U.S. patent application number 10/532836 was filed with the patent office on 2006-01-19 for highly pure bases of 3,3-dipheyl propylamine monoesters.
This patent application is currently assigned to Schwarz Pharma AG. Invention is credited to Armin Breitenbach, Roland Drews, Claus Meese, Hans-Michael Wolff.
Application Number | 20060014832 10/532836 |
Document ID | / |
Family ID | 33154113 |
Filed Date | 2006-01-19 |
United States Patent
Application |
20060014832 |
Kind Code |
A1 |
Breitenbach; Armin ; et
al. |
January 19, 2006 |
Highly pure bases of 3,3-dipheyl propylamine monoesters
Abstract
The invention relates to a compound of general formula (I)
wherein A represents deuterium or hydrogen, R represents a group
selected from C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl or phenyl,
which can be substituted by C1-3 alkoxy, fluorine, chlorine,
bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or
deuterium. The C atom marked with a * (star) can be present in an
(R) configuration, in an (S)-configuration or a mixture thereof.
The invention is characterised in that the above-mentioned
compounds are free bases with a degree of purity of more than 97 wt
%. The invention also relates to a method for the production of
highly pure compounds of general formula (I) and to the use thereof
in the production of medicaments. ##STR1##
Inventors: |
Breitenbach; Armin;
(Monheim, DE) ; Meese; Claus; (Monheim, DE)
; Wolff; Hans-Michael; (Monheim, DE) ; Drews;
Roland; (Monheim, DE) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Assignee: |
Schwarz Pharma AG
Monheim Am Rhein
DE
40789
|
Family ID: |
33154113 |
Appl. No.: |
10/532836 |
Filed: |
April 3, 2004 |
PCT Filed: |
April 3, 2004 |
PCT NO: |
PCT/EP04/03567 |
371 Date: |
April 26, 2005 |
Current U.S.
Class: |
514/540 ;
560/136 |
Current CPC
Class: |
A61P 13/00 20180101;
A61P 13/02 20180101; C07C 219/28 20130101; A61K 9/7053 20130101;
A61P 13/10 20180101; A61K 31/135 20130101 |
Class at
Publication: |
514/540 ;
560/136 |
International
Class: |
C07C 229/52 20060101
C07C229/52; A61K 31/24 20060101 A61K031/24 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 8, 2003 |
DE |
103 15 917.7 |
Claims
1-34. (canceled)
35. A compound of the following Formula I: ##STR16## wherein each A
is independently hydrogen or deuterium, R is C.sub.1-6-alkyl,
C.sub.3-10-cycloalkyl or phenyl, which may each be substituted with
C.sub.1-3-alkoxy, fluorine, chlorine, bromine, iodine, nitro,
amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom
marked with a star ".star-solid." may be present in the
(R)-configuration, the (S)-configuration or as a mixture of such
configurations, and the compound is present as a free base in a
degree of purity of above 97 percent by weight.
36. A compound of claim 35 wherein R is methyl, ethyl, isopropyl
1,1-propyl, 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and
hexyl.
37. A compound of claim 35 wherein the compound is
2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl
isobutyrate.
38. A compound of claim 35 wherein the C-atom marked with
".star-solid." is present in the (R)-configuration.
39. A compound of claim 35 wherein the compound is
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl
isobutyrate (Fesoterodine).
40. A method of producing a compound of the following Formula I
##STR17## wherein in Formula I each A is independently hydrogen or
deuterium, R is C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl or phenyl,
which may each be substituted with C.sub.1-3-alkoxy, fluorine,
chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or
deuterium and where the C-atom marked with a star ".star-solid."
may be present in the (R)-configuration, the (S)-configuration or
as a mixture of such configurations, the compound being a free base
having a purity of at least 97 percent by weight, the method
comprising: releasing the compound of Formula I as a base from a
crystalline salt of the following Formula II: ##STR18## with a
degree of purity of at least 97 percent by weight where in Formula
II each A and R are the same as defined for Formula I and X.sup.-
is the acid residue of a physiological compatible acid and where
the C-atom marked with ".star-solid." (a star) can be present in
the (R)-configuration, in the (S)-configuration or as a mixture of
such configurations, wherein the releasing of the compound of
Formula II comprises use of a releasing reagent in aqueous
solution, whereby the releasing reagent has a pK.sub.B of 8-11 and
does not lead to the precipitation of the compound of Formula
I.
41. The method of claim 40 wherein the free base of Formula I is
released from the crystalline salt of Formula II by use of an added
reagent chosen from among: (a) alkaline, alkaline earth- or
ammonium hydrogen carbonates, (b) amines, polyamines and alkaline
polyamino acids, and (c) alkaline ionic exchangers.
42. The method of claim 40 wherein the compound of Formula I is
released from a crystalline salt of the Formula II through the
addition of an alkaline, earth-alkaline or ammonium hydrogen
carbonate.
43. The method of claim 40 wherein after release of the base of
Formula I from the salt of Formula II, the aqueous solution is
extracted with an organic solvent, and the base of Formula I is
then isolated in the organic phase of the extraction.
44. The method of claim 43 wherein the organic solvent is one or
more of dichloromethane, ethyl methyl ketone, ethyl acetate,
tertiary butyl methyl ether, diethylether, and toluene.
45. The method of claim 40 wherein R of both Formula I and Formula
II is methyl, ethyl, isopropyl, 1-Propyl, 1-butyl, 2-butyl,
tertiary butyl, iso-butyl, pentyl and hexyl and the C-atom marked
with an ".star-solid." (star) is present in the
(R)-configuration.
46. The method of claim 40 wherein the compound of Formula I is
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl
isobutyrate.
47. The method of claim 40 wherein the compound of Formula II
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl
isobutyrate hydrogen fumarate.
48. The method of claim 40 further comprising admixing the compound
of Formula I with a pharmaceutically acceptable carrier.
49. A pharmaceutical formulation comprising a compound of Formula I
of claim 35 and a pharmaceutically acceptable carrier.
50. A pharmaceutical formulation of claim 49 wherein the
pharmaceutically acceptable carrier is a polymer.
51. A pharmaceutical formulation of claim 49 wherein the
formulation exhibits a stabilization factor of at least 2, as
determined by the division of the average monthly drop in
concentration of the compound of Formula I during storage as oil
and in the absence of the pharmaceutically acceptable carrier at
5.degree. C. by the average monthly drop in concentration of the
corresponding compound of Formula I during storage in the
pharmaceutical formulation at 5.degree. C.
52. A pharmaceutical formulation of claim 49 wherein the
formulation has a pH value of from 3.0 to 6.0.
53. A pharmaceutical formulation of claim 49 wherein the
pharmaceutical formulation is suitable for transdermal
delivery.
54. A pharmaceutical formulation of claim 49 wherein the
pharmaceutical formulation is suitable for transmucosal
delivery.
55. A pharmaceutical formulation of claim 49 wherein the
pharmaceutical formulation comprises a polymer layer that comprises
a compound of Formula I.
56. A pharmaceutical formulation of claim 55 wherein the polymer
layer comprises a contact adhesive which can facilitate attachment
of the pharmaceutical composition to the skin or the mucous
membrane of a patient.
57. A pharmaceutical formulation of claim 56 wherein the contact
adhesive comprises one or more of a silicone, acrylate, SXS-, PIB-
or EVA based contact adhesives.
58. A pharmaceutical formulation of claim 49 wherein the
pharmaceutical formulation is a transdermal therapeutic system of
the active ingredient-in-adhesive type.
59. A kit containing a pharmaceutical formulation of claim 49 and a
drying agent.
60. A dosing unit which comprises at least 3 mg of a compound of
the following Formula I: ##STR19## and at least one
pharmaceutically acceptable carrier, wherein each A is
independently hydrogen or deuterium, R is C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl or phenyl, which may each be substituted with
C.sub.1-3-alkoxy, fluorine, chlorine, bromine, iodine, nitro,
amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom
marked with a star ".star-solid." may be present in the
(R)-configuration, the (S)-configuration or as a mixture of such
configurations, and the free base of the compound of Formula I
being present in a purity of above 97 percent by weight.
61. A dosing unit of claim 60 wherein whereby the compound is (R)
2-[3-(1,1-Diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl
isobutyrate (Fesoterodine).
62. Fesoterodin Hydrogen carbonate.
63. A method for the treatment of a mammal suffering from or
susceptible to incontinence, hyperactivity of the detrusor,
hyperactivity of the bladder, pollakisuria, nocturia or imperative
urinary urgency, the method comprising: administering a compound of
claim 35, 50 or 60 to the mammal.
64. The method of claim 63 wherein the mammal is identified as
suffering from incontinence, hyperactivity of the detrusor,
hyperactivity of the bladder, pollakisuria, nocturia and/or
imperative urinary urgency, and the compound is administered to the
identified mammal.
65. The method of claim 63 wherein the mammal is a human.
66. The method of claim 63 wherein compound is administered to the
mammal transdermally.
67. The method of claim 63 wherein the compound is administered to
the mammal transmucosally.
68. The method of claim 63 wherein the compound is administered to
the mammal with use of a patch.
69. The method of claim 63 wherein Fesoterodin is administered to
the mammal in the form of a pharmaceutical composition that
comprises a self-adhesive polymer layer which comprises Fesoterodin
and delivers Fesoterodin at a flux rate of 3-15 mg/day through
human skin.
Description
[0001] This invention concerns high purity bases of
3,3-diphenylpropylamino monoesters, their manufacture and their use
as drugs, in particular for transdermal and transmucosal
administration.
[0002] The proportion of seniors within the total population has
gone up significantly in the past 50 years. Bladder dysfunctions
belong to the most common geriatric diseases in this group.
Therefore, ever greater and more specific significance is being
attached to the development of a most effective and gentle
treatment of bladder complaints.
[0003] In the case of urge incontinence the dysfunction lies in a
malfunction of the bladder muscle. Frequently the cause is a
stimulation or more precisely a hyperactivity of the muscarinic
receptors. For this reason use of the antimuscarinic active
ingredients Tolterodin and Oxybutynin is preferred for the
treatment of the hyperactive bladder and the associated symptoms
such as increased urinary urgency, abnormally frequent micturation
or nocturia.
[0004] However, oxybutynin is an effective antimuscarinic agent
that has serious side effects. Notably the pronounced dryness of
the mouth is felt by many patients to be extremely unpleasant.
[0005] By comparison with Oxybutynin Tolterodin appears to exhibit
lower muscarinic side effect rates. In an organism Tolterodin is
predominantly dealkylated into active main metabolites
2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenol by the cytochrome P450-isoenzyme 2D6 as well
as--slowly--into inactive metabolites by the cytochrome P 450
isoenzyme 3A4.
[0006] Since Tolterodin is metabolized exclusively through the
P450-isoenzyme, there is the potential danger of interactions with
the breakdown of other agents, for example, with Warfarin (Colucci,
Annals of Pharmacotherapy 33, 1999, 1173), antimycotics such as
Ketoconazol (Brynne, Br J Clin Pharmacol 48, 1999, 564) macrolide
antibiotics or protease inhibitors. This danger is present
particularly in the case of the so-called slow metabolizers, which
have a lack of 2D6, metabolize Tolterodin exclusively through 3A4
and exhibit a distinctly increased Tolterodin concentration in
plasma.
[0007] WO 99/58 478 describes new derivates of
3,3-diphenylpropylamines as active muscarinic ingredients. The
disclosed 3,3-diphenylpropylamine-derivates are prodrugs from
2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy-methyl)phenol
and are hydrolyzed by esterases upon entering through biological
membranes as well as in plasma. For this reason the 2D6-dependent
degradation device does not apply.
[0008] In contradistinction to Tolterodin such
3,3-diphenylpropylamine derivates, for example,
2-[3-(1,1-Diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate (INN: fesoterodine), therefore do not
show a tendency towards accumulation even in the case of slow
metabolizers, they do not interfere with P450 inductors/inhibitors
and they possess an advantageous safety profile with regard to
potential interactions of active ingredients and accumulation of
active ingredients.
[0009] Therefore, the need arose to make the advantages of the
3,3-diphenylpropylamine derivate described in WO 99/58478,
particularly the advantages of the fesoterodine, available to the
collective of patients. The metabolism method of Tolterodin and the
disadvantages of Oxybutynin (dry mouth) alone make clear the
medical need for a medicine that does not exhibit the disadvantages
of both of the previously named substances.
[0010] The bases of 3,3-diphenylpropylamines published in WO
99/58478 are manufactured by
2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol being
converted under alkaline conditions with an appropriate acid
chloride, for example, isobutyric acid chloride (see Example
Execution 3aa of WO 99/58478).
[0011] This reaction, however, only leads disadvantageously to
approximately 90% up to a maximum approximate 94% of the desired
main product (B). The product consistently contains 6-10%
impurities of the starting substance (A), the used acylation agent
as well as undesired reaction products in the form of the
corresponding di-ester of the acylating reagent used (C) of the
monoester (D) of the 4-hydroxy group (see FIG. 1) as well as by
dimerization/polymerization.
[0012] Attempts by the inventor of this patent application to make
the synthesis reaction more selective by, for example, varying the
amount of the acylating reagent and/or the acylating conditions
(temperature, solvent, concentrations, sequence of the addition,
among other things), did not lead to the desired result.
[0013] Even extensive trials to purify the high purity base from
the product mix in the amounts required for pharmaceutical purposes
using conventional procedures remained unsuccessful.
[0014] A purification by crystallization is eliminated because the
bases of the general Formula I, for example, fesoterodine, are
present as viscous oils according to the manufacturing process
described in EP 1 077 912 and up to now are not able to be
crystallized from the product mix.
[0015] Even attempts to purify by distillation did not lead to the
desired success.
[0016] However, a purity of only 90-96 percent by weight is not
adequate for pharmaceutical preparations. Rather a purity of above
97 percent by weight is preferred in general. Therefore a need for
high purity free bases of 3,3-diphenylpropylamines existed.
[0017] WO 01/35957 teaches stable, crystalline salts of
3-3-diphenylpropylamine derivates, which, compared with the
amorphic salts have the advantage of higher stability and higher
purity.
[0018] Salts of this sort are basically suitable for therapeutic
administration and may, for example, be used for oral or parenteral
treatment.
[0019] For a few applications, for example, the transdermal or
transmucosal application, the salt of the active ingredient is less
suitable in many situations because its ionized form hinders
passage of the skin or the mucous membrane in therapeutically
effective amounts. If a transdermal or transmucosal application is
desired, then the active ingredient that contains amines has to be
frequently applied in the form of the base.
[0020] Surprisingly, it was now found that a free base of the
general Formula I (see below) could be yielded in a purity of
consistently above 97 percent by weight, preferably above 98
percent by weight, especially preferably above 98.5 percent by
weight and notably especially preferably above 99 percent by weight
and with a high yield above 80% (mol %) if the free base is
manufactured by releasing it with an appropriate reagency from a
high purity, crystalline salt.
[0021] One aspect of the invention is therefore the use of a
compound of Formula I ##STR2## in which A means hydrogen or
deuterium, R stands for a group that is selected from
C.sub.1-6,-alkyl, C.sub.3-10-cycloalkyl or phenyl, which may each
be substituted with C.sub.1-3-alkoxy, fluorine, chlorine, bromine,
iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and
where the C-atom marked with a star ".star-solid." may be present
in the (R)-configuration, the (S)-configuration or as a mixture of
it,
[0022] characterized by the fact that the free base is present in a
degree of purity of above 97 percent by weight, preferably above 98
percent by weight, especially preferably above 98.5 percent by
weight and notably, especially preferably above 99 percent by
weight.
[0023] In a preferred form of execution R is selected from the
group methyl, ethyl, isopropyl, 1-propyl, 1-butyl, 2-butyl,
tertiary-butyl, iso-butyl, pentyl, hexyl C.sub.4-C.sub.8 cycloalkyl
or phenyl.
[0024] In an especially preferred form of execution R is isopropyl
(i-Pr) so that the compound is
2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate (fesoterodine base).
[0025] In one form of execution of the invention the compounds of
the general Formula 1 are present as a racemate, meaning as
mixtures of the (R)- and (S) configured molecules.
[0026] In another preferred form of execution the C-atom marked
with a star ".star-solid." is present in (R)-format, whereby
preferably over 98 percent by weight of the compound, especially
preferably over 99 percent by weight of the compound and notably
especially preferably over 99.5 percent by weight of the compound
is present in the (R)-configuration.
[0027] In a notably especially preferred form of execution the
compound is the high purity free base from
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate (fesoterodine base) with a purity content
of over 97 percent by weight, preferably above 98 percent by
weight, especially preferably above 98.5 percent by weight and
notably especially preferably above 99 percent by weight.
[0028] In this application "C.sub.1-6 alkyl" is understood to be a
straight chain or branched chain hydrocarbon group with 1-6
C-atoms. Preferred C.sub.1-6 alkyls are non-substituted straight or
branch chain groups, in particular selected from the group of
methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, tertiary-butyl,
pentyl and hexyl.
[0029] The expression "C.sub.3-10 cycloalkyl" is understood to mean
a cyclical hydrocarbon group with 3-10 hydrocarbon atoms.
[0030] In this application "high purity" is understood to mean a
degree of purity of the monoester of the general Formula I of above
97 percent by weight minimum, preferably above 98 percent by
weight, especially preferably above 98.5 percent by weight and
notably especially preferably above 99 percent by weight, meaning
that an appropriately low proportion of diesters, dihydroxy
compounds, 4-monoesters or polymers is present. The degree of
purity is determined as described in the techniques section.
[0031] In the sense of the invention the expression "free base" is
understood to mean that less than 10 percent by weight, preferably
less than 5% or 3%, especially preferably less than 1% is of the
compound of the general Formula I is present in the salt form. The
salt content is thereby determined as described in the techniques
section.
[0032] The high purity bases of the general Formula I in compliance
with the invention can be manufactured by their release from the
high purity, crystalline salts of the general formula II: ##STR3##
where A and R have the significance given above, X.sup.- is the
acid residue of a physiological compatible acid and where the
C-atom marked with ".star-solid." (a star) can be present in the
(R)-configuration, in the (S)-configuration or as a mixture
thereof.
[0033] In the course of this the anion of one of the subsequently
named acids comes into consideration as an acid residue
X.sup.-:
[0034] Hydrochloric acid, hydrobromic acid, phosphoric acid,
sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic
acid, stearic acid, maleic acid, fumaric acid, oxalic acid,
succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic acid,
DL-tartaric acid, L-(+)-tartaric acid, D-(-)-tartaric acid, citric
acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid,
2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid
(pyromucic acid), benzoic acid, 4-hydroxybenzoic acid, salicylic
acid, vanillic acid, 4-hydroxycinnamic acid, gallic acid, hippuric
acid (N-benzoyl-glycin), aceturic acid (N-acetyl glycine),
phloretin acid (3-(4-Hydroxyphenyl)-propionic acid), phthalic acid,
methane-sulphonic acid or orotic acid, where the acid anions
hydrogen fumarate and hydrochloride are especially preferred.
[0035] The corresponding high purity bases are released from this
high purity compound of the general Formula II through the addition
of the appropriate base reagents ("release reagents").
[0036] The release reagents are, for example, alkaline compounds
from the group of [0037] hydroxides, carbonates and alkaline-,
alkaline earth- or ammonium hydrogen carbonates, [0038] amines,
polyamines and alkaline polyamino acids, that may also be present
both in a solution and fixed onto carriers, [0039] alkaline ionic
exchangers, where weak alkaline compounds with a pK.sub.B of 8-11
are preferred.
[0040] Such reagents are preferred as release reagents that inhibit
a precipitation of the bases of the 3,3-diphenylpropylamine
monoesters in the particular solvent. In addition, a hydrolysis of
the ester bond should be avoided.
[0041] For example, in an aqueous environment the conversion of a
compound of the Formula II with a hydrogen carbonate leads
initially to a water soluble hydrogen carbonate salt of a
3,3-diphenylpropylamine monoester being formed as an intermediate
product. When extraction by shaking using an organic solvent, for
example, dichloromethane is conducted, the CO.sub.2 escapes, and
the poor, water soluble free base of the 3,3-diphenylpropyl amino
monoester can be gained from the organic phase without further
purification as high purity oil.
[0042] Precipitation of the base of the 3,3-diphenyl monoester
immediately following release, which may result in a lower purity
and/or a lower yield, is impeded by this method of execution.
Hydrolysis of the ester bond is also avoided.
[0043] The hydrogen carbonate salts of the compounds of the general
Formula I, especially fesoterodine hydrogen carbonate, are
explicitly made the object of the invention as preferred
intermediate products.
[0044] An alkaline-, earth alkaline or ammonium hydrogen carbonate
is especially preferred as the releasing reagent, whereby sodium
hydrogen carbonate is notably especially preferred.
[0045] Therefore, in a preferred manufacturing process the salt of
the Formula II is first absorbed in water and laced with a base
releasing agent, for example, a hydrogen carbonate. This is then
extracted by shaking using an appropriate solvent and the organic
phase evaporated to a low small bulk until the high purity base of
the Formula I remains behind as a viscous oil. Such a process is
shown in more detail in Example Execution 1C.
[0046] Solvents that are suitable for purification of the free base
are in particular dichloromethane, tertiary-butyl-methyl ether,
diethyl ether, ethyl methyl ketone as well as toluene, where
dichloromethane is especially preferred.
[0047] In an alternative manufacturing process the high purity salt
of the Formula II is absorbed in an appropriate solvent and then
conducted over a carrier, which contains immobilized ionic
exchangers, for example. The eluate then contains the high purity
base of the general Formula I.
[0048] (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate hydrogen fumarate is especially preferred
for use as the initial compound of the Formula II for the
production of the high purity free base of
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate.
[0049] One object of the invention is therefore a procedure for the
manufacture of a high purity free base of the general Formula I
##STR4## in which A means hydrogen or deuterium, R stands for a
group that is selected from C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl
or phenyl, which may each be substituted with C.sub.1-3-alkoxy,
fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo,
mercapto or deuterium and where the C-atom marked with a star
".star-solid." may be present in the (R)-configuration, the
(S)-configuration or as a mixture of it in a purity of above 97
percent by weight minimum, preferably above 98 percent by weight,
especially preferably above 98.5 percent by weight and notably
especially preferably above 99 percent by weight,
[0050] whereby the procedure is characterized through the release
of the high purity free base of the general Formula I from a
crystalline salt of the general Formula II ##STR5## with a purity
of 97 percent by weight, preferably above 98 percent by weight,
especially preferably above 98.5 percent by weight and notably
especially preferably above 99 percent by weight, whereby A and R
have the significance given above, X.sup.- is the acid residue of a
physiological compatible acid and where the C-atom marked with
".star-solid." (a star) can be present in the (R)-configuration, in
the (S)-configuration or as a mixture thereof.
[0051] The inventive manufacturing process is preferably used to
manufacture high purity bases of the general Formula I, in which
the C-atom identified with ".star-solid." is present in the
(R)-configuration and/or in which the substituent R is selected
from the methyl, ethyl, iso-propyl, 1-propyl, 1-butyl, 2-butyl,
tertiary-butyl, iso-butyl, pentyl and hexyl group.
[0052] The inventive manufacturing process preferably serves for
the manufacture of the high purity free base
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate, whereby
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate hydrogen fumarate is especially preferred
for use as the initial compound of the Formula II.
[0053] The production of the high purity salts of the Formula II is
known from WO 01/35957. For this purpose a solution of
2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenol is converted in a base solution with an acid
chloride, for example, isobutyric acid chloride. The resulting base
with a low purity content is then laced with an acid, for example,
fumaric acid, while being heated. The resulting salt of the general
Formula II can then be crystallized out in appropriate solvents.
The crystals are then dissolved again and re-crystallized.
[0054] This process can be repeated if necessary until a compound
of the Formula II is obtained with the desired degree of purity.
The high purity free base of the Formula I is yielded from these
salts as described above.
[0055] As a general rule the yield of high purity free base of the
Formula I in amounts to above 90% of the theory based on the amount
of the 3,3-diphenylaminomonoester of the Formula II used.
[0056] Table 1 shows the clean-up of the fesoterodine base using
the inventive process TABLE-US-00001 Process Step .sup.a) Purity B
or E (%) 1. Chemical synthesis of B from A 94.37 2. Production of
the salt E from B (1) 92.58 3. Re-crystallization of the salt E
from (2.) 99.32 4. Released high purity base B from E (3.) 99.14
.sup.a) A, B, C, E: R = i-Pr, see FIG. 1/4
[0057] The inventive pure bases of the general Formula II are
present in the form of an oil following manufacture and are stable
at -20.degree. C.
[0058] At higher temperatures, for example at 2.degree.
C.-8.degree. C. the inventive free bases are preferably stored in
the presence of drying agents.
[0059] The inventive procedure allows for the first time the
efficient isolation of the free base of the general Formula I in a
high purity form. The procedure is up-scalable and makes
manufacture of the high purity compounds possible on an industrial
scale and for the first time makes the high purity bases of the
general Formula I containing pharmaceutical formulations
available.
[0060] A further aspect of this invention is therefore a
pharmaceutical formulation that comprises a compound of the general
Formula I, which comprises ##STR6## as well as at least one
pharmaceutically acceptable carrier, whereby A is either hydrogen
or deuterium, R stands for a group that is selected from
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl or phenyl, which may each be
substituted with C.sub.1-3-alkoxy, fluorine, chlorine, bromine,
iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and
where the C-atom marked with a star ".star-solid." may be present
in the (R)-configuration, the (S)-configuration or as a mixture of
it in a purity of above 97 percent by weight minimum, preferably
above 98 percent by weight, especially preferably above 98.5
percent by weight and notably especially preferably above 99
percent by weight.
[0061] In a further preferred form of execution of the invention
the inventive pharmaceutical formulation contains a compound of the
general Formula 1 where R is selected out of the methyl, ethyl,
1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl,
iso-butyl, pentyl and hexyl group, whereby it is especially
preferable that R be an isopropyl, and whereby it is especially
preferable the C-atom identified with ".star-solid." is present in
the (R)-configuration.
[0062] In a notably especially preferred form of execution of the
invention the pharmaceutical formulation of the free base from
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate (fesoterodine free base) with a degree of
purity of 97 percent by weigh minimum, preferably above 98 percent
by weight, especially preferably above 98.5 percent by weight and
notably especially preferably above 99 percent by weight.
[0063] Since the inventive free bases are sensitive to hydrolysis
or more precisely to interchange esterification, the storage of the
pharmaceutical formulations should preferably be done at
<25.degree. C., especially preferably at <8.degree. C. and in
the presence of drying agents.
[0064] Preferably the inventive free bases are present in the
pharmaceutical formulation in a slightly acidic environment,
meaning at a pH of 3-7, preferably pH 3-6 or pH 3-5, since the
stability of the free bases is highest under these conditions.
[0065] Furthermore, for reasons of stability it is preferred that
the pharmaceutical formulations be free from short chain C.sub.1-8
alcohols and from C.sub.1-4 alcohols in particular.
[0066] The arrangement of the pharmaceutical formulation primarily
depends on the mode of administration as well as on the desired
properties of the respective form of administration.
[0067] Consequently, for example the possibilities are: [0068] Oral
forms: Powders, granulates, tablets, dragees, capsules, solutions
or suspensions [0069] Parenteral forms: solutions or suspensions
[0070] Transdermal forms: transdermal therapeutic systems (TTS),
ointments, creams, foils, lotions, sprays, gels or foams. [0071]
Transmucosal forms: [0072] buccal or sublingual forms: quick
releasing tablets, sprays, drops, wafer-shaped forms of drugs as
well as mucoadhesive pellets or patches [0073] nasal forms:
Lotions, drops, sprays, ointments [0074] pulmonal forms:
aerosols
[0075] Essentially, the auxiliary agents known to the specialist in
the area of pharmaceutical technology are qualified as
pharmaceutically acceptable carriers, such as they are described in
Sucker, Fuchs and Speiser, Pharmazeutische Technologie, Georg
Thieme Verlag, Stuttgart, for example, and other reviews on
appropriate forms of drugs.
[0076] Such a pharmaceutical formulation may be conventional but
may also be arranged as a fast-releasing or retarding formulation
dependent upon the special requirements of the patient.
[0077] The bases of the general Formula I, for example,
fesoterodine, have emerged as passing surprisingly well through
membranes. For this reason suitable pharmaceutical formulations for
transdermal or transmucosal applications in particular are being
offered.
[0078] It is preferred that the inventive high purity bases of the
general Formula I with controlled release of the active ingredient
be used in pharmaceutical formulations for the transdermal or
transmucosal application. The pharmaceutical formulations, which
after an initial burst effect phase, are ensuring a constant flux
rate through the skin or mucous membrane of a patient over a
minimum of 24 hours, preferably over a minimum of 48 hours, are
especially preferred.
[0079] To guarantee such controlled delivery of an active
ingredient the pharmaceutical formulation contains at least one
polymer layer in which a high purity base of the general Formula I
is dispersed or dissolved.
[0080] The release behavior of the active ingredient can be
influenced through the composition of such a polymer layer. So, for
example, the solubility behavior of active ingredients in the
polymer matrix decisively determines the release of the active
agent from transdermal/transmucosal therapeutic systems and by
doing so determines the flux rates through the skin or the mucous
membrane as well.
[0081] Furthermore, the polymer layer may contain pressure
sensitive adhesive substances that make the attachment of the
pharmaceutical composition to the skin or the mucous membrane of
the patient possible.
[0082] For example, a buccal formulation may be arranged as a
mucoadhesive system from out of which there is retarded release of
the active ingredient. Adhesive polymers/copolymers such as PVP,
pectin, carbopol, polyacrylates, cellulose derivates, chitosane or
polyoxyethylene are used for the adhesion to the mucous membrane.
Appropriate examples and overviews are found, for example in U.S.
Pat. No. 6,210,699; U.S. Pat. No. 4,855,142; U.S. Pat. No.
4,680,323; U.S. Pat. No. 5,700,478; U.S. Pat. No. 4,948,580; U.S.
Pat 4,715,369; U.S. Pat. No. 4,876,092; U.S. Pat. No. 5,750,136;
Woodley, Clin Pharmacokinet 40, 2001, 77 or Singla, Drug Dev Ind
Pharm 26 (2000) 913. These adhesive polymers/copolymers may
function as the adhesive outer coating of tablets, for example, but
in a buccal patch may also be a component of an adhesive polymer
matrix in which the active ingredient is present either dissolved
or dispersed (Wong, Int J Pharm. 178, 1999, 11).
[0083] In one form of execution of the invention the pharmaceutical
formulation for the transdermal delivery of a high purity base of
the Formula I is therefore arranged as a buccal formulation, in
particular as a buccal patch, which incorporates at a minimum a
polymer layer, in which the high purity base of the general Formula
I is present either dissolved or dispersed. This polymer layer that
contains the high purity base preferably has mucoadhesive
properties.
[0084] In a particularly preferred form of execution of the
invention the pharmaceutical formulation for the transdermal
delivery of a high purity base of the Formula I is arranged as a
transdermal patch.
[0085] Transdermal patches (also often identified as transdermal
therapeutic systems TTS) may be categorized in different ways
whereby a distinction is often made between the following three
main groups: [0086] The reservoir type, in which the active
ingredient is present in a solution or a gel and which are applied
to the skin of the patient using a speed-regulating membrane.
[0087] The matrix type, which can be further subdivided into [0088]
The laminate type, in which the active ingredient is present in a
layer (matrix) of non-adhesive polymers. The TTS may contain other
layers for attachment to the skin, for example, an adhesive layer;
however it may also be attached to the skin by separate adhesive
foils (over tapes). [0089] The monolithic type, in which the active
ingredient is present in a contact adhesive layer (adhesive
matrix). An example for a typical structure of a monolithic TTS is
reproduced in FIG. 4/4. The model monolithic TTS consists of the
adhesive matrix which contains the active ingredient (1), a backing
being impermeable and inert for the ingredients of the adhesive
matrix, which after the administration of the patch on the skin of
the patient finds itself on the site of the TTS remote to the skin
(2) as well as a detachable layer for protection which is removed
immediately before application of the TTS onto the skin (3). [0090]
Iontophoretic systems in which the flux of the active ingredient
through the skin is supported by the application of an electrical
current.
[0091] Especially preferred drugs in the sense of this invention
are TTS of the matrix type, whereby monolithic TTS, in which the
active ingredient is present in the adhesive matrix, are notably
especially preferred.
[0092] Under the term "polymer matrix" or "matrix" in this patent
application a layer or paste that contains polymers is comprehended
whereby the term "polymer matrix" is incorporated by this.
[0093] In this patent application the expression "total weight of
the polymer matrix" is understood to mean the weight of the polymer
matrix including the active ingredient introduced into it and
possible auxiliary agents.
[0094] Non-limiting examples for adhesive polymers/copolymers that
are suitable for the manufacture of transdermal devices and which
may contain the active ingredient of the general Formula I in
dissolved, partially dissolved or dispersed form are silicone
adhesives, ethyl vinyl acetate (EVA)-adhesives, styrene block
copolymer (SXS)-adhesives, acrylate adhesives, polyurethane
adhesives, vinyl acetate adhesives as well as the adhesive gums,
for example, polyisobutylene, polybutadiene, neoprene or
polyisoprene as well as suitable mixtures of these adhesives.
[0095] The polymer adhesives known in patch technology of the
silicone type, of the acrylate type, the SxS type, the ethyl vinyl
acetate (EVA type) that are known from the state of the art are
particularly suitable as contact adhesives. The properties of these
contact adhesives will be further explained more closely below.
[0096] The dosing of the compounds in compliance with invention is
dependent on the age, weight a status of the patient, the type of
application and the interval. Generally speaking the effective
daily dose lies in the 0.5-20 mg range. Typically, in the case of
oral administration at least 3 mg/day, for example 3-15 mg/day,
preferably 4-12 mg/day is used. A typical transdermal or
transmucosal daily dose, for example, for fesoterodine, for an
adult patient lies, for example, at a minimum of 3 mg, preferably
in the 3-15 mg range and especially preferred between 4 and 12
mg.
[0097] A pharmaceutical composition, which is suitable for once
daily administration should therefore preferably contain 3-15 mg of
a high purity base of the general Formula I.
[0098] For safety reasons, if the pharmaceutical composition is a
transdermal formulation, it will generally be given around twice
the amount of active ingredient to be administered. A typical
formulation for transdermal delivery of a high purity compound of
the general Formula I in compliance with the invention consequently
contains at least 6 mg active ingredient, but depending on the
level of dosage and the application interval, it may also contain
more than 10 mg, 20 mg, 30 mg, 40 mg or 50 mg of the high purity
active ingredient of the general Formula I, for example,
fesoterodine, per dosing unit. If a five or even seven day
application interval is scheduled the active ingredient content of
an individual dosing unit may also be above 70, 80, 90 or even over
100 mg.
[0099] In this patent application the expression "dosing unit" is
understood to mean a pharmaceutical formulation that contains a
defined amount of active ingredient and that releases this
following the one-time administration in patients over a
predetermined period of time in a therapeutically effective amount.
In this patent application the term "dosing unit" comprises both a
tablet for application three times a day as well as a patch for
weekly administration.
[0100] An object of this invention is therefore a dosing unit that
comprises at least 3 mg of a compound of the general Formula I,
##STR7## as well as at least one pharmaceutically acceptable
carrier, whereby A is either hydrogen or deuterium, R stands for a
group that is selected from C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl
or phenyl, which may each be substituted with C.sub.1-3-alkoxy,
fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo,
mercapto or deuterium and where the C-atom marked with a star
".star-solid." may be present in the (R)-configuration, the
(S)-configuration or as a mixture of it and whereby the free base
of the compound I is present in a purity of above 97 percent by
weight minimum, preferably above 98 percent by weight, especially
preferably above 98.5 percent by weight and notably especially
preferably above 99 percent by weight.
[0101] In other forms of execution of the invention the dosing unit
is given at least 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, 80 mg,
90 mg or even over 100 mg high purity active ingredient of the
general Formula I.
[0102] In a preferred form of execution of the invention the
inventive dosing unit contains a compound of the general Formula 1
where R is selected out of the methyl, ethyl, 1-propyl, isopropyl
(i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and
hexyl group, whereby it is especially preferred that R is an
isopropyl and whereby it is especially preferable that the C-atom
identified with ".star-solid." be present in the
(R)-configuration.
[0103] In a notably especially preferred form of execution of the
invention the dosing unit contains the free base from
(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenyl isobutyrate (fesoterodine free base) with a degree of
purity of 97 percent by weight minimum, preferably above 98 percent
by weight, especially preferably above 98.5 percent by weight and
notably especially preferably above 99 percent by weight.
[0104] If the pharmaceutical formulation is arranged as a
transdermal form of administration, the flux rate through the skin
of the patient should be as constant as possible in order to avoid
fluctuations of the concentration in the plasma.
[0105] The daily dose should therefore be administered in the case
of an application area of 50 cm.sup.2, preferably a maximum of 40
cm.sup.2, in a steady state flux through the human skin of more
than 6 .mu.g/cm.sup.2/hour, preferably of more than 8
.mu.g/cm.sup.2/hour, especially preferably of more than 10
.mu.g/cm.sup.2/hour and notably especially preferably of more than
12 .mu.g/cm.sup.2/hour, whereby the flux rates are determined
according to Tanojo in a model of human skin in-vitro as described
in Example Execution 3.2.
[0106] The invention also concerns the manufacture of drugs.
[0107] The high purity bases in compliance with the invention are
for use during manufacture of a medicine, particularly for the
treatment of incontinence, notably especially for the treatment of
urge incontinence, as well as for the treatment of hyperactivity of
the detrusor, pollakisuria, nocturia or imperative urinary
urgency.
[0108] One aspect of the invention is therefore the use of a free
base of the general Formula I, ##STR8## in which A means hydrogen
or deuterium, R stands for a group that is selected from
C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl or phenyl, which may each be
substituted with C.sub.1-3-alkoxy, fluorine, chlorine, bromine,
iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and
where the C-atom marked with a star ".star-solid." may be present
in the (R)-configuration, the (S)-configuration or as a mixture of
it and whereby the free base is present in a purity of above 97
percent by weight minimum, preferably above 98 percent by weight,
especially preferably above 98.5 percent by weight and notably
especially preferably above 99 percent by weight for the
manufacture of a medicine, preferably a medicine for transdermal or
transmucosal delivery.
[0109] In a preferred form of execution of the invention the
compound of the general Formula I, where R is selected out of the
methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl,
tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is
especially preferred that R is an isopropyl and whereby it is
especially preferred that the C-atom identified with ".star-solid."
be present in the (R)-configuration, is used for the manufacture of
the above names drugs.
[0110] The high purity bases of the Formula I may, for example, be
used for manufacture of the more available buccal drugs, e.g.
sprays, mucoadhesive pellets or fast dissolving wafers, as
described in WO 02/02085 for example.
[0111] Other preferred medicine forms of the bases of the Formula I
are transdermal formulations, for example, ointments, creams,
lotions, sprays, pastes, foils or patches containing an active
ingredient.
[0112] In the course of this the high purity base of the general
Formula I is preferably used for the manufacture of a medicine for
retarded transdermal or transmucosal delivery and for this purpose
is preferably introduced into an adhesive or a non-adhesive polymer
matrix.
[0113] One object of the invention is therefore the use of a free
base of the general Formula I, ##STR9## in which A is hydrogen or
deuterium, R stands for a group that is selected from
C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl or phenyl, which may each be
substituted with C.sub.1-3-alkoxy, fluorine, chlorine, bromine,
iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and
where the C-atom marked with a star ".star-solid." may be present
in the (R)-configuration, the (S)-configuration or as a mixture of
it and whereby the free base is present in a purity of above 97
percent by weight minimum, preferably above 98 percent by weight,
especially preferably above 98.5 percent by weight and notably
especially preferably above 99 percent by weight,
[0114] for the manufacture of a medicine, preferably a medicine for
transdermal or transmucosal delivery characterized by the fact that
the compound of the Formula I is present either dissolved or
dispersed in a polymer layer, preferably in a self-adhesive polymer
layer.
[0115] In a preferred form of execution of the invention the
compound of the general Formula I is used for the manufacture of
the above named transdermal medicine, whereby R is selected out of
the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl,
tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is
especially preferred that R be an isopropyl and whereby it is
especially preferred the C-atom identified with ".star-solid." be
present in the (R)-configuration.
[0116] It is preferable that the high purity compound of the
general Formula libe present in the form of the free base with a
combined salt part of less than 10 percent by weight, especially
preferable less than 5% or 3%, notably especially preferable less
than 1%.
[0117] If the high purity salts from 3,3-diphenylpropylamine
derivates known from WO 01/35957, for example, the fumarate salt
from fesoterodine, only lead in the case of transdermal delivery to
flux rates not sufficient for transdermal treatment, even the
addition of loaded molecules such as silicates or Chitosan, for
example, or of skin penetration amplifiers like oleic acid or PGML
(polyglycol monolaurate) to the matrices containing the active
ingredient salt does not lead to satisfactory flux rates (Table
2).
[0118] Even an in-situ release of the base from the corresponding
salt through the addition of calcium silicate during manufacture of
the adhesive matrix, as described in WO 94/07486, does not lead to
the flux rates through the human skin desired (Table 2), because
the in-situ conversion to the free base is generally not absolute
so that too high a proportion of the active ingredient in its
protonated form is present in the matrix.
[0119] The compound of the general Formula I should therefore be
added to the polymer matrix paste, preferably already in the form
of the high purity free base at the time of the manufacture of the
inventive devices. TABLE-US-00002 TABLE 2 Loading of the active
Flux .mu.g/cm.sup.2/Day ingredient (in steady state; (Percent by
Matrix after 24 hours) Contact weight weight Mouse Human Lot-No
adhesive Procedure fesoterodine) (g/m.sup.2) Skin skin
20111080.sup.1 Acrylate Solvent 15 100 705 n.d. 20302060.sup.1
Acrylate Solvent 15 87 n.d. 332.64 20111085.sup.1 EVA Hot melt 15
84 510 323.7 20111086.sup.1 Silicone Hotmelt 15 63 495 n.d.
20302062.sup.1 Silicone Hotmelt 15 100 n.d. 544.89 20111087.sup.1
SxS Hotmelt 15 89 460 383.8 20302063.sup.1 Silicone + Hotmelt 15 83
n.d. 501.09 PVAc.sup.6 20002031.sup.2 Acrylate Solvent 15 Fumarate
105 27 n.d. 20104035.sup.2,3 Acrylate/OL Solvent 15 Fumarate 110 84
n.d. 20106061.sup.4 Silicone Solvent 15 Fumarate 60 n.d. 24,2
20106043.sup.5 Silicone Hotmelt 15 DiOH.sup.5 101 n.d. 2,3 n.d. =
not determined; .sup.1= fesoterodine was added to the matrix as the
free base; .sup.2= Comparison example manufactured through the use
of fesoterodine-fumarate salt; .sup.3= Comparison example
manufactured through the use of fesoterodine-fumarate salt with
oleic acid as the permeation enhancer; .sup.4= Comparison example
manufactured through the in-situ release of the base from the
fumarate salt into the adhesive matrix; .sup.5= Comparison example
manufactured through the use of the dihydroxymetabolites
(2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy
methyl)phenol) from fesoterodine; .sup.6PVAc = Poly Vinyl
Acetate.
[0120] FIG. 2 shows that in those cases which the high purity base
of (R)-fesoterodine in an amount of 15 percent by weight was
introduced into appropriate adhesive matrices of the SXS or EVA
type, TTS leads to flux rates that make therapeutically desired
daily doses with the corresponding application surface of 5-50
cm.sup.2 possible in the case of the trials using in-vitro human
skin as follows (Table 3): TABLE-US-00003 TABLE 3 Flux rate
fesoterodine through human skin (mg/day) based on the TTS size
Contact TTS size adhesive 5 cm.sup.2 10 cm.sup.2 20 cm.sup.2 30
cm.sup.2 40 cm.sup.2 50 cm.sup.2 EVA 1.6 3.2 6.5 9.7 13 16 SXS 1.9
3.8 7.6 11.4 15.2 19 Silicone/ 2.5 5 10 15 20 25 Cer + PVAc
Acrylate 1.7 3.3 6.6 10 13.3 16.7 (Durotak 87-4287)
[0121] The in-vitro model used according to Tanojo (J. Control Rel.
45 (1997) 41-47) has proven to be an excellent model in which the
in-vitro flux rates measured correlated outstandingly with the
in-vivo flux rates, which were measured in several clinical
studies. The result of this is that the therapeutically desired
daily flux rates of active ingredient of a minimum 3 mg, for
example, 3-15 mg, preferably of 4-12 mg or 6-12 mg can be achieved
through use of the inventive TTS.
[0122] Flux rates of fesoterodine (high purity free base) through
mammalian skin comparable to in-vitro could be achieved from
acrylate and silicone based matrices as well (FIG. 3, Table 2).
[0123] Therefore in one form of execution the invention concerns
the use of a free base of the general Formula I, ##STR10## in which
A is hydrogen or deuterium, R stands for a group that is selected
from C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl or phenyl, which may
each be substituted with C.sub.1-3-alkoxy, fluorine, chlorine,
bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium
and where the C-atom marked with a star ".star-solid." may be
present in the (R)-configuration, the (S)-configuration or as a
mixture of it and whereby the free base is present in a purity of
above 97 percent by weight minimum, preferably above 98 percent by
weight, especially preferably above 98.5 percent by weight and
notably especially preferably above 99 percent by weight,
[0124] for manufacture of a medicine for transdermal delivery,
characterized by the fact that the compound of the general Formula
I is introduced into a polymer layer, preferably into a
self-adhesive polymer layer and that the medicine a compound of the
general Formula I is released in a daily dose of 0.5 mg-20 mg/day,
preferably of at least 3 mg/day, for example, 3-15 mg/day,
preferably 4-12 mg/day and notably especially preferably 6-12
mg/day through the skin of a mammal, in particular through human
skin.
[0125] In a preferred form of execution of the invention the
compound of the general Formula I where R is selected out of the
methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl,
tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is
especially preferred that R be an isopropyl and whereby it is
especially preferred that the C-atom identified with ".star-solid."
be present in the (R)-configuration, is used for the manufacture of
the above named drugs.
[0126] In particularly preferred forms of execution the medicine
contains the high purity base of fesoterodine as the active
ingredient.
[0127] In a particularly preferred form of execution the invention
therefore concerns the use of a high purity compound of the general
Formula I used for the manufacture of a medicine, whereby the
medicine [0128] (a) comprises a self-adhesive polymer matrix that
contains the high purity base of fesoterodine and [0129] (b)
delivers high purity base of fesoterodine with a flux rate of
0.5-20 mg/day, preferably of at least 3 mg/day, for example, 3-15
mg/day, especially preferably 4-12 mg/day through human skin.
[0130] As FIG. 2 shows, the delivery of the active ingredient from
such drugs is largely constant over a minimum 24 hours following an
initial burst effect phase.
[0131] Therefore, in a different special form of execution the
invention concerns the use of a high purity combination of the
general Formula I, for example, fesoterodine for the manufacture of
a medicine, whereby the medicine after an initial burst effect
phase releases the solution of the general Formula I over a minimum
of 24 hours, preferably over a minimum of 36 hours at a constant
flux rate.
[0132] In this patent application the expression "steady-state" is
understood to mean a dynamic equilibrium that adjusts itself after
an initial lag phase following application of the inventive device
for the first time.
[0133] "Steady-state flux rate" is understood to mean a flux-rate
that adjusts after the initial lag phase.
[0134] In this patent application the expression "constant flux
rate" is understood to mean a steady-state flux rate in the case of
which a compound of the general Formula I is transported at an
average flux rate through human skin, which exhibits an
intra-individual variability CV over the time of a maximum of 30%,
preferably a maximum of 20% where CV is determined according to the
equation CV=(sd:x).times.100% (see the Cawello (ED) calculation in
"Parameters for Compartment-free Pharmacokinetics", Shaker Verlag,
Aachen, 1999, Page 112). In the course of this a daily dose is
administered at an average flux rate of daily dose: 24 (mg/hour)
with a CV of 30%. To the skilled person it is clear that a steady
flux rate is only adjusted following an initial burst effect phase
("lag phase") after application for the first time of the device.
The lag phase is therefore not taken into consideration in the
calculation of the steady flux rate.
[0135] In this patent application, unless expressly stated
otherwise, the expression "flux rate through human skin" is
understood to mean a flux rate that was measured according to
Tanojo in an in-vitro human skin model as described in Example
Execution 3.2.
[0136] The preferred polymer matrices are self-adhesive polymer
matrices of the EVA-, SXS, silicone or acrylate type, the
properties and manufacture of which are described in more detail in
the following:
[0137] Silicone Adhesives:
[0138] The preferred silicone adhesives are amine resistant,
pressure sensitive, polymeric organosiloxane adhesives.
[0139] In most cases silicone contact adhesives represent polymeric
dimethylsiloxanes; however in principle other organic residues,
such as ethyl or phenyl groups, for example, may also be available
instead of the methyl groups. Amine resistant silicone contact
adhesives are generally characterized in that they contain not any
or only a few free silanol functions because the Si--OH-groups were
alkylated. Such adhesives are described in EP 180 377. Condensates
or mixtures of silicone resins and polymeric organosiloxane
adhesives such as described in US RE 35 474 are especially
preferred adhesives.
[0140] Suitable adhesives are sold, for example, by Dow Corning as
the so-called Bio-PSA adhesives. In the process mixtures of the
contact adhesive Bio PSA Q7-4301 and Q7-4201 are particularly
suitable, especially in a 40:60 to 60:40 ratio.
[0141] Patch matrices based on silicone adhesives are processed
predominantly in solvent based procedures. For this purpose a
solution of contact adhesives and active ingredient are
manufactured in a first step in an organic solvent or a mixture of
solvents. In a second step the solution is spread out and
laminated, and the solvent is then removed. Such a procedure is
described as an example in WO 99/49852.
[0142] An alternative procedure that dispenses with the use of
organic solvents is the hot melt procedure. In this procedure the
polymer or the contact adhesive are melted at temperatures between
70 and 200.degree. C., preferably between 90 and 160.degree. C. and
especially preferably between 100 and 150.degree. C. and the active
ingredient introduced into the homogenized matrix melt. After brief
homogenization the adhesive matrix that contains the active
ingredient is cooled again so that the active ingredient is exposed
to a thermal load in general for less than 5 minutes, if desired
even for 4, 3, and 2 or even for less than 1 minute. Following this
the active ingredient is present in the solidified polymer melt.
During the process the active ingredient is broadly shielded from
critical environmental influences (light, oxygen).
[0143] This procedure has the advantage over the solvent based
procedure that the high purity bases of the general Formula I are
not exposed to any solvent influences but instead are able to be
added immediately into the hot melt, where after a short
homogenization they are stabilized in the cooling polymer matrix.
The hot melt procedure is preferably carried out in an extruder,
for example, in a twin screw extruder, as described in WO
99/48493.
[0144] At the above mentioned processing temperatures the silicone
adhesives are generally too viscous, meaning they have a dynamic
viscosity of above 150 Pa's. Various procedures were described in
the patent literature to make the viscosity of the silicone
adhesives hot-meltable through the admixing of suitable additives
(softeners). Examples of those softeners for silicone are glycerol
monolaurate or lauryl acetate as described in EP 835 136, waxes of
the formula R--C(O)--OR' as described in EP 360 467, alkylmethyl
siloxane waxes as described in EP 524 775, siloxanated polyether
waxes as described in EP 663. 431 or organic waxes as described in
US RE 36 754.
[0145] Generally speaking the softeners are added to the silicone
adhesive in a quantity of 1-30 percent by weight based on the total
mixture of the hot-meltable adhesive mixture. The preferred
softeners are organic waxes as described in US RE 36 754, for
example, ozokerite wax, ceresine wax, paraffin wax, candelilla wax,
carnauba wax, beeswax or mixtures of these waxes, where ozokerite
and ceresine are absolutely, especially preferred.
[0146] Ready-made hot-meltable silicone contact adhesives, in
particular mixtures of silicone contact adhesives with ceresine or
ozokerite may be obtained at Dow Corning, Mich.
[0147] For example, through the addition of 10 percent by weight
ceresine wax to a silicone contact adhesive, it was possible to
lower the dynamic viscosity of the resulting contact adhesive
mixture from above 150 Pa's to below 50 Pa's at a processing
temperature of 150.degree. C. Such a silicone based contact
adhesive mixture can be processed very well in a temperature range
of from 70.degree. C. to 200.degree. C., and in particular in the
range between 100.degree. C. and 150.degree. C. in a hot melt
procedure.
[0148] Surprisingly, it was determined that hot-meltable silicone
contact adhesives are excellently suited for the transdermal
delivery of the compounds of the general Formula I.
[0149] One object of the invention is therefore a device for the
transdermal delivery of a compound of the Formula I ##STR11## in
which A means hydrogen or deuterium, R stands for a group that is
selected from C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl or phenyl,
which may each be substituted with C.sub.1-3-alkoxy, fluorine,
chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or
deuterium and where the C-atom marked with a star ".star-solid."
may be present in the (R)-configuration, the (S)-configuration or
as a mixture of it,
[0150] characterized by the fact that the compound of the general
Formula I was introduced into a polymer layer (adhesive matrix) in
the form of a free base, with a degree of purity of above 97
percent by weight, preferably above 98 percent by weight,
especially preferably above 98.5 percent by weight and absolutely
especially preferably above 99 percent by weight, whereby the
adhesive matrix incorporates an amino-resistant silicone.
[0151] In an especially preferred form of execution of the
invention the adhesive matrix is based on a hot-meltable mixture of
a silicone based contact adhesive and at least one softener, in
particular an organic wax, for example, ozokerite. In preference
the inventive silicone-based matrix was into the high purity base
of fesoterodine as the active ingredient.
[0152] In the process "hot-meltable" is understood to mean that the
adhesive exhibits a dynamic viscosity of at the highest 150,
preferably 120 Pa's at the highest, at an accepted working
temperature during a hot melt procedure of, for example,
160.degree. C.
[0153] A further aspect of the invention is a medicine for the
transdermal delivery of a compound of the general Formula I
comprising an adhesive matrix that comprises: [0154] (a) 50-99
percent by weight of a contact adhesive mixture consisting of
[0155] (i) 70-99 percent by weight of an amino resistant silicone
adhesive, [0156] (ii) 1-30 percent by weight, preferably 3-15
percent by weight of an appropriate softener, preferably an organic
wax, which especially preferably is selected from the group
ozokerite wax, ceresine wax, paraffin wax, candelilla wax, carnauba
wax, beeswax or mixtures of these waxes where ozokerite wax and
ceresine are especially preferred, [0157] (b) 1-40 percent by
weight of a compound of the general Formula I is introduced into
the matrix in the form of the high purity free base.
[0158] Silicone adhesives can be bought commercially and are sold,
for example, by Dow Corning as Bio-PSA Q7-4300 or Bio-PSA Q7-4200.
Hot-meltable silicone adhesives incorporating mixtures of PSA
7-4300 with organic waxes like ozokerite or ceresine are also
obtainable from Dow Corning.
[0159] FIG. 3/4 shows the in-vitro flux through mouse skin that was
achieved using a silicone based patch manufactured in a hot melt
procedure that contains ozokerite as a softener for the adhesive
matrix and that contains the high purity free base of fesoterodine
in the adhesive matrix.
[0160] EVA-Adhesives
[0161] EVA adhesives are hot-meltable contact adhesives, which are
based on ethylene vinyl acetate-copolymers ("EVA-contact
adhesive"). EVA-adhesives such as these are described in U.S. Pat.
No. 4,144,317 for example. EVA-adhesives feature good adhesive
properties, simple manufacture and processing as well as good skin
compatibility. EVA-adhesives can be obtained, for example, at
Beardow Adams (1 3/BA).
[0162] What was said under silicones essentially applies for the
processing in a hot melt procedure where no softeners have to be
added to the EVA-contact adhesives.
[0163] One object of the invention is therefore a device for the
transdermal delivery of a compound of the Formula I ##STR12## in
which A means hydrogen or deuterium, R stands for a group that is
selected from C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl or phenyl,
which may each be substituted with C.sub.1-3-alkoxy, fluorine,
chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or
deuterium and where the C-atom marked with a star ".star-solid."
may be present in the (R)-configuration, the (S)-configuration or
as a mixture of it,
[0164] characterized by the fact that the compound of the general
Formula I was introduced into a-self adhesive polymer layer
(adhesive matrix) in the form of a free base, with a degree of
purity of over 97 percent by weight, preferably above 98 percent by
weight, especially preferably above 98.5 percent by weight and
notably especially preferably above 99 percent by weight, whereby
the adhesive matrix comprises an adhesive of the EVA type.
[0165] In an especially preferred form of execution of the
invention the EVA-based adhesive matrix has been manufactured in a
hot, melt procedure. In preference the inventive EVA-based matrix
was introduced into the high purity base of fesoterodine as the
active ingredient.
[0166] FIGS. 2 and 3 illustrate the in-vitro flux rates through
human skin and mouse skin respectively, that were achieved using an
EVA-based patch manufactured in a hot melt procedure that contains
the high purity base of fesoterodine in the adhesive matrix.
[0167] SxS-Contact Adhesives
[0168] SxS contact adhesives may be processed in both solvent based
manufacturing procedures and hot melt procedures. In this patent
application the term "SxS contact adhesives" is understood to mean
styrene block copolymer based adhesives that carry non-elastomeric
styrene blocks at the ends and elastomeric blocks in the middle.
The elastomeric blocks may, for example, consist of polyethylene
butylene, polyethylene propylene, polybutadiene, polyisobutylene or
polyisopropene.
[0169] Suitable SxS adhesives are described in U.S. Pat. No.
5,559,165 or U.S. Pat. No. 5,527,536 for example and feature good
adhesive properties, simple manufacture and processing as well as
good skin compatibility.
[0170] SxS contact adhesives may be obtained both commercially
(e.g. as Duro Tak 378-3500 at National Starch & Chemical) and
manufactured for oneself using hot melt extrusion equipment during
the production of patches containing an active ingredient.
[0171] For instance, for this purpose appropriate amounts (of the
following components at a minimum) of a styrene block copolymer
(e.g. Shell Kraton GX1657 or Kraton D-1107CU) are dosed into the
extruder with an aliphatic and/or aromatic resin (e.g. Keyser
Mackay Regalite R1090 or Regalite R1010 or Regalite R1100) and an
oil (e.g. Shell Ondina 933 or Ondina 941) from the individual
dosing stations, mixed there and melted. In the last step the
active ingredient is dosed into the contact adhesive manufactured
in this way in the extruder and the paste laminated on foil sheets.
Typical exemplary parts by weight: polymer:resin: oil are e.g.
100:120:20 or 100:200:50. The properties of the SxS contact
adhesives can be adapted to the desired properties of the TTS
(adhesive strength, minimum cold flow, duration of adherence,
releasing profile of the active ingredient, etc.) by varying these
proportions of amounts.
[0172] One object of the invention is therefore a device for the
transdermal delivery of a compound of the Formula I ##STR13## in
which A means hydrogen or deuterium, R stands for a group that is
selected from C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl or phenyl,
which may each be substituted with C.sub.1-3-alkoxy, fluorine,
chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or
deuterium and where the C-atom marked with a star ".star-solid."
may be present in the (R)-configuration, the (S)-configuration or
as a mixture of it,
[0173] characterized by the fact that the compound of the general
Formula I was introduced into a self-adhesive polymer layer
(adhesive matrix) in the form of a free base, with a degree of
purity of over 98 percent by weight, preferably above 97 percent by
weight, preferably above 98 percent by weight, especially
preferably above 98.5 percent by weight and absolutely especially
preferably above 99 percent by weight, whereby the adhesive matrix
incorporates a contact adhesive on an SXS-basis.
[0174] In an especially preferred form of execution of the
invention the SXS-based adhesive matrix has been manufactured in a
hot melt procedure. In preference the inventive SXS-based matrix
was introduced into the high purity base of fesoterodine as the
active ingredient.
[0175] FIGS. 2 and 3 illustrate the in-vitro flux rates through
human skin and mouse skin respectively, that were achieved using an
SXS-based patch manufactured in a hot melt procedure into which the
high purity free base of fesoterodine was introduced.
[0176] Due to the potential oxidative effect of the SXS adhesives,
antioxidants are preferably added to SXS-based adhesive matrices.
An example for a commercially obtainable, suitable antioxidant is
Irganox.RTM. (CIBA).
[0177] Acrylate Adhesives:
[0178] Polyacrylates are produced through the radical
polymerization of (meth)acrylic acid derivates, whereby other
suitable compounds, such as vinyl acetate, for example, may be used
as other monomers. The expression "polyacrylate" in this patent
application includes polymers that comprises units that are based
on acrylic acids and/or meth-acrylic acids as well as copolymers
and mixtures of them.
[0179] As a matter of principle, in the selection of appropriate
monomers the resulting contact adhesives can be constituted in such
a way that they exhibit specific properties, meaning a favorable
solvent capacity for the active ingredient, a desired movability of
the active ingredient in the matrix as well as a desired
transfer-rate through the skin. The transfer rate is significantly
limited by the distribution coefficients and the resorption of the
active ingredient through the skin.
[0180] The pressure sensitive contact adhesive of the polyacrylate
type may be a homopolymer and/or copolymer of at least one acrylic
acid and/or meth-acrylic acid derivative in the form of a solution
in an organic solvent. The polyacrylate type contact adhesive may
be cross-linkable or non-cross-linkable. The cross-linking reagent
links the polymer chains using reactive groups. This may result in
an increased cohesion of the contact adhesive.
[0181] Preferably the polymer contact adhesive of the polyacrylate
type consists of the following monomers at a minimum:
[0182] Acrylic acid, acrylamide, hexyl-acrylate,
2-ethyl-hexyl-acrylate, hydroxy-ethyl-acrylate, octyl-acrylate,
butyl-acrylate, methyl-acrylate, glycidyl-acrylate,
methyl-acrylate, meth acrylic acid, methacrylamide,
hexyl-methacrylate, 2-ethyl-hexyl amide-acrylate,
octyl-methacrylate, methyl-methacrylate, glycidyl-methacrylate,
vinyl acetate, vinyl pyrrolidon, allyl-acrylate.
[0183] The polymer contact adhesives of the acrylate type,
cross-linkable contact adhesives that are polymerized from a
combination of the following monomers are preferred: [0184]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/butyl-acrylate/acrylic
acid, [0185] 2-ethyl-hexyl-acrylate/N-butyl-acrylate//vinyl
acetate/acrylic acid, [0186] 2-ethyl-hexyl-acrylate/vinyl
acetate/acrylic acid, [0187] 2-ethyl-hexyl-acrylate/vinyl
acetate/allyl-acrylate, [0188] 2-ethyl-hexyl-acrylate/vinyl
acetate/divinyl-benzol/acrylic acid, [0189]
2-ethyl-hexyl-acrylate/vinyl acetate/allyl-methacrylate/acrylic
acid, [0190] 2-ethyl-hexyl-acrylate/vinyl
acetate/2-hydroxy-ethyl-acrylate, [0191]
2-ethyl-hexyl-acrylate/vinyl acetate/2-hydroxy-ethyl-methacrylate,
[0192] 2-ethyl-hexyl-acrylate/fumaric acid-diethyl-ester/acrylic
acid, [0193] 2-ethyl-hexyl-acrylate/maleic
acid-diethyl-ester/2-hydroxy-ethyl-acrylate.
[0194] The following compounds can be named as preferred
cross-linking preparations: Diphenyl-methane-4-diisocyanate,
hexamethylene-diisocyanate, titanium-acetyl acetonate,
aluminum-acetyl acetonate, ferrous-acetyl acetonate, zinc-acetyl
acetonate, magnesium-acetyl acetonate, zirconium-acetyl acetonate,
2-ethyl-1,3-hexanediol-titanate, tetra-isooctyl-titanate,
tetra-nonyl-titanate, polyfunctional propylene-imine-derivate,
ether-derivate from melamine-formaldehyde-resin, high methylated
urethane-resin, imine-melamine-resin.
[0195] The non-cross linkable contact adhesives may be polymerized,
preferably from a combination of the following monomers: [0196]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate, [0197]
2-ethyl-hexyl-acrylate/vinylacetate, [0198]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate/allyl-acrylate,
[0199]
2-ethyl-hexyl-acrylate/N-N-butyl-acrylate/allyl-methacrylate,
[0200]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate/divinyl-benz-
ol, [0201] 2-ethyl-hexyl-acrylate/fumaric
acid-diethyl-ester/allyl-acrylate, [0202]
2-ethyl-hexyl-acrylate/maleic acid-diethyl-ester/allyl-acrylate,
[0203]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/acrylamide/vinylacetate/allyl-acr-
ylate, [0204]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/iso-butyl-acrylate/vinylacetate/a-
llyl-acrylate.
[0205] Furthermore a few contact adhesives may be used in the form
of an aqueous dispersion (the dispersive type). The usage of these
dispersive type contact adhesives may bring the advantage that no
inflammable or toxic solvents become vaporized during the coating
and drying.
[0206] Dispersive type contact adhesives may be polymerized
preferably from a combination of the following monomers: [0207]
N-butyl-acrylate/iso-butyl-acrylate/acrylic acid. [0208]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/acrylic acid, [0209]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/2-hydroxy-ethyl-acrylamide,
[0210] 2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinyl
acetate/acrylamide, [0211]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinyl
acetate/2-hydroxy-ethyl-acrylate, [0212]
2-ethyl-hexyl-acrylate/N-butyl-acrylate/allyl-acrylate/acrylic
acid, [0213] 2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinyl
acetate/divinyl-benzol.
[0214] Suitable polyacrylates for use in this invention are
cross-linked by multivalent metal ions in order to improve the
physical properties of the contact adhesive or in order to adapt it
to the specific requirements. The metal ions are normally applied
in the form of metal chelate compounds, which are soluble in
organic solvents. Especially suitable cross-linking agents are
aluminum acetyl acetonate and titanium acetyl acetonate.
[0215] If the contact adhesive used in compliance with this
invention is a polyacrylate contact adhesive, the solubility
capacity generally depends on the type and the quantity of the free
functional groups in the contact adhesive.
[0216] The most preferred contact adhesives for use in the device
of this invention are the polyacrylates with polar groups, in
particular with the free hydroxy groups. Examples of such contact
adhesives are the polyacrylates for the manufacture of which polar
monomers, such as e.g. hydroxy-ethyl-acrylate,
hydroxy-ethyl-methacrylate, acrylic acid or methacrylic acid are
used in an amount of approximately 1-10% (w/w), especially
preferably in a quantity of 3-8% (w/w), absolutely especially
preferably in an amount of 4-6% (w/w). Such contact adhesives are
obtainable commercially under the brand name Duro-Tak.RTM.
(National Starch & Chemicals; Hamburg).
[0217] Notably, especially preferred for use in the device of this
invention are the contact adhesives of the polyacrylate type, where
hydroxy-ethyl-acrylate and/or hydroxyl-ethyl-methacrylate monomers
are admixed during polymerization in a quantity of 3-8% (w/w),
notably especially preferably in a quantity of 4-6% (w/w).
[0218] Such a contact adhesive may be obtained according to the
general procedure that is described in US patent 5,498,418 as
follows: The contact adhesive can be obtained through radical
polymerization. In a first step a mixture consisting of 21 to 40
percent by weight vinyl acetate, 55-70 percent by weight of an
acrylic acid C.sub.24-alkyl ester and 3 to 10 percent by weight of
an acrylic acid C.sub.2-4 hydroxyl acrylic ester is manufactured in
an organic solvent with 100 percent by weight monomers in the
mixture.
[0219] In a second step a conventional cross-linked agent in an
organic solvent and--optionally--the active ingredient of the
quality required in the transdermal device (patch) for the intended
usage is admixed, if necessary in an organic solvent.
[0220] Finally, in a third step the mixture of the particular
acrylate vinyl acetate copolymer obtained is cross-linked in an
additional step, conducted through heating and through the removal
of the organic solvent or the mixture of solvents used. The active
ingredient obtained is "built into" the contact adhesive substance
in a special way through the successive and additional
cross-linking of the special acrylate vinyl acetate copolymer.
[0221] Alternatively the acrylate vinyl acetate copolymer can be
polymerized and cross-linked in the absence of the active
ingredient. The active ingredient is then added during the
application of the acrylate vinyl acetate copolymer when the patch
is manufactured. The acrylate vinyl acetate copolymer has a
relative viscosity of 3.0 to 4.2 at 20.degree. C.
[0222] Preferably the mixture contains 2-ethyl hexane acrylate and
hydroxyl ethyl acrylate monomers in addition to vinyl acetate.
Preferably the subsequent cross-linking of the special acrylate
vinyl acetate copolymers is performed with a titanium acid ester
consisting of polybutyl-titanate and/or titanium acetyl acetonate,
preferably in a quantity of 0.3 to 3 percent by weight proportional
to the weight of the copolymer.
[0223] The following steps can cover a process for the manufacture
of a TTS in compliance with this invention: As a first step the
manufacture of a solution of a copolymer, in which the active
ingredient, in the amount required for the intended use of the TTS
as well as a conventional cross-linker or a mixture of it, is
optionally contained, and whereby the copolymer is obtained through
the radical polymerization of a mixture of monomers consisting of
21 to 40 percent by weight vinyl acetate, 55 to 70% by weight of an
acrylic acid-C.sub.2-8 alkyl ester and 1 to 10 percent by weight of
an acrylic acid-C.sub.2-4 hydroxy. alkylester, the coating of the
above named solution in the layer thickness required on the
protective film of the TTS and the removal of the solvent or the
mixing of the solvents by heating, which results in an additional
cross-linking of the special acrylate vinyl acetate copolymer.
[0224] One form of execution of such a process is characterized by
the fact that the acrylate vinyl acetate copolymer--optionally--the
active ingredient and the cross-linkable agent are dissolved at the
start in a solvent, which contains 20 to 40 percent by weight
ethanol or an ethanol methanol mixture, with a ratio of solid
components consisting of 40 to 60 percent by weight of the mixture
of the special acrylate vinyl acetate copolymer of the
cross-linkable agent and the active ingredient.
[0225] In a different--preferred--form of execution of the
invention the active ingredient is only added to the dispersion
after cross-linking of the acrylate, which is then spread on the
protective film following homogenization.
[0226] A particular example of execution for the preparation of
such an acrylate-vinyl acetate contact adhesive is published in
U.S. Pat. No. 5,498,418, column 2, lines 61 to column 3, line 10,
quoted here as a reference.
[0227] A particularly preferred contact adhesive for use in this
invention are the commercially available contact adhesives
Duro-Tak.RTM. 387-2287 and Duro-Tak.RTM. (3)87 (National Starch
& Chemicals; Hamburg). In an especially preferred form of
execution of the invention the Duro-Tak contact adhesive is mixed
in an appropriate solvent with the desired amount of the active
ingredient and the resulting homogenous dispersion spread out in
the thickness desired. Finally the solvent or the mixture of
solvents is removed at raised temperatures (50-70.degree. C.).
[0228] One object of the invention is therefore a device for the
transdermal delivery of a compound of the Formula I ##STR14## in
which A means hydrogen or deuterium, R stands for a group that is
selected from C.sub.1-6-alkyl, C.sub.3-10-cycloalkyl or phenyl,
which may each be substituted with C.sub.1-3-alkoxy, fluorine,
chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or
deuterium and where the C-atom marked with a star ".star-solid."
may be present in the (R)-configuration, the (S)-configuration or
as a mixture of it,
[0229] characterized by the fact that the compound of the general
Formula I was introduced into a polymer layer, preferably a
self-adhesive polymer layer (adhesive matrix) in the form of a free
base, with a degree of purity of above 97 percent by weight,
preferably above 98 percent by weight, especially preferably above
98.5 percent by weight and notably especially preferably above 99
percent by weight, whereby the polymer layer incorporates at least
one polymer of the acrylate and/or methacrylate type.
[0230] In preference the high purity base of fesoterodine as the
active ingredient was introduced into the inventive acrylate-based
matrix.
[0231] FIG. 3 shows the in-vitro flux rates through mouse skin that
were achieved with an acrylate based patch manufactured in a hot
melt procedure in which the high purity free base of fesoterodine
was introduced into the adhesive matrix.
[0232] Auxiliary Agents and Additives
[0233] The above described polymer matrices of the transdermal
devices containing an active ingredient in compliance with the
invention may contain other auxiliary agents and additives.
Examples are buffers, solutizing agents, chemical stabilizers,
antioxidants, other auxiliary agents for retarding as well as skin
penetration enhancers.
[0234] Skin penetration enhancers may be added, for example, to
enlarge the amount of active ingredient that permeates through the
skin or to shrink the application area of the device. Non-limiting
examples of common penetration enhancers are alcohols, in
particular short chained alcohols such as ethanol, fatty alcohols,
e.g. lauryl alcohol, polyalcohols such as glycerin, amides, e.g.
aromatic amides like N,N-diethyl-m-toluamide, amino acids, azones,
oils like menthol or peppermint oil; fatty acids and their esters
like oleic acids, lauryl acids, isopropyl myristate or glycerol
monolaurate; macrocycles such as for example, cyclopentadecanon;
phospholipides such as lecithin for example; 2-pyrrolidones,
sulfoxides such as dimethyl sulfoxide for example.
[0235] On account of the good penetration properties of the free
bases of the general Formula I, forms of execution of the invention
are preferred in which the addition of an enhancer is dispensed
with.
[0236] A hydrophilic component such as a hydrophilic polymer for
example, may be added to the adhesive matrix as another component.
These hydrophilic polymers may serve as solubility facilitators or
crystallization inhibitors for the compounds of the general Formula
I and contribute to a uniform distribution of the active ingredient
in the adhesive matrix.
[0237] Appropriate hydrophilic polymers for use in the TTS in
compliance with the invention may, for example, be chosen from the
group of the polysaccharides, substituted polysaccharides,
polyethylene oxides, polyvinyl acetates, polyvinyl pyrrolidones
(PVP), PVP with appropriate softeners, polyethylene glycols,
polypropylene glycols, polyacrylates, copolymers from polyvinyl
pyrrolidone and (poly)vinyl acetate, copolymers from ethylene and
vinyl acetate as well as polyvinyl alcohols with a suitable
softener, for example, glycerin.
[0238] Preferred hydrophilic polymers are PVP, polyethylene oxide
(PEO), polyvinyl acetate (PVAc) as well as copolymers from PVP and
vinyl acetate.
[0239] The hydrophilic polymers may be added to the adhesive layer,
for example, in a portion of 0.5-40 percent by weight based on the
total weight of the adhesive layer. Preferably 2-25 percent by
weight, especially preferably 2-15 percent by weight of 2-10
percent by weight hydrophilic polymers are added.
[0240] Those hydrophilic polymers that exhibit a dynamic melting
viscosity of a maximum 150 Pa's, preferably less than 120 Pa's and
especially preferred below 80 Pa's, at temperatures below
170.degree. C. are especially suitable for use in a hot melt
procedure. A suitable softener, for example, glycerin, is
eventually to be added beforehand if the dynamic viscosity of the
hydrophilic polymer is too low at the desired processing
temperature.
[0241] The addition of the above-named hydrophilic polymers may be
advantageous, particularly in the case of very hydrophobic adhesive
matrices, for example, silicone, polyisobutylene or SXS
matrices.
[0242] As already described in WO 01/35957, the free bases of the
3,3-diphenylpropylamine-monoester tend towards a drop in
concentration, for example, as a result of hydrolysis and
interchange esterification. It was then surprisingly determined
that the 3,3-diphenylpropylamine-monoesters can be stabilized
significantly in matrices with hydrophilic constituent parts.
[0243] While, for example, the free base of fesoterodine is
decomposed as an oil after storage for 6 months at 5.degree. C. to
around 3-4%, a drop in concentration cannot be established or only
established essentially to a lesser extent when fesoterodine is
incorporated in matrices, which contain polar components.
[0244] Examples for these such matrices, which lead to the
stabilization of the monoester of the general Formula I are
matrices, for example, that contain polyacrylates, in particular
polyacrylates with polar groups, EVA or mixtures of silicone
adhesives with hydrophilic polymers, for example, PVP or PEO,
(Table 4). TABLE-US-00004 TABLE 4 Stabilization of fesoterodine in
various matrices during storage 5.degree. C. 25.degree. C./60% RH
Stabilization Stabilization Production Matrix Factor.sup.1
Factor.sup.1 procedure EVA 7-fold 4.5-fold Hot melt
Silikon/Cer.sup.3 -- -- Hot melt Silicone + 2% PVP 2-fold 2-fold
Solvent Silikon/Cer.sup.3 + 3-fold 2.5-fold Hot melt 5% PEO
Polyacrylate No decomposition 13-fold Solvent detectable.sup.2 PIB
-- -- Solvent SXS -- 1.1-fold Hot melt .sup.1The stabilization
factor was determined by the division of the average monthly drop
in concentration of the fesoterodine base during storage as a raw
material (oil) by the average monthly drop in concentration during
storage in matrices; .sup.2the end of the period of measurement
after 6 months; .sup.3Cer = Ceresine
[0245] .sup.1The stabilization factor was determined by the
division of the average monthly drop in concentration of the
fesoterodine base during storage as a raw material (oil) by the
average monthly drop in concentration during storage in matrices;
.sup.2until the end of the period of measurement after 6 months;
.sup.3Cer=Ceresine
[0246] As Table 4 shows, the incorporation of fesoterodine in
matrices consisting of EVA adhesives, polyacrylate adhesives or
mixtures of silicone adhesives with hydrophilic polymers such as
PEO or PVP leads to a distinct stabilization of the fesoterodine
and is independent of the manufacturing process (the hot melt or
the solvent procedure).
[0247] One form of execution of the invention therefore concerns
matrices or pharmaceutical formulations or devices in which the
compounds of the general Formula I as a free base are subject to a
slower drop in concentration than is the case if the free base is
stored under identical conditions, not embedded in a polymer as an
oil. Preferred forms of execution are those which at 5.degree. C.
and/or at 25.degree. C. lead to a 2-, 3-, 7- or 10-fold
stabilization of the 3,3-diphenylpropylamine monoester by
comparison with storage as a free base.
[0248] Especially preferred pharmaceutical formulations or devices
in compliance with the invention are those in which the free base
is present in a polymer layer, in which a drop in concentration of
a compound of the general Formula I of less than 3%, preferably of
less than 2% or 1% in the case of 6-month storage at 4.degree. C.
and of less than 10%, preferably less than 5% and especially
preferably less than 3% or 1.5% in the case of 3-month storage at
25.degree. C. and 60% atmospheric moisture occurs.
[0249] Preferred matrices are those which contain 50-95 percent by
weight of an contact adhesive that is chosen from the group of the
[0250] Acrylate adhesives as well as their copolymers, in
particular acrylate adhesives with polar groups, for example with
free hydroxy groups, [0251] EVA-adhesives [0252] Silicone adhesives
which contain 2-25 percent by weight, preferably 2-10 percent by
weight of a hydrophilic polymer, in particular chosen from PEO, PVP
or PVAc, [0253] SXS- or PIB adhesives which contain 2-25 percent by
weight, preferably 2-10 percent by weight of a hydrophilic polymer,
[0254] Mixtures of hydrophilic contact adhesives (e.g. polar
polyacrylates) with hydrophobic contact adhesives (e.g. silicone,
SXS or PIB adhesives).
[0255] Notably especially preferred contact adhesives for the
manufacture of the matrices in compliance with the invention are
polyacrylates, in particular those with polar groups. These
matrices exhibit both an excellent releasing profile for
fesoterodine and outstanding stabilization properties for
3,3-diphenyl propylamine monoesters.
[0256] Based on experience surfaces up to maximum TTS sizes of
approximately 50 cm.sup.2 are accepted by patients. The size of the
TUS is typically up to 40 cm.sup.2, preferably sizes are between 5
and 35 cm.sup.2 and especially preferably between 10 and 30
cm.sup.2.
[0257] The matrix weight of the TTS typically varies between 30 and
300 g/m.sup.2, whereby the matrices with a weight of 40-200
g/m.sup.2 and especially 40-150 g/m.sup.2, are preferred.
[0258] The loading of the active ingredient depends on the
absorption/liberation capacity of the respective matrix for the
active ingredient as well as on the manufacturing procedure.
[0259] Generally speaking the loading rate of the active ingredient
makes sense between 5 and approximately 40 percent by weight based
on the total weight of the matrix containing the active ingredient
whereby the lower maximum loading rates between 7 and 30 percent by
weight are preferred, and in particular between 8 and 20 percent by
weight for the manufacture of a 1-3 day TTS. If a medicine is to be
manufactured for a 7-day administration of a compound of the
general Formula I, then comparatively higher active ingredient
concentrations above, for example, 15-40 percent by weight are
used.
[0260] A loading of active ingredient (mg/cm.sup.2 matrix base) of
0.1-12, preferably 0.25-7.5, especially preferably from 0.3 to 4
and notably especially preferably of 0.6 to 2.5 results. In the
case of devices for a 7-day application the loading lies preferably
at a minimum of 2 mg/m.sup.2.
[0261] Another object of the invention is a method as a prevention
and/or treatment of is incontinence, hyperactivity of the detrusor,
hyperactivity of the bladder, pollakisuria, nocturia or imperative
urinary urgency through the administration of a compound of the
general Formula I as a free base, and with the degree of purity in
compliance with the invention as described in the above, on a
mammal, in particular on a person, who requires the prevention
against or the treatment of the above named diseases.
[0262] The following examples serve for further illustration of the
invention.
EXAMPLE EXECUTIONS
[0263] 1. Manufacture of the High Purity Free Base of
Fesoterodine
[0264] A. Manufacture of the Fesoterodine Base (B. Wee FIG. 1.
R=i-Pr)
[0265] Drops of a solution of 18.6 g isobutyric acid chloride in
250 ml dichloromethane were added in approximately 10 minutes to a
solution of 59.8 g (175.1 mol)
(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol
cooled to -3.degree. C. (A, see FIG. 1) dissolved in 750 ml
dichloromethane with agitation and cooling by ice bath. A white
substance precipitated after approximately 5 minutes. For this
purpose drops of a solution of 17.7 g triethylamine in 250 ml
dichloromethane were added in 5 minutes under agitation and ice
bath cooling. The batch was washed once with each of 250 ml water,
250 ml. approximate 5% aqueous NaHCO.sub.3 solution and 250 ml
water. The dichloromethane extract dried over Na.sub.2SO.sub.4 was
evaporated to a low small bulk on a rotary evaporator to constant
weight, whereby a pale yellow, high viscosity oil was left.
[0266] Raw yield: 63.7 g (88.5% of the theory).
[0267] The purity of B in the HPLC in this example amounted to
94.1%. Typical range for B: 90.5% -94.4%.4%. Decomposition occurred
in the case of the high vacuum distillation trial with the
formation of A and C.
[0268] B. Manufacture of the Fumarate Salt (E: FIG. 1: R=i-Pr.
X.sup.-=Hydrogen Fumarate) of Fesoterodine
[0269] A solution of 41.87 g (102 mmol)
(R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl
isobutyric acid ester (B) in 90 ml 2-butanon was laced with fumaric
acid (11.81 g, 102 mmol) with heating. Cyclohexane (20-30 ml) was
slowly added with agitation until the onset of clouding after
dissolving of the acid. The colorless, homogenous batch was
initially left for 18 hours at room temperature and then for
several more hours at 0.degree. C. The precipitated, colorless
crystals were suctioned off, washed with a little
cyclohexane/2-butanon (90:10, percent by volume) and vacuum dried
at 30.degree. C.
[0270] Yield: 44.6 g (83.1% of the theory) of the hydrogen fumarate
salt (E) of the
(R)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl
isobutyric acid ester in the form of colorless small plates
[0271] Melting point: 98.8.degree. C., a second crystallization
from the same mixture of solvents yielded the product with a
melting point of 103.degree. C.
[0272] [.alpha.].sub.D.sup.20=+6.0 (c=1.0, ethanol); -19.3 (c=1.0,
acetonitrile).
[0273] .sup.1H-NMR (CDCl3): among other things 6.84 ppm for CH.dbd.
from hydrogen fumarate anion.
[0274] .sup.13C-NMR (CDCl.sub.3): among other things 135.58 ppm and
170.56 ppm for olefin- and carbonyl carbon from the hydrogen
fumarate-anion.
[0275] The purity in this example at E (determined with HPLC)
amounted to 99.2%.
[0276] C. Manufacture of the High Purity Fesoterodine Base (B: FIG.
1, R=i-Pr)
[0277] 250 g (0.474 mol) crystalline
(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hyhdroxymethyl)-phenyl-2-m-
ethylpropanoate-fumaric acid salt (E) was added to 1 liter water
with agitation and heated to 30.degree. C. An almost clear solution
was present after approximately 30 minutes. 96.0 g sodium hydrogen
carbonate was added with agitation in portions in approximately 10
minutes to the solution cooled to room temperature. 1 liter of
dichloromethane was added to the almost clear, colorless solution
of fesoterodine hydrogen carbonate. After some stirring time at
room temperature (strong development of CO.sub.2) the
dichloromethane phase was cut off and each washed once with 0.2
liters of 5% aqueous sodium hydrogen carbonate solution and then
with 0.2 liters of water. The filtered, clear, colorless
dichloromethane phase was evaporated to a low small bulk on a
rotary evaporator at a bath temperature of approximately 40.degree.
C. to a constant weight, whereby in a final step a diaphragm pump
vacuum (ultimate vacuum 5 mbar) was applied. In the course of this
(R)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl
isobutryic acid chloride (B) remained as an almost colorless,
viscous oil.
[0278] Yield: 180.6 g (92.6%)
[0279] [.alpha.].sub.D.sup.20=+5. (c=1., ethanol); -6. (c=1.,
acetonitrile)
[0280] NMR (CDCl.sub.3): 19.01, 19.95, 20.59, 21.12, 34.28, 36.89,
41.88, 42.32, 43.90, 48.78, 64.68, 122.57, 125.59, 126.16, 126.86,
127.96, 128.54, 136.88, 138.82, 143.92, 147.90, 175.69 (ppm).
[0281] In this example the purity in the HPLC amounted to 99.0%.
Typical purities lie between 98.7% and 99.5%.
[0282] .sup.1H-- and .sup.13C-NMR: No resonance peaks detectable
for the hydrogen fumarate anion (compare with E). The long-term
storage is preferably done in the dark under argon at -20.degree.
C.
[0283] D. Manufacture of the Hydrogen Carbonate Salt (E. FIG. 1: 1;
R=i-Pr, X.sup.-=Hydrogen Carbonate)
[0284] Fesoterodine (107.7 mg
(R)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyl
isobutyric acid ester, B) is covered with a layer distilled water
and stirred at room temperature. After two days of stirring, the
reaction batch remains unchanged two-phase. No organic material (B
or E) could be detected by thin layer chromatography in the aqueous
phase at the top (silica gel, solvent system petroleum
ether/acetone/triethylamine, 70/20/10 percent by volume).
[0285] A slight flow of carbon dioxide gas is fed into the second
phase reaction batch at room temperature with agitation. After two
days the lower oil phase (fesoterodine) has dissolved totally and
clearly in the aqueous phase.
[0286] .sup.13C-NMR-spectrum of the hydrogen carbonate salt of
fesoterodine (.delta.-values):
[0287] 14.11, 15.36, 15.51, 29.32, 31.09, 38.95, 43.31, 52.38,
60.45, 120.04, 124.07, 124.33, 124.83, 126.12, 131.97, 136.55,
139.06, 144.60, 157.46 (HCO.sub.3.sup.-), 175.75.
[0288] A good conformity with the .sup.13C-NMR-specturm of the
hydrochloride of fesoterodine, manufactured through the dissolution
of the base in 1M aqueous hydrochloric acid(.delta.-value): 13.26,
15.32, 15.48, 29.29, 31.06, 38.95, 43.34, 52.42, 60.49, 120.10,
124.18, 124.38, 124.85, 126.13, 131.97, 136.50, 139.02, 144.61,
175.94.
[0289] 2. Manufacture of the TTS Matrices
[0290] 2.1. Manufacture of a Silicone Based Matrix in a Hot Melt
Procedure
[0291] 8.5 g of a silicone-based contact adhesive mixture from the
silicone adhesive Bio-PSA 7-4300 (Dow Corning, Mich.) was heated to
150.degree. C. with 5 percent by weight ozokerite or ceresine
(obtainable from Dow Corning) for around 20 minutes until a
homogenous melt came into being. 1.5 g fesoterodine (high purity
free base) was added and the mixture kept for a further 5 minutes
at 150.degree. C. The mixture was then homogenized by hand and
laminated onto a pre-warmed foil (120.degree. C., gap width 250
.mu.m). 5 cm.sup.2 pieces were cut out for the releasing tests.
[0292] 2.2. Manufacture of an Acrylate Based Matrix in the Solvent
Procedure
[0293] 1.5 g high purity fesoterodine base was dissolved in
dichloromethane and added to a solution of 8.5 g DuroTakR 387-2287
(in ethyl acetate). The resulting mixture was stirred until a
homogeneous dispersion was achieved. The dispersion was then spread
out on foil and dried (Erichsen 100 .mu.m, 6 mm/sec, drying time:
30 minutes at 50.degree. C.).
[0294] 2.3. Manufacture of an SXS Based Matrix in a Hot Melt
Procedure
[0295] 100 parts SIS (Kraton D1107CU), 150 parts Regalite R 1090,
20 parts Ondina oil and 1 part Irganox were mixed and melted at
140.degree. C. 1.5 g fesoterodine (high purity free base) was added
to 8.5 g of each melt and the mixture kept at 140.degree. C. for a
further 1-5 minutes. The mixture was then mechanically homogenized
and laminated on a pre-warmed sheet (120.degree. C., 250 .mu.m).
Pieces of the size desired were cut out.
[0296] 2.4. Manufacture of an EVA Based Matrix in a Hot Melt
Procedure
[0297] 8.5 g of the EVA hot melt adhesive was heated for around 20
minutes at 160.degree. C. until a homogenous melt was obtained. 1.5
g or more precisely 1.65 g high purity fesoterodine base was added
as well and the mixture then homogenized manually. The mixture was
then laminated on a chill roll brought to a specified temperature
(120.degree. C.). In each case 5 cm.sup.2 was cut out (for
permeation experiments).
[0298] 3. Releasing Experiments
[0299] 3.1. Determination of the Flow of Active Ingredient in the
Mouse Skin Model
[0300] Belly and back skin in a thickness of approximately 120 to
150 .mu.m was used for the flux measurements through mouse skin in
a horizontal diffusion cell. Medium: phosphate buffer solution
(0.066 molar) pH 6.2, 32.degree. C.
[0301] Release of the active ingredient was determined by HPLC.
[0302] 3.2. Determination of the Flow of Active Ingredient in the
Human Skin Model
[0303] (a) Experimental Design
[0304] The determination of the fesoterodine flux through human
skin was essentially performed as described in H. Tanojo et al, J.
Control Rel. 45 (1997) 41-47, where instead of the silicone
membrane, a dialysis membrane was used [Diachema Dialysemembran,
type 10. 14, obtained from the company Dianorm, Munich, Germany,
manufactured from neutral cellulose, exclusion size 5000 Da,
thickness (dry): 25 .mu.m; pretreatment in accordance with
manufacturer information].
[0305] Human skin in a thickness of approximately 250 .mu.m was
obtained from the abdomen. A TTS with a surface of 2.545 cm.sup.2
was applied on a surface similar to human skin, where the skin lay
on a silicone membrane acceptor side up (Diagram 1). PBS (0.066
molar) was used as the acceptor phase at pH 6.2 and a temperature
of 32.+-.0.5.degree. C. The experiments were performed over 72
hours with a 5 mL/hour flux, whereby samples were taken every 3
hours. At the times when the samples are taken, the releasing
medium is replaced with fresh medium thermo stated at
32.+-.0.5.degree. C. and the amount of the released fesoterodine
measured per HPLC.
[0306] The determination of the flux rate Q(t) was done based on
the area of the measuring cell (0.552 cm.sup.2) in compliance with
the formula: Q(t)=.mu.g/cm.sup.2=fesoterodine concentration volume
of the acceptor/0.552 cm.sup.2
[0307] Diagram 1: ##STR15##
[0308] (b) Analytical Chemistry of the Release of the Active
Ingredient
[0309] The measurement of the active ingredient flux through the
skin preparation is made per HPLC (tower spherisorb 5CN 25 cm)
under the following conditions: 4 parts by volume acetonitrile/6
parts by volume H.sub.2O/0.1% parts by volume TFA, 35.degree. C.,
225 nm, 1 ml flux
[0310] 4. Analytical Chemistry: Determining the Purity of the
Active Ingredient
[0311] A HPLC method was used to determine the chemical purity of
fesoterodine that is based on the separation at a stationary
reversed phase and used for the gradient elution of a solvent.
[0312] Materials (Exemplary Model):
[0313] Acetonitrile for the HPLC, methane sulfonic acid (<99%,
Fluka), water (purified, HPCL quality), Waters Pump 510, column
heater (Waters Column Heater Module, 35.degree. C.), a sampling
device (Waters Wisp 717, injection volume 20 .mu.L), UV-detector
(Shimatzu SPD 10A). Column (150.times.3.9 mm, Symmetry Shield RP8,
Waters Part No. WAT 200655).
[0314] Mobile Phase:
[0315] Acetonitrile with 0.05% methane sulfonic acid (v/v, %),
component A Water with 0.05% methane sulfonic acid (v/v, %),
component B Gradient program: Time (minutes) 0.0 with 15% Component
A and 85% Component B, after 15 minutes 60% A and 40% B, after 20
minutes 15% A and 85% B. Flux rate: 1.2 ml/minute
[0316] The concentrations of the reference solutions of A, B and C
(FIG. 1/4, R=i-Pr) amounted to 10-250 .mu.g/mL. Tailing with peak
overlap occurred at the higher concentrations.
[0317] Analysis:
[0318] The average values of all peak surfaces (triple
determinations) were added and compared with 100% for analysis
according to the 100% method. The areas of the individual peaks
were based on this value (as a %). Retention times for A, B and C
(minutes): 5.9, 9.0 and 12.6.
[0319] 5. Analytical Chemistry: Determining the Residual Salt
Content
[0320] 200 MHz or 500 MHz .sup.1H-NMR-spectrums of the free base
fesoterodine is absorbed in CDCl.sub.3 as the solvent and
characteristic resonance signal groups are integrated
electronically, such as:
[0321] .delta.=6.97 ppm (Duplett, aromatic hydrogen, H.sup.6,
1H),
[0322] .delta.=4.59 ppm (Singulent, HO--CH.sub.2, 2H),
[0323] .delta.=4.1 0 ppm (Tripleft, H.sup.1-Propyl, 1H).
[0324] The relation to the resonance signal of the anion, for
example, Hydrogen fumarate (.delta.=6.84 ppm, .dbd.CH--, 2H)
results in the proportion of residual salt (as a molecular %).
* * * * *