with (closed squares) and without (closed triangles) permeation
enhancers
and from an ethanolic solution (open squares).
Figure 2/8 [Example 4] shows the results of the comparison tests for active
ingredient permeation (ethinyl estradiol) from the pharmaceutical preparation
according
to the invention with (closed squares) and without (closed triangles)
permeation enhancers
and from a contraceptive patch (open squares).

CA 02633599 2008-06-17
Figure 3/8 [Example 5] shows the results of the comparison tests for active
ingredient permeation (ethinyl estradiol) from the pharmaceutical preparation
according to
the invention with the polymer DynamX (closed triangles) and from polymer
systems with
other polymers such as Klucel LF (¨ hydroxypropyl cellulose, open squares),
SGM 36 (¨
silicone rubber, closed squares) and Eudragit RL PO (-- ammonium methacrylate
copolymer, open triangles) as well as from an ethanolic solution (open
circles).
Figure 4/8 [Example 6] shows the results of the comparison tests for active
ingredient permeation (levonorgestrel) from the pharmaceutical preparation
according to
the invention with (closed squares) and without (closed triangles) permeation
enhancers
and from an ethanolic solution (open squares).
Figure 5/8 [Example 7] shows the results of the comparison tests for active
ingredient permeation (levonorgestrel) from the pharmaceutical preparation
according to
the invention with permeation enhancers (closed squares) and from the
commercially
available patch Fem7 Combi Phase II (open squares).
Figure 6/8 [Example 8] shows the ethinyl estradiol-plasma levels in pigs after
one-
time administration of the EVRA patch (Animal 1: A, Animal 2: fo, Animal 3:
o.,
Animal 4: s).
Figure 7/8 [Example 8] shows the ethinyl estradiol-plasma level in pigs after
one-
time administration of the film-forming polymer solution (5% ethinyl estradiol
in the
solution) (Animal 5: =, Animal 7: N, Animal 8: o).
Figure 8/8 [Example 8] shows the ethinyl estradiol-plasma levels in pigs after
one-
time administration of the film-forming polymer solution (5% ethinyl estradiol
in the
solution) (animal 6: *).