U.S. patent application number 13/143740 was filed with the patent office on 2011-11-03 for method for developing a liquid composition to be applied to the skin as a foam and a composition that can be applied topically.
Invention is credited to Bernd G. Seigfried.
Application Number | 20110269704 13/143740 |
Document ID | / |
Family ID | 43384132 |
Filed Date | 2011-11-03 |
United States Patent
Application |
20110269704 |
Kind Code |
A1 |
Seigfried; Bernd G. |
November 3, 2011 |
METHOD FOR DEVELOPING A LIQUID COMPOSITION TO BE APPLIED TO THE
SKIN AS A FOAM AND A COMPOSITION THAT CAN BE APPLIED TOPICALLY
Abstract
A liquid pharmaceutical composition to be applied to the skin as
a foam and that has at least one solvent, at least one active
pharmaceutical ingredient, and at least one foaming agent. The foam
volume and the foam stability are determined according to a
standardized SITA measuring method. The foaming agent, the solvent,
and the active pharmaceutical ingredient are varied in regard to
the chemical type and/or concentration thereof until the foam thus
produced by the SITA measuring method has a foam volume of at least
400 ml and such foam stability that after a dwell time of up to ten
minutes the foam still has at least 50% of the foam volume that
originally existed immediately after the foam was produced.
Inventors: |
Seigfried; Bernd G.;
(Limburgerhof, DE) |
Family ID: |
43384132 |
Appl. No.: |
13/143740 |
Filed: |
July 16, 2010 |
PCT Filed: |
July 16, 2010 |
PCT NO: |
PCT/DE2010/000818 |
371 Date: |
July 8, 2011 |
Current U.S.
Class: |
514/29 ; 514/179;
514/396; 514/567; 514/570; 514/626 |
Current CPC
Class: |
A61P 1/08 20180101; A61P
9/00 20180101; A61P 3/02 20180101; A61P 37/04 20180101; A61K 9/0014
20130101; A61P 25/04 20180101; A61P 17/12 20180101; A61P 25/08
20180101; A61P 37/08 20180101; A61K 31/167 20130101; A61K 31/192
20130101; A61P 33/00 20180101; A61P 17/14 20180101; A61P 21/02
20180101; A61P 31/10 20180101; A61P 43/00 20180101; A61P 1/16
20180101; A61P 17/00 20180101; A61P 31/22 20180101; A61P 17/04
20180101; A61P 11/06 20180101; A61P 23/00 20180101; A61P 31/12
20180101; A61P 11/14 20180101; A61P 17/06 20180101; A61K 31/7048
20130101; A61P 3/10 20180101; A61P 31/16 20180101; A61P 25/00
20180101; A61P 31/00 20180101; A61P 31/04 20180101; A61K 9/122
20130101; A61P 17/02 20180101; A61P 25/16 20180101; A61P 23/02
20180101; A61P 29/00 20180101; A61P 37/06 20180101; A61P 7/02
20180101; A61P 31/02 20180101; A61P 11/10 20180101; A61K 31/573
20130101; A61K 31/196 20130101; A61K 31/4174 20130101; A61P 7/10
20180101 |
Class at
Publication: |
514/29 ; 514/570;
514/626; 514/179; 514/396; 514/567 |
International
Class: |
A61K 31/7048 20060101
A61K031/7048; A61K 31/167 20060101 A61K031/167; A61K 31/573
20060101 A61K031/573; A61P 23/02 20060101 A61P023/02; A61K 31/196
20060101 A61K031/196; A61P 29/00 20060101 A61P029/00; A61P 31/00
20060101 A61P031/00; A61P 31/04 20060101 A61P031/04; A61K 31/192
20060101 A61K031/192; A61K 31/4174 20060101 A61K031/4174 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 24, 2009 |
DE |
10 2009 034 603.1 |
Claims
1-52. (canceled)
53. A composition suitable for topical use comprising at least one
systemically and/or topically acting pharmaceutical active
ingredient, wherein the composition in addition to the
pharmaceutical active ingredient also contains at least one solvent
as well as at least one foaming agent and has such a fluid
consistency that it forms a foam when applied, wherein: a) the at
least one foaming agent contained in the liquid composition is a
phospholipidic foaming agent; b) the at least one phospholipid
foaming agent, the at least one solvent and the at least one active
ingredient are attuned to each other in their chemical nature
and/or their concentration so that the composition can be
mechanically foamed without the use of an additional propellant; c)
by mechanically foaming of 250 ml of the liquid composition a foam
is created having a foam volume of at least 400 ml and a foam
stability after a dwell time of up to ten minutes of at least 50%
of the foam volume that was originally present immediately after
the creation of the foam; and d) both the foam volume and the foam
stability are determined by a standardized SITA foam measurement
method.
54. The composition according to claim 1, wherein the foam volume
is between 450 and 1400 ml and the foam stability is between 55%
and 100%.
55. The composition according to claim 53, wherein the foam has a
density between 0.05 g/ml and 0.8 g/ml.
56. The composition according to claim 53, wherein the composition
contains as solvent such a solvent selected from the group
consisting of water, alcohol, especially monovalent to trivalent
alcohol, polyalcohol, and mixtures thereof.
57. The composition according to claim 53, wherein the at least one
active ingredient is an active ingredient for use on humans or
animals and is selected from the group consisting of local
anesthetics, anti-allergic agents, dermatics, active ingredients
against flu infections and colds, active ingredients for the
treatment of neuropathies, active ingredients for the treatment of
disturbed circulation, chemotherapy drugs, quinine, antimycotics,
antibiotics, thalidomide, serotonin, eicosanoids, analgesics,
anticonvulsants, nonsteroidal antirrheumatics, leukotrienes,
leukotriene inhibitors, androgens, antiandrogens, corticoids,
opiate receptor antagonists, blood clotting inhibitory substances,
thrombocyte aggregation inhibitors, histamine antagonists,
regulatory and enzymatically acting peptides and proteins, nucleic
acids (single and double-stranded DNA, single and double-stranded
RNA, snRNA, DNA oligonucleotides, RNA oligonucleotides) and
oligopeptides, antipruritics, antidiabetics, prostaglandins,
prostaglandin synthesis inhibitors, antiviral-acting or
virostatic-acting substances, antimicrobial-acting substances,
active ingredients against prions, immune suppressants, hormones,
active ingredients for treatment of warts or wounds, especially
chronic wounds, vitamins, plant extracts or essences of plant
extracts, psychoactive drugs, active ingredients influencing sleep,
analeptics, general anesthetics, muscle relaxants, antiepileptics,
antiparkinson agents, antiemetics, antiparasitics, ganglion-active
ingredients, sympathetic-active ingredients, parasympathetic-active
ingredients, antibacterial-acting drugs, calcium antagonists,
cardiovascular agents, antiasthmatics, antitussives, expectorants,
hepatics, diuretics, choleretics, disinfectants, trace elements,
antiinfectives, cytostatics, antimetabolites, hormone antagonists,
immune modulators, as well as derivates and salts of the
aforementioned active ingredients.
58. The composition according to claim 53, wherein the at least one
pharmaceutical active ingredient is an analgesic active
ingredient.
59. The composition according to claim 58, wherein the analgesic
active ingredient is selected from the group consisting of
diclofenac, ketoprofen and ibuprofen.
60. The composition according to claim 58, wherein the at least one
analgesic is contained in the composition in a concentration
between 0.1 wt. % and 20 wt. %.
61. The composition according to claim 53, wherein the composition
contains, as the phospholipidic foaming agent, a phosphatidyl
choline isolated from soy beans, and the concentration of the
phosphatidyl choline in the phospholipidic foaming agent is more
than 50 wt. %, in relation to the dry substance of the
phospholipidic foaming agent.
62. The composition according to claim 61, wherein at most 15 wt. %
of lyso-phosphatidyl choline, at most 10 wt. % of phosphatidic acid
and at most 10 wt. % of phosphatidyl ethanolamine are contained in
the phospholipidic foaming agent.
63. The composition of claim 61, wherein the phosphatidyl choline
contained in the phospholipidic foaming agent has an acid number of
at most 10, a peroxide number of at most 10, and an oil
concentration of at most 6 wt. %.
64. The composition of claim 53, wherein the composition has the
phospholipidic foaming agent in a concentration between 2 wt. % and
25 wt. %.
65. A method for treatment of pain, inflammation, rheumatic
diseases or acute trauma, comprising the application of a foam to
the skin of a warm-blooded mammal created by mechanically foaming
of a composition according to claim 53 immediately prior to
application, whereby the composition contains as active ingredient
at least one analgesic.
66. The method of claim 65, wherein the composition contains the
analgesic in a concentration between 0.1 wt. % and 20 wt. %.
67. A method for the development of a pharmaceutical composition to
be applied as a foam to the skin according to claim 53, wherein the
foamable liquid composition contains at least one solvent, at least
one pharmaceutical active ingredient, and at least one
phospholipidic foaming agent, wherein: a) the foam volume and the
foam stability are determined by a standardized SITA measurement
method without the use of a propellant; and b) the at least one
phospholipidic foaming agent, the at least one solvent and the at
least one pharmaceutical active ingredient, contained in the liquid
composition, are varied in regard to their chemical nature and/or
concentration until the foam created by the SITA measurement
method, using 250 ml of the liquid composition, has a foam volume
of at least 400 ml and a foam stability that the foam still has,
after a dwell time of up to ten minutes at least 50% of the foam
volume that was originally present immediately after the creation
of the foam.
68. The method according to claim 67, wherein a correlation is
produced between the foam as specified by the SITA measurement
method and the pharmaceutical properties.
69. The method according to claim 67, wherein a foam applicator is
selected for the mechanical foaming of the liquid composition, a
foam is created from the liquid composition by the selected foam
applicator, and a correlation is produced between the properties,
especially the pharmaceutical properties of the foam created via
the foam applicator and the foam volume and/or the foam stability
as determined via the SITA measurement method.
70. The method according to claim 67, wherein such a foam is
created from the liquid composition by the SITA foam measurement
method that possess a foam density between 0.05 g/ml and 0.8
g/ml.
71. The method according to claim 67, wherein the phospholipidic
foaming agent is a phosphatidyl choline isolated from soy beans and
that the concentration of the phosphatidyl choline in the
phospholipidic foaming agent is more than 50 wt. %, in relation to
the dry substance of the phospholipidic foaming agent.
Description
[0001] The present invention is directed in part to a method for
making or developing liquid pharmaceutical compositions to be
applied as a foam to the skin with the features of the preamble of
the patent claim 1 as well as a corresponding topically applicable
compositions with the features of the preamble of the patent claim
9.
[0002] Topically applied pharmaceutical compositions that exist in
the liquid state and are present as a foam when applied are
familiar. For example, EP 0 510 561 B1 describes one such
pharmaceutical composition applied as foam, wherein the basic
liquid used in the known pharmaceutical composition is foamed
exclusively by mechanical action. The basic liquid composition that
is mechanically foamed contains, as ingredients, a surfactant as
the foaming agent, a solvent or mixture of solvents, as well as a
pharmaceutical active ingredient, wherein this known liquid
composition should be foamable simply by mechanical action, without
the use of a propellant. In example 5 of EP 0 510 561 B1, one such
known composition is described, containing an aqueous
alkylamidobetaine solution as the surfactant. In addition, the
composition described in this example is provided with lecithin,
which serves solely to form liposomes.
[0003] In order to be able to measure the foaming behavior of
liquid compositions, various measurement techniques are known and
also standardized, such as by DIN Standard 53902. The particular
liquid composition being investigated is subjected to a more or
less reproducible mechanical action for a given time in order to
create a foam, whose volume and stability are measured.
[0004] According to DE 197 40 095 A, however, known measurement
techniques do not adequately distinguish between the foam volumes
and foam stabilities of compositions which are similar in terms of
their ingredients.
[0005] Therefore DE 197 40 095 A proposes foaming the liquid
composition being measured by using a stirrer with a given profile,
which is driven at a given speed of rotation. The foam created in
this way is visually measured.
[0006] A further embodiment of this foam measuring technique is
described in EP 1 092 970 B1, wherein the development differs from
the measurement technique previously described in reference to DE
197 40 095 A by providing an automatic determination of the height
of the foam via measuring electrodes. This measurement method,
which is called the "SITA measurement method" in the present text,
allows one to determine the foam volume on the one hand, and on the
other hand the foam stability of liquids, especially dyeing and
cleaning solutions, electroplating agents, emulsions, rinsing
agents, body care products or even beer, so as to obtain a quality
rating of the aforementioned foamable liquids.
[0007] When one needs to develop liquids that are foamable and
therefore are applied as a foam in the field of pharmacy, it is
usually proposed to proceed by selecting a pharmaceutically active
liquid and one then attempts to foam it by varying the mechanical
foaming technique, in particular, by varying the air pressure, the
geometry and configuration of the foam head and the valve of a
particular foam applicator. However, such a development process for
foamable, originally liquid, pharmaceutical compositions is very
time intensive and may suffer from a drawback such that a foam
differing in composition and essentially inhomogeneous can result
from varying the configuration of the aforementioned parameters of
the mechanical foam applicator.
[0008] Thus, one underlying problem of the present invention is to
provide a method for the development of a liquid pharmaceutical
composition to be applied as foam to the skin, by which the
development time for such pharmaceutical compositions is
substantially simplified and shortened.
[0009] Further, another underlying problem of the present invention
is to provide a topically applicable composition that can be
applied as foam and that contains a systemically or topically
acting pharmaceutical active ingredient, whereby this topically
applicable composition is developed preferably by the
aforementioned development process.
[0010] The first stated problem is solved by a method according to
the characteristics of the patent claim 1 and the further problem,
which is mentioned subsequently, is solved by a topically
applicable composition with the features of the preamble of the
patent claim 9.
[0011] In the inventive method of development of a liquid
pharmaceutical composition to be applied as a foam to the skin,
having as minimum components a solvent, a pharmaceutical active
ingredient, and a foaming agent, the method includes foam volume
and the foam stability to be determined by a standardized SITA
measurement method, wherein no propellant is used in this
measurement method. In the provided liquid pharmaceutical
composition, the at least one foaming agent, the at least one
solvent and the at least one pharmaceutical active ingredient are
varied in regard to their chemical nature and/or concentration
until the foam created by the SITA measurement method under
standardized conditions has a foam volume of at least 400 ml,
especially a foam volume between 450 and 1400 ml, and preferably a
foam volume between 600 and 1200 ml. Furthermore, the foam
according to a method of the invention must have such a foam
stability that it still has, after a dwell time of up to ten
minutes and especially after a dwell time of up to five minutes, at
least 50% of the foam volume and especially between 55% and 100% of
the foam volume and preferably between 85% and 99% of the foam
volume that was originally present immediately after the creation
of the foam. In other words, therefore, the development method
according to the invention calls for varying the minimum
ingredients (solvent, pharmaceutical active ingredient, and foaming
agent) contained in the liquid pharmaceutical composition that is
supposed to form the foam when applied in terms of their chemical
nature and/or their concentration until they give rise to a foam by
the SITA measurement method under standardized conditions whose
foam volume possesses the previously quantified volumes and whose
foam stability possesses the previously quantified stabilities.
[0012] The above-described method of the invention has a number of
advantages. Thus, it has been established, surprisingly, that the
method of the invention enables an especially easy and rapid
development of such liquid pharmaceutical compositions as can be
reproducibly foamed with a number of foam applicators, so that
unlike the prior art described at the outset one can develop
pharmaceutical foams that are especially reproducible in terms of
their foam consistency and their foam composition. For example, if
the goal of such a development is to provide a liquid composition
whose foam should have a relatively short stability after being
foamed by means of a suitable mechanical foam applicator, so that
it quickly breaks down after being applied to the skin, in the
method of the invention one will vary the chemical nature and/or
the concentration of the ingredients until a foam results in the
SITA measurement method whose foam stability is distinguished in
that, within two to four minutes, the foam volume still takes on a
value between 50% and 70% of the original foam volume. In contrast,
when the objective is to create an especially stable foam, the
chemical nature and/or the concentration of the minimum ingredients
of the liquid composition which afterwards forms the foam will be
varied so that a foam results whose foam stability is so high that
after eight to ten minutes there is still present between 85% and
99% of the foam volume that was originally present immediately
after the foaming process. If, on the other hand, a liquid,
foamable composition which has an especially large foam volume is
desired, then the nature and/or the concentration of the minimum
ingredients of the liquid composition will be varied so that an
especially high foam volume results in the SITA measurement method,
i.e., a foam volume that varies between 600 ml and 1200 ml or even
up to 1400 ml. Thus it should be noted that the method of the
invention proposes a standardized method in which, by variation of
the chemical nature of the ingredients and/or their concentration,
one can develop a foam quantified in the above sense with regard to
the foam volume and the foam stability, and which can accordingly
be applied to the skin of humans and animals.
[0013] The term "and/or" used in the present specification means
that all or some elements of the particular listing are to be
construed additively or that some or all elements of the respective
listing are to be construed alternatively, whereas the standardized
SITA measurement method which is used in the present invention is
described in detail at the beginning of the examples. Moreover, it
should be stated that all terms used in the singular case in the
present specification of invention also include the plural of these
terms.
[0014] A first embodiment of the inventive method for development
of a liquid pharmaceutical composition to be applied as a foam to
the skin proposes that include producing a correlation between the
foam as specified by the SITA measurement method and the desired
pharmaceutical properties. By desired pharmaceutical properties is
meant in particular the transport of active ingredient through the
layers of the foam into and/or through the skin, i.e., the
permeation and/or penetration of the skin and/or the fine
distribution of the active ingredient and/or the resulting
pharmaceutical effect. For example, if a goal of the development in
the method of the invention is, that the active ingredient should
quickly get onto the skin surface in relatively high concentration,
one will vary the nature and/or concentration of the ingredients in
the liquid composition being foamed by the SITA measurement method
so that the resulting foam has a relatively small foam volume,
especially a foam volume between 450 ml and 600 ml, and a
relatively low foam stability, especially a foam stability after
five minutes between 55% and 70% of the foam volume that was
originally present immediately after creating the foam.
[0015] In a modification of the above specified embodiment of the
invented method, another embodiment calls for selecting a foam
applicator for the mechanical foaming of the liquid composition, a
foam is created from the liquid composition by the selected foam
applicator, and a correlation is produced between the properties,
especially the pharmaceutical properties of the foam created via
the foam applicator and the foam volume and/or the foam stability
as determined via the SITA measurement method. This embodiment of
the invented method allows one to develop foams with defined foam
volumes and foam stabilities, as measured by the SITA measurement
method, especially easily and quickly by varying the nature and/or
the concentration of the ingredients of the liquid pharmaceutical
composition, which then correlate with the foams that are later
applied as foam to the skin by the selected foam applicator.
[0016] Especially when the development method of the invention is
used to create a foam from the liquid composition that possesses a
foam density between 0.05 g/ml and 0.8 g/ml, preferably between
0.15 g/ml and 0.4 g/ml by the SITA measurement method, it has been
found that such liquid compositions provide excellent foams that
can be applied with a number of differently designed,
mechanical-type foam applicators.
[0017] Already above it is referred several times that the chemical
nature and/or the concentration of ingredients (solvent, foaming
agent, active ingredient) are varied in the method of the invention
so as to ensure the foam volume and the foam stability as indicated
above in the development method of the invention.
[0018] In particular, the solvent for the production of the liquid
composition in the method of the invention may be chosen from the
group consisting of: water, at least one alcohol, especially at
least one monovalent to trivalent alcohol, at least one polyalcohol
and mixtures of the aforementioned solvents. Of course, in choosing
the solvent one will make sure that these solvents are
skin-tolerated and especially do not result in any skin irritation,
so that they are appropriately pharmaceutically applicable.
Preferred solvents are 2-propanol, propylene glycol, glycerin as
well as polyols, while the term water comprises all aqueous
systems, especially also aqueous pharmaceutical buffer systems.
[0019] In an especially suitable embodiment of the method of the
invention, the pharmaceutical active ingredient itself is used as
the foaming agent, so that this embodiment of the invented method
is based on the fact that it contains, besides the solvent, only
the pharmaceutical active ingredient whose concentration and whose
chemical nature are varied so that the foam volumes and foam
stabilities indicated in the method of the invention and measured
according to the SITA method are guaranteed.
[0020] Alternatively or in addition to this, a modification of the
method of the invention proposes that the foaming agent for the
production of the liquid composition is chosen from the group
comprising surfactants, especially anionic, cationic, nonionic and
ampholytic surfactants, silicones, fats, fatty acids, fatty acid
derivates, phospholipids, sugar derivates, lipids, especially
sphingolipids and glycolipids, and mixtures and derivates of the
aforementioned substances.
[0021] In principle foaming agents, whether the active ingredient
itself or the above listed foaming agents, may be capable of
provide the aforementioned foam volumes and foam stabilities as
soon as the liquid composition is foamed in purely mechanical
fashion, without the use of a propellant. Preferred surfactants
include the fatty alkyl ether sulfates, the alkyl phosphates, the
alkyl ether phosphates, the alkyl benzene sulfonates, the petroleum
sulfonates, the olefin sulfonates and/or the esters of
sulfosuccinic acid. Among the silicones, one should mention
especially modified siloxanes, polydialkyl siloxanes and preferably
linear or cyclical polydimethyl siloxanes. Fats and modified fats,
such as fatty acids, fatty acid derivates, fatty acid esters, as
well as synthetic, plant and animal phospholipids, especially
phosphatidyl choline and/or hydrogenated phospholipids and
preferably hydrogenated phosphatidyl choline, are among the
preferred foaming agents, in addition to the sphingolipids,
glycolipids and sugar derivates, preferably sugar or sorbitol
esters.
[0022] Among the fat derivatives, especially the sulfates of fatty
acids, sulfonates of fatty acids, salts of sulfates of fatty acids,
salts of sulfonates of fatty acids, soaps and mixtures and
derivates of the aforementioned substances are especially suitable
as foaming agents for use in the method of the invention. This
holds likewise for alkoxylated fatty acids and alkoxylated fatty
acid derivates, alkoxylated fatty alcohols, alkoxylated phenols as
well as mixtures and derivates of the aforementioned
substances.
[0023] Furthermore, preferred surfactant foaming agents are chosen
from the group consisting of: alkylcarboxylates, alkylsulfates,
alkylsulfonates, alkylethercarboxylates, sulfates of fatty acids,
phosphates of fatty acids, sulfonates of fatty acids, salts of
sulfates of fatty acids, salts of sulfonates of fatty acids, fatty
acid amides, polyalkylenes, fluorosurfactants, soap, metal soaps,
especially alkaline soaps, such as sodium, potassium and ammonium
salts of aliphatic carboxylic acids, organic amino-soaps,
especially organic amine soaps of aliphatic carboxylic acids,
quaternary ammonium compounds, especially benzalkonium chloride,
octadecylammonium chloride, sulfonium salts, amidoamines, fatty
acid esters, preferably monoglycerin, diglycerin and triglycerin
esters, fatty acid ethers, alkoxylated, especially ethoxylated
fatty acids, alkoxylated, especially ethoxylated fatty acid
derivates, alkoxylated, especially ethoxylated fatty alcohols,
alkoxylated, especially ethoxylated phenols, alkoxylated,
especially ethoxylated fatty acid amides, mono- and
dialkylalkanolamides or alkylpolyglucosides, especially
coco-mono-ethanolamides, coco-di-ethanolamides,
coco-mono-isopropanolamides, coco-diglucosides, betaine, betaine
derivates, preferably N-alkylbetaine, alkyl-amidopropylbetaine,
sulfobetaine, alkylsulfobetaine, alkylglycinate and
alkylcarboxyglycinates, wherein the alkyl residue each time
comprises in particular a carbon skeleton with 8 to 18 carbon
atoms, acylamino acid, alkylimidazoline, N-substituted alkylamines,
acyllactate, N-acylsarkosinate, alkanolamide, aminoxide,
polyhydroxyalcohol esters, as well as mixtures and derivates of the
aforementioned substances.
[0024] As cationic surfactants that are likewise especially
suitable as the foaming agent in the method of the invention for
the production of the liquid composition, one will select
substances which contain quaternary ammonium compounds, sulfonium
salts, amidoamides and their mixtures as well as their
derivates.
[0025] Preferred ampholytic surfactants for the production of the
liquid composition will be chosen from the group comprising betaine
and betaine derivates.
[0026] As for the active ingredients used in the method of the
invention, these will preferably be active ingredients such as are
described in further detail in connection with the topically
applicable composition according to the invention.
[0027] Besides the repeatedly aforementioned solvent, the
pharmaceutical active ingredient and the foaming agent, in further
embodiments of the invented method for production of the liquid
composition that is foamed in purely mechanical fashion for its
application, there is proposed in particular a complexing agent, a
buffer, a thickening agent, an antioxidant and/or a stabilizer.
However, one must make pay heed that these aforementioned
ingredients can also have an influence on the foam volume and the
foam stability, but this can be determined quite easily and without
problem and within the shortest time in a reproducible manner by
the method of the invention.
[0028] As already mentioned above, the present invention
furthermore concerns a topically applicable composition with the
features of the preamble of patent claim 9.
[0029] The topically applicable composition of the invention, which
is developed preferably but not exclusively according to the above
described method of the invention, has, a pharmaceutical active
ingredient, a solvent as well as a foaming agent. In contrast to
the known liquid composition of EP 0 510 561 for example, which is
applicable as a foam, the topically applicable composition of the
invention proposes a phospholipid foaming agent as the foaming
agent. Furthermore, the at least one phospholipid foaming agent,
the at least one solvent and the at least one active ingredient in
the composition of the invention are attuned to each other in their
chemical nature and/or their concentration so that the composition
can be mechanically foamed exclusively without the use of an
additional propellant. The foam so created by the mechanical
foaming during the application has a foam volume of at least 400
ml, preferably between 450 and 1400 ml and especially a foam volume
between 600 and 1200 ml. Furthermore, the composition according to
the invention has such a foam stability that the foam still has,
after a dwell time of up to ten minutes and especially after a
dwell time of up to five minutes, at least 50% of the foam volume
and especially between 55% and 100% of the foam volume and
preferably between 85% and 99% of the foam volume that was
originally present immediately after the creation of the foam,
wherein both the aforementioned foam volume and the aforementioned
foam stability can be determined by the standardized SITA foam
measurement method. In other words, topically applicable
composition of the invention is characterized not only by the
nature of its ingredients and/or their concentration, but also by
the foam created from it, wherein the foam is specified and
quantified in terms of the foam volume and the foam stability by
the standardized SITA measurement method.
[0030] The composition of the invention has a number of advantages.
When the composition of the invention is applied to human or animal
skin, where the term skin as already defined above covers the
mucous membranes of mouth, nose, vagina and foreskin, the skin
areas of the ear and especially the inner ear, the skin areas of
the anus and the rectum, the nails and the eyes, especially the
conjunctiva, the cornea and the lacrimal sac, the foam created from
the composition of the invention has, first of all, an excellent
adhesion to these application sites, so that it cannot easily be
wiped off unintentionally. Moreover, the foam produced in exclusive
mechanical fashion from the liquid composition of the invention has
a naturally homogeneous composition, and the pharmaceutical active
ingredient is present in this foam in an especially uniform
ultrafine distribution, so that once the foam breaks down after
being applied this ultrafine distribution is retained in the liquid
layer formed on the skin surface, with the result that the
pharmaceutical active ingredient is transported with a high rate of
penetration and/or permeation into and/or through the skin. This,
in turn, means that the active ingredient so applied has a high
pharmaceutical efficacy, so that if desired the concentration of
active ingredient in the composition of the invention can be
reduced as compared to traditional compositions or, alternatively,
the time intervals between consecutive applications can be
lengthened appropriately, especially since the active ingredient
forms a depot in the skin. Due to the fact that a phospholipid
foaming agent is present as the foaming agent in the composition of
the invention, this phospholipid foaming agent has the effect of
producing a faster penetration or permeation into or through the
skin, which proves to be an additional advantage of the composition
of the invention.
[0031] Especially when the foam created from the composition of the
invention by the SITA measurement method has a foam density between
0.05 g/ml and 0.8 g/ml, preferably between 0.15 g/ml and 0.4 g/ml,
such embodiments of the compositions according to the invention
have the aforementioned advantageous properties to an enhanced
degree.
[0032] As already explained above for the method of the invention,
the composition according to the invention includes, as a solvent,
especially water, at least one alcohol, especially at least one
polyvalent to trivalent alcohol, and/or at least one polyalcohol,
and such solvents are chosen in particular for such phospholipid
foaming agents as contain a phospholipid and/or a phospholipid
mixture isolated from plant components, especially soy beans.
[0033] For clarity it is pointed out that the term phospholipid
mixture or phospholipids in the above description covers all
phospholipids of plant origin, animal origin, or synthetic origin.
In particular, this includes the ester phospholipids, especially
phosphatidyl choline, lyso-phosphatidyl choline, phosphatidyl
ethanolamine, lyso-phosphatidyl ethanolamine, phosphatidyl serine,
lyso-phosphatidyl serine, phosphatidyl inositol, lyso-phosphatidyl
inositol, phosphatidyl glycerin, diphosphatidyl glycerin and the
phosphatidic acids, the ether phospholipids, especially choline
plasmalogen and ethanol aminoplasmalogen, as well as the
sphingosine phospholipids, especially ceramide phosphoryl choline
and phytoglycolipid and derivates of the ester phospholipids, the
ether phospholipids and/or the sphingosine phospholipids,
regardless of whether they have been isolated from natural
substances, such as plants or plant components, especially plant
seeds, or animal components, such as eggs, or synthetically
produced. Typical derivates of these phospholipids which can be
contained in the composition of the invention as foaming agent are
preferably the hydrogenated or partly hydrogenated phospholipids,
especially hydrogenated or partly hydrogenated phosphatidyl
choline.
[0034] Regarding the active ingredient, it should be noted that the
at least one active ingredient contained in the composition of the
invention is one that is suitable for use on humans or animals and
especially for topical and systemic application, especially on the
skin, wherein an especially preferred active ingredient is chosen
from the group comprising local anesthetics, anti-allergic agents,
dermatics, active ingredients against flu infections and colds,
active ingredients for the treatment of neuropathies, active
ingredients for the treatment of disturbed circulation,
chemotherapy drugs, quinine, antimycotics, antibiotics,
thalidomide, serotonin, eicosanoids, analgesics, anticonvulsants,
nonsteroidal antirrheumatics, leukotrienes, leukotriene inhibitors,
androgens, antiandrogens, corticoids, opiate receptor antagonists,
blood clotting inhibitory substances, thrombocyte aggregation
inhibitors, histamine antagonists, regulatory and enzymatically
acting peptides and proteins, nucleic acids (single and
double-stranded DNA, single and double-stranded RNA, snRNA, DNA
oligonucleotides, RNA oligonucleotides) and oligopeptides,
antipruritics, antidiabetics, prostaglandins, prostaglandin
synthesis inhibitors, antiviral-acting or virostatic-acting
substances, antimicrobial-acting substances, active ingredients
against prions, immune suppressants, hormones, active ingredients
for treatment of warts or wounds, especially chronic wounds,
vitamins, plant extracts or essences of plant extracts,
psychoactive drugs, active ingredients influencing sleep,
analeptics, general anesthetics, muscle relaxants, antiepileptics,
antiparkinson agents, antiemetics, antiparasitics, ganglion-active
ingredients, sympathetic-active ingredients, parasympathetic-active
ingredients, antibacterial-acting drugs, calcium antagonists,
cardiovascular agents, antiasthmatics, antitussives, expectorants,
hepatics, diuretics, choleretics, disinfectants, trace elements,
antiinfectives, cytostatics, antimetabolites, hormone antagonists,
immune modulators, as well as derivates and salts of the
aforementioned active ingredients.
[0035] Depending on the particular use of the invented composition,
the inventive compositions include an active ingredient or a
special active ingredient mixture, which is chosen from the
following listed special active ingredients, presented under their
particular main groups.
[0036] Preferably, for the main group of the 5.alpha.-reductase
inhibitors,alphatradiol and 17.alpha.-estradiol can be used; for
the main group of weight loss agents, appetite curbing or
antiobesity agents: norephedrine, phenylpropanole amine,
D-norpseudoephedrin, orlistate and sibutramine; for the main group
of ACE-inhibitors: benazepril, cilazapril, quinapril, ramipril,
spirapril and trandolapril; for the main group of acidosis
therapeutic or antihypoxemic agents:
calcium-sodium-hydrogen-citrate; for the main group of astringents:
aluminium chloride, aluminum diacetate, aluminum formate, bismuth
chloride oxide, bismuth gallate, polycresulene, tannin and zinc
oxide; for the main group of acne agents: azelainic acid and
benzoyl peroxide; for the main group of aldosterone antagonists:
canrenionic acid, potassium canrenoate, dolasetrone and eplerenone;
for the main group of alcohol withdrawal agents: acamprosate and
disulfiram; for the main group of .alpha.1-receptor blockers:
alfuzosin, bunazosin and dihydroergotamine; for the main group of
.alpha.2-receptor agonist: apraclonidine, brimonidine, doxozosine
and moxonidine; for the main group of .alpha.- and
.beta.-sympathomimetics: adrenaline, dobutamine, dopexamine and
epinephrine; for the main group of aminoglycoside antibiotics:
gentamycin, kanamycin, neomycin, netilmycin, streptomycin and
tobramycin; for the main group of amino acids: alanine, aminoacetic
acid, glycine, arginine, asparagine, asparaginic acid, cysteine,
cystine, glycocoll, ornithine, proline and serine; for the main
group of amino acid substitution: alanylglutamine, arginine
glutamate, desmeninol, glycyl glutamine and glycyl tyrosine; for
the main group of analeptics or antihypoxemics: camphor and
caffeine; for the main group of analgesics or antirheumatics:
abatacept, acetylsalicylic acid, acetaminophen, ademetionin,
anakinra, aurothiomalate sodium, buprenorphin, diethylamine
salicylate, etanercept, etoricoxide, fentanyl, flufenamine acid,
flupirtin, glucosamine, hydromorphone, 2-hydroxybenzoic acid,
diethylazane salt, hydroxychloroquin, hydroxyethylsalicylate,
leflunomide, levomethadone, meptazinol, metamizol,
methylsalicylate, misoprostol, morphine, nalbuphine, sodium
aurothiomalate, nicoboxil, nonivamide, noramidopyrine,
novaminsulfone, oxaceprol, oxycodone, paracetamol, penicillamine,
pethidine, phenazone, piritramide, propylnicotinate,
propyphenazone, salazosulfapyridine, sulfasalazine, tilidine,
tramadol and ziconotide; for the main group of acidification
agents: malic acid; for the main group of antacids: almasilate,
aluminum hydroxide, aluminum hydroxide-magnesium carbonate gel,
aluminum phosphate, carbaldrate, magaldrate, magnesium carbonate,
magnesium hydroxide and magnesium trisilicate; for the main group
of antihelminthics: albendazol, mebendazol, niclosamide,
praziquantel, pyrantel and pyrviniumembonate; for the main group of
antiallergics: chromoglycinic acid, lodoxamide, mequitazine,
mizolastine and olopatadine; for the main group of antianemics:
calcium folinate, darbepoeton alpha, iron, iron carboxymaltose,
iron (II) chloride, iron (II) fumarate, iron (II) gluconate, iron
(II) succinate, iron (II) sulfate, iron glycine sulfate, iron (III)
hydroxide-dextran complex, iron (III) hydroxide-polymaltose
complex, iron (III) hydroxide-saccharose complex, iron (III)
sodium-gluconae complex, epoetin alpha, epoetin beta, epoetin zeta,
erythropoetin, folic acid and methoxy-polyethylglycol-epoetin beta;
for the main group of antiandrogens: bicalutamide, chlormadione and
cyproterone; for the main group of antiarrhythmics: ajmalin,
amiodaron, quinidine, detajmium bitartrate, flecainide, lidocaine,
mexiletin, orciprenalin, prajamalium bitartrate, propafenon and
sotalol; for the main group of antibiotics or anti-infectives:
amikacin, aminosidine, paromomycin, chloramphenicol, ciprofloxacin,
clindamycin, colistimethate-sodium, colistin, enfuvirtid, enoxacin,
flucloxacillin, fosfomycin, fusafungin, levofloxacin, linezolid,
mefloquin, metronidazol, mezlocillin, moxifloxacin, norfloxacin,
ofloxacin, oxacillin, penicillin G, penicillin V,
phenoxymethylpenicillin, phenoxymethylpenicillin-benzathin,
pipemidinic acid, piperacillin, piperacillin+tazobactam, proguanil,
propicillin, pyrimethamine, retapamulin, rifaximin, roxithromycin,
sulbactam, sulbactam+ampicillin, sulfadiazine, spiramycin,
sultamicillin, tazobactam+piperacillin, teicoplanin, telithromycin,
tigecyclin and vancomycin; for the main group of antidementia
agents (nootropics): galantamine, nicergolin, nimodipin, pyracetem,
pyritinol and rivastigmin; for the main group of antidepressants:
agomelatin, amitriptylin, amitriptylin oxide, bupropion, citapram,
clomipramin, duloxetin, escitalopram, fluoxetin, fluvoxamin,
maprotilin, mianserin, mirtazapin, nortriptylin, opipramol,
paroxetin, reboxetin, sertralin, tranylcypromin, trazodon and
trimipramin; for the main group of antidiabetics: acarbose,
exenatid, glibenclamide, gliclacid, glimepirid, gliquidon,
insulinaspart, insulinaspart biphasic, insulindetemir,
insulinglargin, insulinglulisin, human insulin, human
insulin-isophan biphasic, insulin-isophan, insulinlispro,
isophan-insulin, metformin, miglitol, nateglinid, pioglitazon,
repaglinid, rosiglitazon, sitagliptin and vildagliptin; for the
main group of antidotes: bis-sulfanyl propane sulfonic acid,
deferasirox, deferoxamin, deferipron, dimercapto-propane sulfonic
acid, dimethylaminophenol, disodium folinate, iron
hexacyanoferrate, eserin, flumazenil, fomepizol, naloxone, sodium
folinate, sodium thiosulfate, obidoxim chloride, pentetic acid,
physostigmin, silbinin and tolonium chloride; for the main group of
antiemetics or antivertigo agents: aprepitant, beta-histine,
domperidon, flunarizin, fosaprepitant, granisetron, ondansetron,
palonosetron and tropisetron; for the main group of antiepileptic
agents: carbamazepin, clonazepam, diphenylhydantoin, phenytoin,
dipropylacetic acid, valproic acid, ethosuximid, felbamat,
gabapentin, potassium bromide, lacosamid, lamotrigin,
levetiracetam, mesuximid, oxcarbazepin, phenobarbital, primidon,
propylvalerianic acid, rufinamide, sultiam, tiagabin, topiramate,
valproic acid, vigabatrin and zonisamide; for the main group of
antiestrogens: clomife; for the main group of antihemorrhagics,
antifibrinolytics and other hemostatic agents: aminomethylbenzoic
acid, human blood clotting factor 1, blood clotting factor Vlla,
blood clotting factor Vll (CHO), recombinant blood clotting factor
Vlll, human blood clotting factor Vlll, recombinant blood clotting
factor 1X, human blood clotting factor 1X, blood clotting factor
Xlll, eptacog alpha (activated), fibrinogen, gelatins, moroctocog
alpha, nonacog alpha, octocog alpha (BHK), phytomenadione, human
plasma proteins, human plasma proteins with factor VIII inhibitor
bypass activity, proconvertin, protamine hydrochloride, tranexamic
acid and troxerutin; for the main group of antihistamines:
anazolin, azelastin, bamipin, cetirizin, chlorphenamine,
chlorphenoxamine, cyproheptadine, desloratadine,
dexchlorpheniramine, dimenhydrinate, dioxopromethazine,
diphenhydramine, diphenylpyraline, ebastine, emedastine,
epinastine, fexofenadine, hydroxyzine, levocabastine,
levocetirizine, loratadine, rupatadine, terfenadine, tripelennamine
and triprolidine; for the main group of antihypertonics: aliskiren,
ambrisentan, amiloride+hydrochlorothiazide,
hydrochlorothiazide+amiloride, bosentan, candesartan, captopril,
clonidine, delapril, enalapril, enalaprilate, eprosartan,
hydralazine, imidapril, indapamide, indoramine, lercanidipine,
manidipine, methyldopa, minoxidil, moexipril, nilvadipin,
nitrendipin, nitroprusside sodium, olmesartan, prazosin, reserpine,
nitrogen monoxide, sitaxentan, telmisartan, terazosin, treprostinil
and urapidil; for the main group of antihypoglycemics: diazoxide
and glucagon; for the main group of antihypotonics: amezinium
methyl sulfate, cafedrin, dopamine, etilefrin, levarterenol,
norepinephrine, midodrin, noradrenaline, oxilofrin and
theodrenaline; for the main group of anticoagulants: bivalirudin,
certoparin sodium, dabigatran, dalteparin sodium, danaparoid
sodium, drotrecogin alpha (activated), enoxaparin sodium,
fondaparinux, heparin, heparin (low-molecular), nadroparin calcium,
reviparin sodium, tinzaparin sodium, lepirudin, nadroparin calcium,
pentosanpolysulfate sodium, protein C, reviparin sodium,
rivaroxaban, tinzaparin sodium and warfarin; for the main group of
antimycotics: amorolfin, amphotericin B, anidulafungin, bifonazole,
caspofungin, ciclopirox, ciotrimazole, econazole, fenticonazole,
fluconazole, flucytosin, griseofulvin, hexamidine, isoconazole,
itraconazole, ketoconazole, micafungin, miconazole, naftifin,
natamycin, nystatin, oxiconazole, posaconazole, sertaconazole,
terbinafin, tioconazole, tolnaftat, undecylenic acid and
voriconazole; for the main group of antineoplastic agents:
alemtuzumab, alitretinoin, bevacizumab, arsenic trioxide,
asparaginase, bexaroten, buserelin, celecoxib, cetuximab and
colaspase; for the main group of antiparasitic agents: allethrin 1,
acetic acid, permethrin and piperonylbutoxide; for the main group
of antiphlogistics: aescin, ammonium bituminosulfonate, ammonium
bituminosulfonate bright, benzydamine, bufexamac, cumarin,
dimethylsulfoxide, guaiazulene, sodium bituminosulfonate and
serrapeptase; for the main group of antipruriginosics: crotamiton,
levomenthol, menthol and coal tar; for the main group of
antipsoriatics: acitretin, dimethylfumarate and
ethylhydrogenfumarate; for the main group of antipsychotics:
aripiprazole; for the main group of antiseptics: ethacridin,
ethanol, denatured ethanol, fenchon, glyoxal, hexetidin,
hydroxyquinoline sulfate, potassium thiocyanate, methenamine-silver
nitrate 1:2, phenoxyethanol, ionic silver and colloidal silver; for
the main group of antiscabies agents: benzylbenzoate; for the main
group of antitussives or expectorants: anethol, benproperin,
cineol, codeine, dextromethorphan, dihydrocodeine, dropropizin,
eucalyptol, guaifenesin, guajacol glycerine ether, levodropropizin,
narcotin, sodium dibunate, noscapin, pentoxyverin, thymol and
tyloxapol; for the main group of anticoagulants: argatroban; for
the main group of anxiolytics: buspiron; for the main group of
appetite curbing agents: amfepramon and cathine; for the main group
of aromatase inhibitors: anastrozole, exemestan and letrozole; for
the main group of arteriosclerosis agents:
dodecyltetradecylhydroxypolyoxyethylene polyoxypropylene; for the
main group of balneotherapeuticals and thermotherapy agents: humic
acids; for the main group of .beta.-lactam antibiotics: aztreonam,
imipenem, cilastatin, doripenem, ertapenem, loracarbef, meropenem;
for the main group of beta-receptor and calcium channel blockers
and inhibitors of the renin-angiotensin-aldosterone system:
acebutolol, atenolol, bisoprolol, betaxolol, bupranolol, carteolol,
celiprolol, esmolol, fosinopril, gallopamil, irbesartan,
levobunolol, lisinopril, losartan, metipranolol, metoprolol,
nebivolol, nifedipine, nisoldipin, oxprenolol, penbutolol,
perindopril, pindolol, propranolol, talinolol, valsartan and
verapamil, for the main group of bisphosphonates: alendronate,
alendronatic acid, clodronate, clodronic acid, etidronate and
etidronic acid; for the main group of broadband penicillin:
amoxicillin and ampicillin; for the main group of broadband
penicillin+.beta.-lactamase inhibitors: clavulanic acid and
sulbactam; for the main group of bronchodilators: aminophyllin and
bambuterol; for the main group of broncholytics or antiasthmatics:
carbocisteine, ciclesonide, clenbuterol, fenoterol, formoterol,
ipratropium bromide, ketotifen, montelukast, omalizumab,
reproterol, salbutamol, salmeterol, terbutalin, theophyllin,
theophyllin ethylene diamine, tiotropium bromide and tulobuterol;
for the main group of calcium antagonists: amlodipin, diltiazem,
felodipin and isradipin; for the main group of calcium replacement
agents: calcium aminoethyl phosphate, calcium aspartate, calcium
bis-(hydrogen aspartate), calcium chloride, calcium citrate,
calcium gluconate, calcium hydrogen phosphate, calcium hydrogen
phosphate, calcium lactobionate, calcium lactogluconate and calcium
salts; for the main group of carboanhy[d]rase inhibitors:
acetazolamide, binzolamide and dorzolamide; for the main group of
cephalosporin: cefaclor, cefadroxil, cefalexin, cefazolin, cefepim,
cefixim, cefotaxim, cefotiam, cefepodoxim, ceftazidim, ceftibuten,
ceftriaxon, cefuroxim and ceph; for the main group of chemotherapy
agents: co-trimoxazole, dapson, nifuratel, nitrofural,
nitrofurantoin, nitrofurazon, nitroxolin, octenidin, pentamidin,
ulfamethoxazole, taurolidin and trimethoprim; for the main group of
cholagogues and bile duct therapeutic agents: menthon,
.alpha.-pinene, .beta.-pinene and ursodesoxycholic acid; for the
main group of cholinergics: acetylcholine chloride, carbachol,
distigmin bromide, neostigmin and pyridostigmin bromide; for the
main group of corticoids: fludrocortisone for the main group of
depot penicillin: benzylpenicillin-benzathin and
benzylpenicillin-procaine; for the main group of dermatic agents:
ammonium dodecylsulfate, betacarotene, DFMO, eflornithine,
difluormethylornithine, dodecylbenzene sulfonic acid,
nitrilotriethanol salt, ectoin, estradiol benzoate, ethyl linolate,
framycetin, fusidinic acid, synthetic tannin, phenol-methanal-urea
polycondensate sulfonated, urea, hexamethylene tetramine,
hydroquinone, isotretinoin, potassium hydroxide, keratin, copper
(II) nitrate, lithium succinate, methane thelinium bromide,
methenamine, methoxypsoralene, mupirocin, nadifloxacin,
pimecrolimus, podophyllotoxin, salicylic acid, nitric acid,
selenium disulfide, sulfadiazine-silver, tacalcitol, tretinoin and
tyrothricin; for the main group of disinfectants:
aminopropyldodecylpropane diamine, cocospropylene diamine,
dodecylpropane diamine, ethylene dioxydimethanol and triclosan; for
the main group of disinfectants or antiseptics: aethacridin,
aluminum acetate tartrate, amylmetacresol, bibrocathol,
benzalkonium chloride, benzethonium chloride, benzyl alcohol,
bishydroxymethyl urea, biphenyl-2-ol, bromchlorophen,
cetylpyridinium chloride, 8-quinolinol sulfate, clioquinol,
didecyldimethylammonium chloride, didecylmethyloxyethlammonium
propionate, quinolinol sulfate potassium sulfate, chlorhexidin,
chlorhydroxybenzoic acid, clorofen, cocospropylene diamine
guanidinium acetate, dequalinium chloride, dibromhydroxybenzene
sulfonic acid, dichlorbenzyl alcohol, dithranol, ethylhexanol,
formaldehyde, glucoprotamine, glutaral, magnesium
monoperoxyphthalate, mecetronium ethyl sulfate,
oligodiiminoimidocarbonyliminohexamethylene, ortho-phthalaldehyde,
peracetic acid, polyhexanid, povidone iodine, 1-propanol,
2-propanol, tetrahydrotetrakishydroxymethylimidazoimidazoldione,
tosylchloramide sodium and hydrogen peroxide; for the main group of
deodorants: chlorophyllin; for the main group of dietetics or
nutritional supplements: methyloxobutyric acid, methyloxovalerianic
acid (3), methyloxovalerianic acid (4) and oxophenylpropionic acid;
for the main group of diagnostic agents and diagnosis preparation
agents: aminolavulinic acid, aminolevulinic acid,
5-amino-4oxopentanoic acid, ceruletid, human corticorelin, iron
oxide, ferumoxsil, fluorescein, gadobenic acid, gadobutrol,
gadodiamide, gadofosveset, gadopentetic acid, gadoteridol,
gadoteric acid, gadoxetic acid, galactose,
.sub.13C-urea, hexylaminooxopentanoate, indocyanine green,
mangafodipir, palmitic acid, patent blue V, perflutren, polyvinyl
chloride, protirelin, secretin, starch hydrolyzate, somatorelin,
TRH and tuberculin purified for human use; for the main group of
direct parasympathomimetics: bethanechol chloride; for the main
group of diuretics: bumetanide, furosemide, piretanide,
spironolactone, torasemide, triamterene,
triamterene+hydrochlorothiazide and xipamide; for the main group of
dopamine agonists: .alpha.-dihydroergocryptin; for the main group
of circulation promoting agents: alprostadil, cinnarizin,
moxaverin, naftidrofuryl, pentoxifyllin, prostaglandin E1 and
xanthinol nicotinate; for the main group of iron replacement:
ammonium iron sulfate; for the main group of emetics: apomorphine;
for the main group of withdrawal agents/agents for treatment of
addictive diseases: naltrexone, nicotine and vareniclin; for the
main group of enzyme replacement therapy for Fabry's syndrome:
agalsidase alpha and agalsidase beta; for the main group of enzyme
inhibitors, enzyme deficiency products and transport proteines:
carglumic acid, L-carnitine, levocarnitine, C.sub.1-esterase
inhibitor, galsulfase, hyaluronidase, idursulfase, imiglucerase,
laronidase and miglustat; for the main group of enzyme replacement
therapy in Pompe's disease: alglucosidase alpha; for the main group
of estrogens: estriol, conjugated estrogens and ethinylestradiol;
for the main group of fibrinolytics: alteplase, reteplase,
streptokinase, tenecteplase and urokinase; for the main group of
film forming agents: carbomer and carmellose; for the main group of
gallstone dissolvers: chenodesoxycholic acid; for the main group of
gestagens: dienogest, drospirenone, dydrogesterone, gestodene,
hydroxyprogesterone caproate, levonorgestrel, medrogestone,
medroxyprogesterone, megestrolacetate, norelgestromin,
norethisterone, norgestimate and D-norgestrel; for the main group
of glaucoma treatment: bimatoprost and latanoprost; for the main
group of geriatrics: potassium metabisulfite; for the main group of
antipodagrics: probenecide; for the main group of glucocorticoids:
alclometasone, amcinonide, beclometasone, betamethasone,
budesonide, clobetasol, clobetasone, clocortolone, cloprednol,
deflazacort, desoximetasone, dexamethasone, diflorasone,
diflucortolone, flumetasone, flunisolide, fluocinolonacetonide,
fluocinonide, fluocortolone, fluorometholone, fluprednidene,
fluticasone, halometasone, hydrocortisone, hydrocortisone
aceponate, hydrocortisone acetate, hydrocortisone-17-butyrate,
hydrocortisone hydrogen succinate, methylprednisolone,
mometasonfuroate, prednicarbate, prednisolone, prednisone,
rimexolone, triamcinolone, triamcinolone acetonide,
triamcinolone-16,21-diacetate and triamcinolone hexacetonide; for
the main group of gonadorelin inhibitors: cetrorelix; for the main
group of gynecologicals: gemeprost, copper, metergolin,
methylergometrin, lactic acid, nonoxinol, progesterone,
prostaglandin E2, quinagolide and sulprostone; for the main group
of hemopoietic growth factors: becaplermin; for the main group of
hemostyptics: cellulose oxidized regenerated, desmoressin and
collagen; for the main group of hepatics: acetylmethionine, betaine
dihydrogen citrate, choline hydrogen tartrate,
potassium-iron-phosphate-citrate complex, ornithine aspartate and
zinc acetate; for the main group of cardioglycosides (Digitalis
lanata): .beta.-acetyldigoxin, digitoxin and digoxin; for the main
group of hyperemization agents: benzylnicotinate and
isobornylacetate; for the main group of hypnotics or sedatives:
brotizolam, chloralhydrate, clomethiazole, doxylamine,
flunitrazepam, flurazepam, lormetazepam, melatonin, midazolam,
nitrazepam, temazepam, zaleplon, zolpidem and zopiclon; for the
main group of pituitary and hypothalamus hormones, other regulatory
peptides and their inhibitors: carbetocin, choriogonadotropin
alpha, choriongonadotropin, tetracosactid,
.beta.-1-24-corticotropin, follitropin alpha, follitropin beta,
ganirelix, gonadorelin, gonadotrophinum chorionicum,
gonadotrophinum hypophysicum, menotropin, lanreotid, LH-RH,
lutropin alpha, mecaserim, nafarelin, octreotid, oxytocin,
somatostatin, somatropin, terlipressin, thyrotrophin,
urofollitropin, urogonatropin and human growth hormone; for the
main group of immunomodulators: eculizumab, glatiramer,
lenalidomide, lenograstim, palivizumab and pegvisomant; for the
main group of immune stimulants: aldesleukin, dimepranolacedoben,
filgrastim, inosine, interferon alpha-2a, interferon alpha-2b,
interferon beta-1.degree., interferon beta-1b, interferon gamma-1b,
pegfilgrastim, peginterferon alpha-2a and peginterferon alpha-2b;
for the main group of immune suppressants: adalimumab, azathioprin,
basiliximab, cyclosporine, cladribin, cyclosporine, daclizumab,
efalizumab, everolimus, immunglobulin G rabbit antihuman-T-cell,
infliximab, muromonab-CD3, mycophenolate mofetil, mycophenolic
acid, natalizumab, sirolimus, tacrolimus and tocilizumab; for the
main group of infusion and standard injection solutions or organ
perfusion solutions: N-acetyltyrosine, gelatine polysuccinate,
glucose, glutamine, glycerol dihydrogen phosphate, human albumen,
potassium hydrogen glutamate, mannitol, sodium aminoethylhydrogen
phosphate, sodium chloride, sodium hydrogen carbonate, oleic acid,
2-oxoglutaric acid, polyhydroxyethyl starch, hydrochloric acid,
taurine, trometamol and xylitol; for the main group of inhaled
narcotics: desfluran, dinitrogen monoxide and isofluran; for the
main group of intestinal antiphlogistics: 5-aminosalicylic acid,
mesalazin, (-)-.alpha.-bisabolol, levomenol, bromelain and choline
stearate; for the main group of potassium replacement agents:
potassium acetate, potassium chloride, potassium hydrogen
aspartate, potassium hydrogen carbonate, potassium lactate and
potassium malate; for the main group of potassium-sparing
diuretics: amiloride; for the main group of capillary sealing
agents: calcium dobesylate; for the main group of cardiacs:
enoximon, icatibant, .beta.-methyldigoxin, methyldigoxin, milrinon
and oubain; for the main group of caries and parodontosis agents
and other dental preparations: dectaflur, sodium fluoride and
olaflur; for the main group of carminatives: dimethylpolysiloxane
and dimethicone; for the main group of coronary drugs: ivabradin
and molsidomine; for the main group of laxatives: bisacodyl,
glycerine, glycerol, lactulose, macrogol, magnesium peroxide,
sodium dioctylsulfosuccinate, sodium laurylsulfoacetate, sodium
monohydrogen phosphate, sodium picosulfate, sodium sulfate, syrupy
paraffin, polyethylene glycol and white vaseline oil paraffin; for
the main group of photoprotective agents: actinoquinol; for the
main group of lipid lowering drugs: atorvastatin, bezafibrate,
colestyramine, cholestyramine, etofibrate, etofyllin clofibrate,
ezetimib, fenofibrate, fluvastatin, gemfibrozil, lovastatin,
magnesium pyridoxal phosphate glutamate, nicotinic acid,
omega-3-acid ethyl ester, pravastatin and simvastatin; for the main
group of topical anesthetics or neural therapeuticals: aethoform,
p-aminobenzoic acid ethyl ester, articaine, benzocaine,
bupivacaine, carticaine, chlorethane, cinchocaine, ethyl choride,
felypressin, macrogol lauryl ether, mepivacaine, prilocaine,
procaine, proxymetacaine, quinisocaine, ropivacaine and tetracaine;
for the main group of gastrointestinal agents: hydrotalcit,
lansoprazole, loperamide, methylnaltrexone bromide, metoclopramide,
sodium alginate, olsalazin, omeprazole, oxetacaine, pancreas
powder, pancreatin, pantoprazole, pepsin, pirenzepine,
polymethylsiloxane, rabeprazole, racecadotril, ranitidine, silicon
dioxide, simethicone, sucralfate, smectite, tannin-protein and
tilactase; for the main group of magnesium replacement agents:
magnesium chloride, magnesium salts and magnesium sulfate; for the
main group of macrolide antibiotics: azithromycin, bacitracin,
clarithromycin, daptomycin and erythromycin; for the main group of
migraine agents: almotriptan, eletriptan, ergotamine, frovatriptan,
naratriptan, rizatriptan, sumatriptan and zolmitriptan; for the
main group of mineral preparations: calcium lactate, calcium
saccharate, iron hydrogen aspartate, potassium aminoethylphosphate,
potassium citrate, magnesium aminoethylphosphate, magnesium
aspartate, magnesium bis(hydrogenaspartate), magnesium citrate,
magnesium gluconate, magnesium hydrogen citrate, magnesium hydrogen
glutamate, magnesium hydrogen phosphate, magnesium orotate and
magnesium oxide; for the main group of homocysteinuria treatment
agents: betaine; for the main group of scleroderma and induratio
penis plastica treatment agents: 4-aminobenzoic acid; for the main
group of mucolytics: acetylcysteine; for the main group of
mucolytics: desoxyribonuclease and dornase alpha; for the main
group of muscle relaxants and reversers: alcuronium chloride,
atracurium besylate, quinine, cisatracurium besylate, dantrolen,
mivacurium chloride, orphenadrin, pancuronium bromide, pridinol,
rocuronium bromide, succinyl choline chloride, suxamethonium
chloride, sugammadex, tetrazepam, tizanidin, tolperison and
vecuronium bromide; for the main group of myotonolytics: baclofen
and methocarbamol; for the main group of narcosis agents:
esketamine, etomidate, hydroxybutyiric acid, ketamine, propofol,
remifentanil, sevofluran, sufentanil and thiopental-sodium; for the
main group of neuroleptics: amisulpride, aaphenothiazine,
pothipendyl, benperidol, bomperidol, butyrophenone, chlorprothixen,
clozapine, diphenylbutylpiperidine, droperidol, fluspirilen,
pimozide, flupentixol, fluphenazine, levomepromazine and melperone;
for the main group of neuropathy drugs and other neurotropic
agents: cytidine phosphate, A-liponic acid, thioctic acid,
pregabalin, riluzol and uridine phosphate; for the main group of
nonsteroidal anti-inflammatory drugs: flurbiprofen,
ketorolac-tromethanol, lornoxicam and parecoxib; for the main group
of nonsteroidal antirheumatics: acecolfenac, aemetacin, alizapride,
chloroquin, dexibuprofen, diclofenac, etofenamate, ibuprofen,
indomethacin, ketoprofen, meloxicam, nabumeton, naproxen,
phenylbutazone, piroxicam, proglumethacin and tiaprofenic acid; for
the main group of ophthalmics: chondroitin sulfate, gramicidine,
hydroxypropyl-guar, hydroxypropylmethylcellulose, hypromellose,
inosine phosphate, lomefloxacin, methylhydroxypropylcellulose,
naphazolin, nedrocromil, oxybuprocaine, pegaptanib, pilocarpin,
polymyxin B, poly(vinylalcohol), povidone, ranibizumab,
scopolamine, sulfacetamide, tafluprost, tetryzolin, timolol,
travoprost, tropicamide, verteporfin and wool wax alcohols; for the
main group of osteoporosis/calcium/bone metabolism regulators:
alphacalcidol, calcitonin, disodium fluorophosphate, eptotermin
alpha, hydroxycolecalciferol, ibandronate, ibandronic acid,
pamidronate, pamidronic acid, human parathyroid hormone,
paricalcitol, raloxifen, distrontium ranelate, risedronate,
risedronic acid, teriparatid, tiludronate, tiludronic acid,
zoledronate and zoledronic acid; for the main group of otologic
agents: docusate-sodium; for the main group of parkinson drugs and
other agents against extrapyramidal disturbances: benserazide,
bromocriptine, budipine, cabergoline, carbidopa, entacapone,
levodopa, lisuride, metixene, pergolide, piribedil, pramipexol,
procyclidine, rasagiline, ropinirole, rotigotine, selegiline,
tetrabenazine, tiapride, tolcapone and trihexypenidyl; for the main
group of penicillins: benzylpenicillin and dicloxacillin; for the
main group of phosphate binders: algeldrate, hydrated aluminum
oxide, calcium acetate and calcium carbonate; for the main group of
phosphate replacement agents: sodium glycerophosphate; for the main
group of photosensitizers: ammoidine and methoxsalene; for the main
group of polyaromatic retinoids: adapalene; for the main group of
progestagenics: desogestrel and etonogestrel; for the main group of
protease inhibitors: atazanavir and lopinavir; for the main group
of proteinase inhibitors: antithrombin lll; for the main group of
protozoan agents: artemether and lumefantrine; for the main group
of psychoanaleptics: atomoxetin, metamfepramon and methylphenidate;
for the main group of psychoenergetics: deanol; for the main group
of psychopharmaceuticals: doxepin, haloperidol, imipramine, lithium
salts, lorazepam, medazepam, memantin, moclobemide, modafinil,
olanzapine, oxazepam, paliperidone, perazine, perphenazine,
phenothiazines, pimozide, pipamperone, prazepam, promethazine,
prothipendyl, quetiapine, risperidone, sertindole, sulpirid,
thioridazine, thiocanthene, venlafaxine, ziprasidone, zotepine and
zuclopenthixol; for the main group of rhinologics or sinusitis
agents: Emser salt, synthetic Emser salt, natural sea salt,
oxymetazolin, silver-protein acetyl tannate, tramazoline, xanthan
gum and xylometazoline; for the main group of roborants or tonics:
iron (III) citrate and glutaminic acid; for the main group of X-ray
contrast agents: amidotrizoic acid, barium sulfate, diatrizoate,
iobitridol, iodixanol, iohexol, iomeprol, iopamidol, iopromide
iosarcol, iotrolan, iotroxic acid, ioxaglic acid and ioxitalamic
acid; for the main group of saluretics: bemetizide,
bendroflumethiazide, chlorthalidone, clopamide,
hydrochlorothiazide, hydrochlorothiazide+amiloride,
hydrochlorothiazide+triamterene and mefruside; for the main group
of thyroid therapeutic agents: cinacalcet, potassium iodide,
levothyroxin, liothyronin, sodium iodide, sodium perchlorate,
propylthiouracil, thiouracils and L-thyroxin; for the main group of
essential amino acids: histidine, isoleucine, leucine, lysine,
phenylalanine, threonine, tryptophan, tyrosine and valine; for the
main group of secretolytics: ambroxol and bromhexine; for the main
group of serums, immunglobulins and inoculants: immunglobulin
(anti-D), immunglobulin (botulismus), immunglobulin (cytomegalia),
immunglobulin (hepatitis B), immunglobulin (human), immunglobulin
(tetanus), immunglobulin (rabies) and immunglobulin
(varicella-zoster); for the main group of sexual hormones and their
inhibitors: estradiol, estradiol valerate, mestranol, mifepristone,
prasterone, testosterone and tibolone; for the main group of
spasmolytics or anticholinergics: atropine, atropine sulfate,
biperiden, bornaprine, borneol, butylscopolaminium bromide,
camphen, cyclopentolate, darfenacin, glycopyrronium bromide,
hymecromone, hyoscine butylbromide, mebeverine and pipenzolate
bromide; for the main group of trace elements:
bis(L-histidinato)zinc, chromium chloride, chromium hydrogen
aspartate, cobalt hydrogen aspartate, iron (III) chloride, copper
(II) chloride, copper (II) hydrogen aspartate, manganese (II)
chloride, manganese (II) hydrogen aspartate, sodium molybdate,
sodium selenite, zinc aspartate, zinc bishydrogen aspartate, zinc
chloride, zinc gluconate, zinc histidine, zinc orotate and zinc
sulfate; for the main group of replacement agents: disodium
hydrogen citrate, magnesium acetate, sodium acetate, sodium
hydroxide and sodium lactate; for the main group of
sympathomimetics: dipivefrin and ephedrine; for the main group of
tetracyclines: chlortetracycline, demeclocycline, doxycycline,
meclocycline, minocycline, oxytetracycline and tetracycline; for
the main group of platelet clotting inhibitors: abciximab,
cilostazol, clopidogrel, eptifibatide, iloprost, ticlopidine and
tirofiban; for the main group of thyreostatics: carbimazole,
methimazole and thiamazole; for the main group of tocolytics:
atosiban; for the main group of toxoplasmosis, pneumocystis carinii
and pneumonia drugs: atovaquone; for the main group of
tranquilizers (benzodiazepin): alprazolam, bromazepam,
chlordiazepoxide, clobazam, diazepam and dipotassium clorazepate;
for the main group of tuberculosis drugs: aminosalicylic acid,
ethambutol, isoniazide, protionamide, pyrazinamide, rifampicin and
terizidone; for the main group of ulcer therapeuticals: bismuth
nitrate, bismuth tetraoxodialuminate, cimetidine, esomeprazole and
famotidine; for the main group of uricostatics: allopurinol and
benzbromarone; for the main group of urologicals: dutasteride,
fesoterodine, finasteride, flavoxate, potassium aminobenzoate,
potassium sodium hydrogen citrate, lanthanum (III) carbonate,
mercaptamine, methionine, oxybutynine, phenoxybenzamine,
phytosterol, polystyrene divinylbenzene sulfonic acid, polystyrene
sulfonic acid, propiverine, propyl-4-hydroxybenzoate, sevelamer,
solifenacin, tamsulosin, tiopronin, tolterodine, trospium chloride
and yohimbin; for the main group of uterus agents: dinoprostone;
for the main group of vasodilators: adenosine, buflomedil,
carvedilol, codergocrin, dihydralazine, dihydroergotoxin,
dipyridamol, glycerol trinitrate, isosorbide dinitrate, isosorbide
mononitrate, nitroglycerin, pentaerythrityl tetranitrate,
sildenafil, tadalafil, trapidil and vardenafil; for the main group
of venous therapeuticals: heparinoids, mucopolysaccharide
polysulfuric acid esters, oligo(O-sulfo)rutoside, polidocanole,
rutin and rutoside; for the main group of vein tonic agents:
diosmin; for the main group of virustatics: abacavir, aciclovir,
adefovir, amantadine, brivudin, cidofovir, darunavir, didanosine,
efavirenz, emtricitabine, entecavir, etravirine, famciclovir,
fosamprenavir, ganciclovir, idoxuridine, imiquimod, indinavir,
interferon
beta, lamivudine, maraviroc, nelfinavir, nevirapine, oseltamivir,
raltegravir, ribavirin, ritonavir, saquinavir, stavudine,
telbivudine, tenofovir, tipranavir, trifluridine, tromantadine,
valaciclovir, valganciclovir, zanamivir and zidovudine; for the
main group of vitamins: aneurin, ascorbic acid, benfotiamine,
biotin, calcifediol, ergocalciferol, calciferol, calcipotriol,
calcitriol, calcium pantothenate, colecalciferol, cyanocobalamine,
dihydrotachysterol, hydroxocobalamine, purified silicon dioxide,
sodium ascorbate, sodium pantothenate, nicotinamide, nicotinic acid
amide, pyridoxin, retinol, riboflavin, thiamine, thiamine
dihydrogen phosphate-dihydrogen phosphate (ester salt), thiamine
disulfide, thiamine nitrate,
.alpha.-tocopherol, RRR-.alpha.-tocopherol, .alpha.-tocopherol
acetate, RRR-.alpha.-tocopherol acetate, DL-.alpha.-tocopherol
hydrogen succinate, RRR-.alpha.-tocopherol hydrogen succinate,
vitamin A, vitamin-A-acid, vitamin B.sub.1, vitamin B.sub.2,
vitamin B.sub.6, vitamin B.sub.12, vitamin C, vitamin D.sub.2,
vitamin D.sub.3, vitamin E and vitamin K.sub.1; for the main group
of wound and scar treatment agents: allantoin, calcium alginate,
dexpanthenol, ethylcyanoacrylate, lactide-caprolactone copolymers,
poly(butylmethacrylate-co-methylmethacrylate) (x:y), polyurethane
and titanium dioxide; for the main group of urine acidification
agents: ammonium chloride; for the main group of cytoreductive
agents: anagrelid; for the main group of cytostatics, other
antineoplastic agents and protectives: adriamycin, amethopterin,
bendamustine, bleomycin, bortezomib, busulfan, capecitabine,
carboplatin, CCNU, lomustine, chlorambucil, cisplatin,
cyclophosphamide, cytarabine, dacarbazine, dasatinib, daunorubicin,
dexrazoxan, docetaxel, doxorubicin, epirubicin, erlotinib,
estramustine, etoposide, fludarabine, fluorouracil, flutamide,
5-FU, fulvestrant, gemcitabine, goserelin, hydroxycarbamide,
ibritumomabtiuxetan, idarubicin, ifosfamide, imatinib, irinotecan,
lapatinib, leuprorelin, melphalan, mercaptopurine, mesna,
methotrexate, methylaminooxopentanoate, miltefosine, mitomycin,
mitotane, mitoxantrone, nelarabine, nilotinib, nimustin,
oxaliplatin, paclitaxel, palifermin, panitumumab, pegaspargase,
pemetrexed, porfimer-sodium, procarbazine, rasburicase, rituximab,
sorafenib, sunitinib, tamoxifen, tegafur, temoporfin, temozolomide,
temsirolimus, thiotepa, thioguanine, topotecan, toremifene,
trabectedine, trastuzumab, treosulfan, triptorelin, trofosfamide,
uracil, vinblastin, vincristin, vindesine and vinorelbine; for the
main group of biomaterials or medical plastics or various
materials: hydroxylapatite, methylmethacrylate,
poly(methylacrylate-co-methylmethacrylate) (x:y), tricalcium
bisphosphate and zirconium (IV) oxide as special active ingredient
or active ingredient mixture.
[0037] An especially suitable embodiment of the composition
according to the invention proposes that this embodiment of the
invented composition has, as active ingredient, an analgesic,
especially an analgesic that is chosen from the above indicated
special analgesics, and the concentration of this analgesic in the
liquid composition that is mechanically foamed is varied in
particular between 0.1 wt. % and 20 wt. %, preferably in a
concentration between 2 wt. % and 10 wt. %.
[0038] If the composition of the invention is to be used as foam
for treatment of fungal infections, then it includes, as
pharmaceutical active ingredient, at least one antimycotic,
especially an antimycotic that is chosen from the above indicated
special antimycotics. Preferably this antimycotic is chosen from
the group comprising chlotrimazol, biphonazol, econazol,
phenticonazol, isoconazol, oxyconazol, sertaconazol, thioconazol,
terbinafin, myconazol, ketoconazol, itraconazol, fluconazol,
voriconazol, as well as derivates of the aforementioned substances.
In particular, the concentration of an antimycotic active
ingredient varies between 0.01 wt. % and 10 wt. %, especially
between 0.2 wt. % and 5 wt. %, in terms of the liquid composition
that is exclusively mechanically foamed during application. A foam
produced in exclusively mechanical fashion from such a liquid
composition during its application can then be used in particular
with a very high pharmaceutical efficacy for nail and foot fungal
infections and for saccharomycete infections, the high
pharmaceutical efficacy being manifested in that these fungal
infections are curtailed already after a few applications and also
healed in a short time after the application is repeated.
[0039] Another embodiment of the composition according to the
invention includes as an active ingredient, at least one corticoid
active ingredient, especially a corticoid active ingredient that is
chosen from the above indicated special corticoid active
ingredients, wherein the corticoid active ingredient is chosen
preferably from the group consisting of glucocorticoids, mineral
corticoids and derivates of these. Depending on the particular
corticoid active ingredient contained in the composition of the
invention, the concentration of this corticoid active ingredient
varies between 0.001 wt. % and 3 wt. %, preferably between 0.1 wt.
% and 0.8 wt. %.
[0040] Preferred glucocorticoids are chosen from the group
consisting of clobetasol-17-propionate, diflucortolone-21-valerate,
amcinonide, betamethasone-17,21-dipropionate,
betamethasone-17-valerate, desocimethasone,
diflucortolone-21-valerate, fluocinolone acetonide, fluocinonide,
fluocortolone, fluprednidene-21-acetate,
fluthicasone-17-propionate, halcinonide,
hydrocortisone-21-acetate-17-propionate,
hydrocortisone-17-butyrate-21-propionate,
hydrocortisone-17-butyrate, methylpredisolonaceponate, momethasone,
momethasone furoate, prednicarbate, triamcinolonacetonide,
clobethasone butyrate, clocortolone-21-pivalate, fluocortinbutyl,
flumethasone-21-pivalate, hydrocortisone and derivates of the
aforementioned substances.
[0041] Another embodiment of the composition according to the
invention proposes that the composition of the invention contain,
as active ingredient, at least one topical anesthetic, especially a
topical anesthetic that is chosen from the above indicated special
topical anesthetics, and the concentration of this topical
anesthetic, depending on the particular active ingredient, varies
in particular between 3 wt. % and 15 wt. %, especially between 6
wt. % and 12 wt. %, in terms of the concentration of active
ingredient in the liquid composition.
[0042] Especially preferred topical anesthetics are chosen from the
group consisting of benzocaine, procaine, tetracaine, lidocaine,
etidocaine, prilocaine, mepivacaine, bupivacaine, S-ropivacaine,
articaine and their derivates.
[0043] Another embodiment of the composition according to the
invention calls for the composition to contain at least one
immunomodulator in a concentration between 0.03 wt. % and 0.1 wt.
%, and the above indicated special immunomodulators are especially
preferred.
[0044] An especially suitable modification of the composition of
the invention comprises, as an active ingredient or mixture of
active ingredients, a nonopioid analgesic/antiphlogistic agent,
especially a non-opioid analgesic/antiphlogistic that is chosen
from the above indicated special non-opioid
analgesics/antiphlogictics. These include in particular the
salicylates, preferably acetylsalicylic acid and/or diflunisal,
acetic acid derivates such as indomethacin, acemethacin, diclofenac
and/or lonazolac, propionic acid derivates such as ibuprofen,
flurbiprofen, ketoprofen, dexketoprofen, dexibuprofen,
tarenflurbil, nimesulide, naproxen and/or thiaprofen acid, oxicams,
such as pyroxicam, tenoxicam, meloxicam and/or lornoxicam,
anthranylic acid derivates such as mefenaminic acid and/or
flufenaminic acid, aniline derivates such as paracetamol, and
1-phenyl-2,3-dimethyl-3-pyrazolin-5-on derivates, such as
phenazone, propyphenazone and/or metamizol, their salts and their
derivates.
[0045] Depending on the particular application of the
above-described embodiments of the composition of the invention,
the concentration of the analgesic/antiphlogistic active ingredient
in the liquid composition will vary between 0.5 wt. % and 8 wt. %,
especially between 1 wt. % and 5 wt. %.
[0046] Of course, it is also possible for the composition of the
invention to include, as active ingredient, a mixture of active
ingredients, as long as this mixture of ingredients is mutually
compatible. Such embodiments of the composition of the invention
will be used for treating generally milder skin ailments, such as
milder forms of eczema, acne, lichen, insect bites, mycoses and/or
treatments of surface wounds with the foam created from the
composition of the invention, in which case the active ingredient
or mixture of active ingredients is chosen from the group
containing terbinafin, clobethasone butyrate, erythromycin,
benzocaine, dexamethasone, calcipotriol, tretinoin, minoxidil,
bifonazole, dexpanthenol, salicylic acid, prednicarbate,
momethasone furoate.
[0047] It should be clarified that all concentration figures
indicated in this specification refer each time to the liquid
composition prior to its foaming, unless otherwise expressly
indicated.
[0048] An especially suitable embodiment of the composition of the
invention includes, as the phospholipid foaming agent, a
phosphatidyl choline isolated from soy beans, and in particular the
concentration of this phosphatidyl choline in the phospholipid
foaming agent is more than 50 wt. %, preferably between 50 wt. %
and 95 wt. %, in relation to the dry substance of the phospholipid
foaming agent.
[0049] Especially when this phospholipid foaming agent contains at
most 15 wt. % of lyso-phosphatidyl choline, at most 10 wt. % of
phosphatidic acid and at most 10 wt. % of phosphatidyl
ethanolamine, one can create a foam with this special foaming agent
that can be diversely adapted to the particular requirements of the
application site by varying its concentration.
[0050] Furthermore, in some embodiments, it may be important for
the aforementioned special foaming agent that the phosphatidyl
choline contained in the phospholipid foaming agent have an acid
number of at most 10, a peroxide number of at most 10, and an oil
concentration of at most 6 wt. % in terms of the dry substance of
this phospholipid foaming agent, the liquid composition forming the
basis of the foam has an especially long shelf life, without
requiring a higher concentration of antioxidants or stabilizers,
especially for the aforementioned phospholipid foaming agent.
[0051] Principally it is recorded that the concentration of the
phospholipid foaming agent contained in the liquid composition
should be chosen so that the foams mentioned at the outset for the
method of the invention and for the composition of the invention
and specified by the foam volume and by the foam stability can be
created. Preferably, the liquid composition which is purely
mechanically foamed has the phospholipid foaming agent in a
concentration between 2 wt. % and 25 wt. %, especially in a
concentration between 4 wt. % and 15 wt. %.
[0052] The general remarks given above on the method of the
invention also hold for the composition of the invention, wherein
the composition of the invention contains, besides water,
preferably an alcohol and especially propylene glycol, whose
concentration, depending on the desired and above-specified foam,
varies between 2 wt. % and 25 wt. %, especially between 5 wt. % and
15 wt. %.
[0053] As regards the pH value, it is to point out that especially
the liquid composition of the invention has a pH value that is
skin-tolerated and, depending on the particular site of
application, lies between 4.8 and 8.8.
[0054] In order to assure the above-indicated pH value, it is
especially advantageous to add to the composition of the invention
at least one buffer, especially sodium dihydrogen phosphate
dihydrate and/or disodium hydrogen phosphate dodecahydrate.
[0055] The composition of the invention as described in detail
above can principally be foamed with any suitable foam applicator,
e.g., the applicators made by Rexam/Airspray
(www.rexamairspray.com) and made and marketed under the name M3
mini foamer ("M3 Minischaumer") or those of made by
Calmar/MeadWestvaco (Keltec). According to this special foam
applicators it is refered to EP 0 565 713 and EP 0 613 728 where
further technical details about these foam applicators will be
found.
[0056] Thus, in particular, the present invention contemplates a
foam applicator that includes a composition of the invention as
described in detail above.
[0057] Moreover, the present invention relates to methods for
treatment of the following illnesses.
[0058] In a first embodiment, a method is contemplated that
includes the treatment of atopic eczema or neurodermitis, wherein
the treatment method of the invention involves the applying of a
foam containing an immunomodulator, as is produced in particular
from the previously described composition of the invention, to the
skin of a warm-blooded mammal in need thereof. In particular,
tacrolimus is chosen as the immunomodulator. Depending on the
particular immunomodulator chosen, its concentration will vary
preferably between 0.03 wt. % and 0.1 wt. %.
[0059] In a second embodiment, a method is contemplated for the
treatment of inflammatory or pruritic skin ailments, psoriasis,
dermatitis, neurodermitis or psoriasis in a patient in need
thereof, comprising the application of a foam containing a
glucocorticoid, as is produced in particular from described
compositions, to the skin of a warm-blooded mammal. In particular,
the glucocorticoid in this treatment method is chosen from the
group consisting of betamethasone, dexamethasone, predincarbate,
mometasone furoate and clobetasone butyrate. Depending on the
glucocorticoid, its concentration varies between 0.01 wt. % and 0.4
wt. %.
[0060] In a third embodiment, a method is contemplated for the
treatment of of pain, inflammation, rheumatic ailments or acute
trauma in a patient in need thereof and comprises the application
of a foam containing an analgesic, as is produced in particular
from the previously described composition of the invention, to the
skin of a warm-blooded mammal. Preferably, the analgesic in this
treatment method is chosen from the group consisting of diclofenac,
ketoprofen and ibuprofen. Depending on the analgesic, its
concentration varies between 0.5 wt. % and 10 wt. %.
[0061] In a fourth embodiment, a method is contemplated for the
treatment of of mycotic infections comprises the application of a
foam containing an antimycotic, as is produced in particular from
the previously described composition of the invention, to the skin
or nails respectively hooves of a warm-blooded mammal in need
thereof. Preferably in this treatment method the antimycotic is
chosen from the group comprising bifonazole and terbinafin.
Depending on the antimycotic, its concentration varies between 0.1
wt. % and 20 wt. %, preferably between 2 wt. % and 10 wt. %.
[0062] In a fifth embodiment, a method is contemplated for the
treatment of infections with Gram positive microbes, anaerobic
microbes and mycoplasms, especially for treatment of acne, in a
patient in need thereof, and comprises the application of a foam
containing an antibiotic, as is produced in particular from the
previously described composition of the invention, to the skin of a
warm-blooded mammal. Preferably in this treatment method the
antibiotic chosen is erythromycin, especially in a concentration
between 2 wt. % and 4 wt. %.
[0063] In a sixth embodiment, a method is contemplated for the
treatment of itching of the skin comprises the application of a
foam containing a topical anesthetic, as is produced in particular
from the previously described composition of the invention, to the
skin of a warm-blooded mammal. Preferably in this treatment method
the topical anesthetic chosen is benzocaine and/or lidocaine,
especially in a concentration between 1 wt. % and 20 wt. %,
preferably 2 wt. % and 10 wt. %.
[0064] In a seventh embodiment, a method is contemplated for the
treatment of psoriasis and comprises the application of a foam
containing calcipotriol, as is produced in particular from the
previously described composition of the invention, to the skin of a
warm-blooded mammal in need thereof. Preferably the calcipotriol in
this treatment method is provided in a concentration between 0.005
wt. % and 0.05 wt. %.
[0065] In an eight embodiment, a method is contemplated for the
treatment of acne, especially acne comedonica and acne
papulopustulosa, comprises the application of a foam containing
tretinoin, as is produced in particular from the previously
described composition of the invention, to the skin of a
warm-blooded mammal in need thereof. Preferably in this treatment
method the tretinoin is provided in a concentration between 0.05
wt. % and 0.1 wt. %.
[0066] In a ninth embodiment, a method is contemplated for
treatment of hair loss comprises the application of a foam
containing minoxidil, as is produced in particular from the
previously described composition of the invention, to the skin of a
warm-blooded mammal in need thereof. Preferably in this treatment
method the minoxidil is provided in a concentration between 3 wt. %
and 6 wt. %.
[0067] In a tenth embodiment, a method is contemplated for the
antiseptic treatment of superficial wounds comprises the
application of a foam that includes an antimycotic to the wound of
a warm-blooded mammal in the need thereof, whereby the foam is
preferably produced from the previously described composition of
the invention. In particular in this treatment method the
dexpanthenol is provided in a concentration between 0.03 wt. % and
1 wt. %.
[0068] In an eleventh embodiment, a method is contemplated for the
treatment of herpes and the side effects accompanying herpes in a
patient need thereof and comprises the application of a foam
containing aciclovir, as is produced in particular from the
previously described composition of the invention, to the skin of a
warm-blooded mammal. Preferably in this treatment method the
aciclovir is provided in a concentration between 3 wt. % and 7 wt.
%.
[0069] In a twelfth embodiment, a method is contemplated for the
treatment of mild to medium severe psoriasis of the scalp in a
patient in need thereof and comprises the application of a foam
containing salicylic acid, as is produced in particular from the
previously described composition of the invention, to the scalp of
a warm-blooded mammal. Preferably in this treatment method the
salicylic acid is provided in a concentration between 8 wt. % and
12 wt. %.
[0070] In the above description of the different embodiments of the
method of treatment of the invention the term application is used
in the singular. However, this should also refer to the repeated
application, at intervals of time, within a given period,
especially within 24 hours.
[0071] Likewise, the term skin used throughout the text covers not
only the particular ailing regions of the skin, but also all
surfaces of the human or animal body accessible to the application
of the foam produced from the composition of the invention, and
thus in particular, besides the skin or scalp itself, also nails,
hair, teeth, hooves or the mucosa in mouth, nose, vagina or
foreskin, the regions of the ear and especially the inner ear, the
region of the anus and the colon, the region of the eyes,
especially the region under the eyelid, such as conjunctiva, cornea
and lacrial sac, while the term mammal comprises animals and
humans.
[0072] For clarity, and to avoid repetition, it is pointed out that
the remarks, details and benefits described at the outset in
connection with the method of the invention also apply accordingly
for the composition of the invention and also the above described
treatment procedure of the invention, as do the remarks, details
and benefits described in connection with the composition of the
invention for the method of the invention and the treatment
procedure of the invention.
[0073] Furthermore the present invention concerns a topically
applicable liquid composition comprising at least one phosphlipidic
foaming agent, at least one pharmaceutical active ingredient and at
least one solvent. The inventive composition is foamable
exclusively by a mechanically foaming without using an propellant
to such an extent, that by mechanically foaming of 250 ml of the
liquid composition a foam is created having a foam volume of at
least 400 ml and a foam stability, that the foam still has after a
dwell time of nearly five minutes and preferably of a dwell time up
to five minutes, measured at 25 .degree. C., at least 50% of the
foam volume that was originally present immediately after the
creation of the foam. Both the afore mentioned foam volume and the
afore mentioned foam stability are measured by a standardized SITA
foam measurement method, described hereafter. In connection
herewith it is to note, that the liquid composition, specified by
the foam volume and foam stability, is exclusively mechanically
foamed prior to use without using a propellant, as repeated
described before, so that the foam, created in that way is used for
topical application. This embodiment of the inventive composition
has identical or analogue all the benefits, as described before.
This is also the same for the afore described embodiments.
[0074] Preferably the afore described inventive composition has a
foam volume, which varies between 450 ml and 1400 ml, especially
between 600 ml and 1200 ml.
[0075] Especially when the inventive composition has such a foam
stability, that after five minutes after creating the foam a foam
volume results, that correspondes to 55% till 85% of the foam
volume, immediately after creating the foam, this embodiment of the
inventive composition has a high pharmaceutical efficacy. This
advantage is also present, when the foam volume is within ten
minutes after creating the foam at least 50%, preferably between
85% and 100%, of the foam volume that was originally present
immediately after the creation of the foam.
[0076] Especially has the foam created from the inventive liquid
composition a density between 0.05 g/ml and 0.8 g/ml, preferably
between 0.15 g/ml and 0.4 g/ml.
[0077] Concerning the solvent contained in the inventive
composition it is to point out, that this solvent is preferably an
anorganic and/or an organic solvent, whereby the anorganic solvent
is preferably water and the organic solvent is an alcohol or a
mixture of alcohols and more preferably a polyalcohol and/or is the
solvents described before in claim 5.
[0078] Furthermore the present invention preferably concerns a
method for making and/or development of a foamable liquid
composition, for topical use, whereby the inventive method
comprises the following steps: [0079] a. providing a liquid
composition comprising at least one pharmaceutically active
ingredient, at least one solvent, and at least one foaming agent,
preferably at least one phospholipidic foam agent; [0080] b.
mechanically creating a foam of the liquid composition; [0081] c.
scanning the foam surface to determine the stability and the volume
of the foam; [0082] d. varying the concentration of at least one of
the pharmaceutically active ingredient, the at least one solvent,
or the at least one foaming agent; [0083] e. repeating steps b and
c until 250 ml of the liquid composition, after the mechanical
creation of the foam, has a foam volume of at least 400 ml and such
a foam stability that at least about 50% of the original foam
volume is still present after about 5 minutes at 25.degree. C.
[0084] Also this inventive method has identical or analogue the
afore described benefits and embodiments.
[0085] The present invention shall be further described hereafter
by means of the following Examples.
EXAMPLES
[0086] Description of the SITA Measurement Method
[0087] For the determination of the foam volume and the foam
stability, a "SITA foam tester R-2000" (manufactured by SITA
Messtechnik GmbH, Dresden) was used, as is described in detail in
EP 1 092 970. This measurement device was provided with a rotor as
shown in FIGS. 2 and 3 of DE 197 40 095 and also described there.
This rotor consists of a stirring shaft and a circular disk
oriented perpendicular to this, with a diameter of 70 mm, above and
below the circular disk there being provided four symmetrical
stirring blades, oriented at right angles to each other. Each
stirring blade has a rectangular base surface of 23 mm.times.12 mm.
In cross section, each stirring blade has the shape of a triangle,
with a height of 5 mm, so that each stirring surface accordingly
forms a roof with a ridge angle of 90 degrees. The stirring blades
each consist of a Conidur fine perforated plate (manufactured by
HeinLehmann, Krefeld) and have a plate thickness of 0.5 mm, a
perforation of 0.5 and a spacing of 3.2.
[0088] In all measurements, the sample volume was 250 ml, being
automatically withdrawn by the measuring device from the reservoir
tank, filled with at least 300 ml of sample. The sample was placed
carefully into the reservoir tank, avoiding any foam formation if
possible. After a waiting time of ten minutes, so that any air
bubbles formed during the filling could migrate to the surface and
thus not falsify the volume, 250 ml of the sample being
investigated was drawn into the measuring space and measured.
[0089] With a rotor speed of 2000 rpm, the sample being measured in
the measuring space was subjected to five rotor cycles of 20
seconds each to create the foam. Between rotor cycles there was a
pause of around 15 seconds.
[0090] By means of the sensors described in DE 199 49 922, which
automatically and continuously scanned the foam surface, the foam
volume was measured immediately after the five rotor cycles were
completed. The foam stability was automatically detected by the
instrument over a period of 35 minutes in total for which the foam
volume was measured every 50 seconds by means of the needle
detectors. The volume values so obtained were recorded directly by
dedicated software and hardware of the instrument.
[0091] The control system of the SITA foam tester is such that,
after the measurement space is filled with 250 ml of sample, the
needle detectors travel only as far as the surface of the sample
and, accordingly, place the zero point for the foam volume on the
surface of the measurement sample and not on the floor of the
measurement space. After elapsing of the aforementioned rotor
cycles for foaming the particular sample, there sometimes remained
in the measurement space a liquid phase of the sample, depending on
the composition of the particular sample being investigated, so
that the volume of this liquid phase was also detected in the above
described measurement according to the particular measurement value
of the foam volume and is defined accordingly as foam volume in the
sense of the present specification, while the time change in this
foam volume is the foam stability. In other words, this means that,
depending on the particular sample measured, the foam volume
consists not only of the volume of the actual foam, but also of the
volume of nonfoamed liquid sample remaining in the measurement
space.
[0092] The following charts 1 to 19 plot all three measurement
values for the particular composition, so that the reproducibility
of the measurement method can be seen quite well from this.
[0093] All the following examples in which diclofenac is indicated
as the active ingredient contain this active ingredient in the form
of the sodium salt of diclofenac, meaning as diclofenac-sodium.
ExampleS 1 to 5
[0094] Following the customary procedure, a composition containing
ketoprofen, one containing lidocaine hydrochloride, one containing
prednicarbate, one containing diclofenac and one containing
clotrimazol were prepared, having the following ingredients:
TABLE-US-00001 Composition in Ingredient wt. % 1 Ketoprofen 10.00 2
Propylene glycol 10.00 3 2-Propanol 8.00 4 Phospholipid foaming
agent A 10.00 5 Sodium hydrogen phosphate dihydrate 0.25 6 Disodium
hydrogen phosphate dodecahydrate, cryst. 0.57 7 Sodium hydroxide
1.55 8 Peppermint oil 0.15 9 Ultrapure water 59.48 TOTAL 100.00
[0095] The foam behavior of this composition 1 is shown in FIG.
1.
TABLE-US-00002 Composition Ingredient in wt. % 1 Lidocaine
hydrochloride 10.00 2 Propylene glycol 10.00 3 2-Propanol 11.00 4
Phospholipid foaming agent A 10.00 5 Sodium dihydrogen phosphate
dihydrate 0.12 6 Disodium hydrogen phosphate dodecahydrate, cryst.
0.66 7 Sodium hydroxide 20% w/w 4.00 8 Peppermint oil 0.15 9
Ultrapure water 54.07 TOTAL 100.00
[0096] The foam behavior of this composition 2 is shown in FIG.
2.
TABLE-US-00003 Composition Ingredient in wt. % 1 Prednicarbate 0.10
2 Propylene glycol 15.00 3 2-Propanol 9.35 4 Phospholipid foaming
agent B 5.00 5 Sodium dihydrogen phosphate dihydrate 0.50 6
Disodium hydrogen phosphate dodecahydrate, cryst. 1.14 7 Sodium
hydroxide 10% w/w 1.00 8 Tegosoft GC 8.60 9 Ultrapure water 59.31
TOTAL 100.00
[0097] The foam behavior of this composition 3 is shown in FIG.
3.
TABLE-US-00004 Composition in Ingredient wt. % 1 Clotrimazol 0.5 2
Propylene glycol 20.00 3 2-Propanol 8.00 4 Phospholipid foaming
agent A 8.00 5 Sodium dihydrogen phosphate dihydrate 0.12 6
Disodium hydrogen phosphate dodecahydrate, cryst. 0.66 7 Sodium
hydroxide 20% w/w 1.00 8 Peppermint oil 0.20 9 Polysorbate 80 13.00
10 Ultrapure water 48.52 TOTAL 100.00
[0098] The foam behavior of this composition 5 is shown in FIG.
5.
[0099] Twenty subjects (11 female, 9 male) suffering from fungal
disease between the toes and also partly on the toe nails had the
fungally attacked regions of the left foot treated twice daily with
a foam prepared by the above-described SITA measurement method. The
treatment was done in that the ailing area was covered with a foam
layer around 0.5 to 1 cm thick and then this foam was manually
rubbed in. The total treatment time lasted up to 14 days.
[0100] The ailing area of the right foot was treated with a
composition 5, identical in ingredients, while this composition 5
was foamed by means of a "M3 mini foamer" from Rexam/Airspray
immediately prior to application.
[0101] Regardless of which foam had been applied to the ailing
areas, 16 subjects reported a direct decrease in itching already
after the first application of the particular foam. Two other
subjects reported this decrease in itching after a two-time
application, and the remaining two subjects reported the decrease
in itching after a four-time application.
[0102] In ten subjects, the fungal infections were eliminated after
a total treatment time of eight days, in six subjects the healing
time was eleven days, and in four subjects the healing time was 14
days. It is to be noted that the latter four subjects were the most
heavily affected by the fungal infection. No subject could find a
difference between the foam created by the SITA measurement method
and the foam produced by the "M3 mini foamer".
Examples 6 to 8
[0103] In order to investigate the influence of the concentration
of active ingredient on the foam formation, the following
compositions 6 to 8 were prepared and investigated in regard to the
concentrations of active ingredient diclofenac.
TABLE-US-00005 Composition in Ingredient wt. % 1 Diclofenac 1.000 2
Propylene glycol 15.000 3 2-Propanol 10.250 4 Ascorbylpalmitate
0.020 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen
phosphate dihydrate, 0.120 ultrapure 7 Disodium hydrogen phosphate
dodecahydrate, cryst. 0.660 8 EDTA 0.040 9 Ultrapure water 59.380
10 Peppermint oil, rectified 0.200 TOTAL 100.00
[0104] The foam behavior of this composition 6 is shown in FIG.
6.
TABLE-US-00006 Composition in Ingredient wt. % 1 Diclofenac 2.000 2
Propylene glycol 15.000 3 2-Propanol 10.250 4 Ascorbylpalmitate
0.020 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen
phosphate dihydrate 0.120 7 Disodium hydrogen phosphate
dodecahydrate, cryst. 0.660 8 EDTA 0.040 9 Ultrapure water 58.380
10 Peppermint oil, rectified 0.200 TOTAL 100.00
[0105] The foam behavior of this composition 7 is shown in FIG.
7.
TABLE-US-00007 Composition in Ingredient wt. % 1 Diclofenac 8.000 2
Propylene glycol 15.000 3 2-Propanol 10.250 4 Ascorbylpalmitate
0.020 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen
phosphate dihydrate 0.120 7 Disodium hydrogen phosphate
dodecahydrate, cryst. 0.660 8 EDTA, Titriplex III 0.040 9 Ultrapure
water 52.380 10 Peppermint oil, rectified 0.200 TOTAL 100.00
[0106] The foam behavior of this compsition 8 is shown in FIG.
8.
[0107] Based on the comparison of the compositions 6 to 8 and the
corresponding FIGS. 6 to 8, one can say that the foam volume
increases with practically unchanged foam stability as the
concentration of active ingredient increases.
Examples 9 to 11
[0108] In order to investigate the influence of the concentration
of phospholipid foaming agent on the foam formation, the following
compositions 9 to 11 were prepared and investigated in regard to
the concentration of phospholipid foaming agent.
TABLE-US-00008 Composition in Ingredient wt. % 1 Diclofenac 4.000 2
1,2-propane diol 15.000 3 2-Propanol 10.250 4 L (+)
ascorbylpalmitate 0.020 5 Phospholipid foaming agent A 2.000 6
Sodium dihydrogen phosphate dihydrate, ultrapure 0.120 7 Disodium
hydrogen phosphate 0.660 dodecahydrate, ultrapure 8 EDTA 0.040 9
Ultrapure water 67.710 10 Peppermint oil, rectified 0.200 TOTAL
100.00
[0109] The foam behavior of this composition 9 is shown in FIG.
9.
TABLE-US-00009 Composition in Ingredient wt. % 1 Diclofenac 4.000 2
1,2-propane diol 15.000 3 2-Propanol 10.250 4 L (+)
ascorbylpalmitate 0.020 5 Phospholipid foaming agent A 5.000 6
Sodium dihydrogen phosphate dihydrate, ultrapure 0.120 7 Disodium
hydrogen phosphate dodecahydrate, 0.660 ultrapure 8 EDTA 0.040 9
Ultrapure water 64.710 10 Peppermint oil, rectified 0.200 TOTAL
100.00
[0110] The foam behavior of this composition 10 is shown in FIG.
10.
TABLE-US-00010 Composition in Ingredient wt. % 1 Diclofenac 4.000 2
1,2-propane diol 15.000 3 2-Propanol 10.250 4 L (+)
ascorbylpalmitate 0.020 5 Phospholipid foaming agent A 20.000 6
Sodium dihydrogen phosphate dihydrate, ultrapure 0.120 7 Disodium
hydrogen phosphate 0.660 dodecahydrate, ultrapure 8 EDTA, Titriplex
III 0.040 9 Ultrapure water 49.710 10 Peppermint oil, rectified
0.200 TOTAL 100.00
[0111] The foam behavior of this composition 11 is shown in FIG.
11.
[0112] Based on the comparison of the compositions 9 to 11 and the
corresponding FIGS. 9 to 11, one can say that the foam volume
decreases with practically unchanged foam stability as the
concentration of the phospholipid foaming agent increases.
Examples 12 to 14
[0113] In order to investigate the influence of the concentration
of isopropanol on the foam formation, the following compositions 12
to 14 were prepared and investigated in regard to the concentration
of isopropanol.
TABLE-US-00011 Composition Ingredient in wt. % 1 Diclofenac 4.000 2
Propylene glycol 15.000 3 2-Propanol 5.000 4 Ascorbylpalmitate
0.020 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen
phosphate dihydrate 0.120 7 Disodium hydrogen phosphate
dodecahydrate, cryst. 0.660 8 EDTA 0.040 9 Ultrapure water 61.630
10 Peppermint oil, rectified 0.200 TOTAL 100.00
[0114] The foam behavior of this composition 12 is shown in FIG.
12.
TABLE-US-00012 Composition Ingredient in wt. % 1 Diclofenac 4.000 2
Propylene glycol 15.000 3 2-Propanol 10.000 4 Ascorbylpalmitate
0.020 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen
phosphate dihydrate 0.120 7 Disodium hydrogen phosphate
dodecahydrate, cryst. 0.660 8 EDTA 0.040 9 Ultrapure water 56.630
10 Peppermint oil, rectified 0.200 TOTAL 100.00
[0115] The foam behavior of this composition 13 is shown in FIG.
13.
TABLE-US-00013 Composition Ingredient in wt. % 1 Diclofenac 4.000 2
Propylene glycol 15.000 3 2-Propanol 20.000 4 Ascorbylpalmitate
0.020 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen
phosphate dihydrate 0.120 7 Disodium hydrogen phosphate
dodecahydrate, cryst. 0.660 8 EDTA 0.040 9 Ultrapure water 46.630
10 Peppermint oil, rectified 0.200 TOTAL 100.00
[0116] The foam behavior of this composition 14 is shown in FIG.
14.
[0117] Based on the comparison of the compositions 12 to 14 and the
corresponding FIGS. 12 to 14, one can say that the foam volume
increases as a function of the concentration of isopropanol with
rising concentration of isopropanol from 5 wt. % to 10 wt. % and
then decreases again in the range of 10 wt. % to 20 wt. %, so that
no stable foam is formed at a concentration of 20 wt. % of
isopropanol. The slight foam volume shown initially in FIG. 14
should be disregarded.
Examples 15 to 17
[0118] In order to investigate the influence of the concentration
of propylene glycol on the foam formation, the following
compositions 15 to 17 were prepared, differing in terms of the
concentration of propylene glycol.
TABLE-US-00014 Composition in Ingredient wt. % 1 Diclofenac 4.000 2
1,2-propane diol 5.000 3 2-Propanol 10.250 4 L (+)
ascorbylpalmitate 0.020 5 Phospholipid foaming agent A 13.330 6
Sodium dihydrogen phosphate dihydrate, ultrapure 0.120 7 Disodium
hydrogen phosphate dodecahydrate, 0.660 ultrapure 8 EDTA 0.040 9
Ultrapure water 66.380 10 Peppermint oil, rectified 0.200 TOTAL
100.00
[0119] The foam behavior of this composition 15 is shown in FIG.
15.
TABLE-US-00015 Composition in Ingredient wt. % 1 Diclofenac 4.000 2
1,2-propane diol 10.000 3 2-Propanol 10.250 4 L (+)
ascorbylpalmitate 0.020 5 Phospholipid foaming agent A 13.330 6
Sodium dihydrogen phosphate dihydrate, ultrapure 0.120 7 Disodium
hydrogen phosphate dodecahydrate, 0.660 ultrapure 8 EDTA 0.040 9
Ultrapure water 61.380 10 Peppermint oil, rectified 0.200 TOTAL
100.00
[0120] The foam behavior of this composition 16 is shown in FIG.
16.
TABLE-US-00016 Composition in Ingredient wt. % 1 Diclofenac 4.000 2
1,2-propane diol 20.000 3 2-Propanol 10.250 4 L (+)
ascorbylpalmitate 0.020 5 Phospholipid foaming agent A 13.330 6
Sodium dihydrogen phosphate dihydrate, 0.120 ultrapure 7 Disodium
hydrogen phosphate dodecahydrate, 0.660 ultrapure 8 EDTA 0.040 9
Ultrapure water 51.380 10 Peppermint oil, rectified 0.200 TOTAL
100.00
[0121] The foam behavior of this composition 17 is shown in FIG.
17.
[0122] Based on the comparison of the compositions 15 to 17 and the
corresponding FIGS. 15 to 17, one can say that the concentration of
propylene glycol has no or only a very slight influence on the foam
volume and the foam stability.
Example 18
[0123] In a comparison investigation on 14 subjects (8 female, 6
male) with pronounced acne in the facial region, the subjects were
treated twice daily (morning and evening) with a foam that was made
from a composition whose ingredients are quantified in the
following table per composition 18.
TABLE-US-00017 Composition in Ingredient wt. % 1 Erythromycin 1.50
2 Propylene glycol 15.00 3 2-Propanol 9.35 4 Phospholipid foaming
agent B 8.00 5 Sodium dihydrogen phosphate-dihydrate 0.50 6
Disodium hydrogen phosphate-dodecahydrate 1.14 cryst. 7 Sodium
hydroxide 10% w/w 1.00 8 Tegosoft GC 7.70 9 Ultrapure water 55.81
TOTAL 100.00
[0124] The foaming behavior of this composition 18 is shown in FIG.
18.
[0125] The treatment was done per application with a defined amount
of 0.4 mg foam per half of the face. The foam was applied directly
to the area being treated and massaged in by circular motions with
2 fingers. The total therapy time amounted to 60 days.
[0126] Each time the left half of the face of each subject was
treated with the foam made by means of the above-described SITA
measurement method and the right half of the face of each subject
by means of a foam made with an "M3 minifoamer" of Rexam/Airspray,
both foams being prepared from composition 18.
[0127] The first success could already be determined for both foams
after 30 days application: the lesions on the left side of the face
were reduced by around 19% and those of the right half by around
21%.
[0128] At the final evaluation on day 60 of the investigation, a
decrease in lesions by around 36% was found for the left half of
the face and a decrease of around 34% for the right half of the
face. It was not possible to determine a significant difference
between the two halves of the face. None of the subjects perceived
the treatment to be unpleasant or reported painful irritation of
the treated areas. Neither could any differences be established in
the toleration of the treatment between the two halves of the
face.
Example 19
[0129] In a double-blind, randomized and placebo-controlled
comparative study of 12 subjects (5 female, 7 male) we investigated
the efficacy [0130] a) of the above-described composition 10,
containing 4% diclofenac-sodium, [0131] b) of the above-described
composition 1, containing 10% ketoprofen, and [0132] c) the
efficacy of a ketoprofen-free composition, which was identical to
composition 1 in terms of ingredients 2 to 9, this ketoprofen-free
composition having no ketoprofen and instead having 10 wt. % more
water than composition 1, in the treatment of an artificially
induced UV erythema. All foams used were produced by means of the
above-described SITA measurement method, as well as the "M3
minifoamer" of Rexam/Airspray, based on the same starting
compositions.
[0133] The artificial UV erythemas were created at 16 test fields
(each one 2.times.2 cm) on the back, 4 test fields to each the left
and right of the spinal column, as well as 4 test fields each in
the upper and lower region of the back. The 8 upper test fields
were exposed to a UV dose of 1.5.times.MED and the lower test
fields with 2.5.times.MED.
[0134] After the UV exposure, ECG rings with an inner diameter of
16 mm were glued to the centers of the UV-exposed test fields. The
untreated fields were likewise marked with ECG rings. The distance
between the test fields was around 3 cm.
[0135] Next, around 10-15 minutes from the end of the UV exposure,
a dose of 25 .mu.g foam according to a random list was applied in
the ECG rings and evenly distributed using a round spatula.
[0136] The foam behavior of composition 19 c) (ketoprofen-free
composition) is shown in FIG. 19.
[0137] Evaluation of the differences was done by the optical
examination of a dermatologist. This was based on the
internationally recognized visual evaluation method of 0=no visible
erythema to 4=intensive erythema for the untreated surface and the
evaluation -1=intensive erythema to 3=completely suppressed
erythema for the irradiated and treated areas. Checks were done
after 2, 3, 4, 5, 6 and 8 hours on the same day as the
application.
[0138] Between the foams produced according to the SITA measurement
method and those using the "M3 minifoamer", a slight difference for
the active ingredient, ketoprofen, was found only at one
measurement time point: 6 hours. This difference was not
significant. Here, an erythema value of 2 was found for the foam
that was made according to the SITA measurement method and a value
of 1 for the foam that was made by means of the "M3 minifoamer". No
other differences could be found between the foams produced in
different ways and containing the active ingredient.
[0139] In comparison with the ketoprofen-free composition (c) and
the untreated test fields, the foams containing active ingredient
showed distinct differences at 1.5 MED and 2.5 MED in the final
measurement after 8 hours.
[0140] Especially at 2.5 MED, a value of 1 was found for the foam
containing diclofenac (slight suppression of the erythema, easily
identifiable), a value of 2 for the foam containing ketoprofen
(distinct suppression of the erythema but still visible) and a
value of -1 for the ketoprofen-free foam (more pronounced
erythema). The foam made from the composition containing ketoprofen
shows a clear therapeutic superiority over the foam containing
diclofenac, the ketoprofen-free foam, and the untreated test
fields.
[0141] All foams containing active ingredient showed a good
toleration. Only for the ketoprofen-free foam three (3) side
effects were found.
[0142] The phospholipid foaming agent A used above in examples 1
and 2, as well as 4 to 17, has the following composition, with the
following values referring to the dry substance.
TABLE-US-00018 Phosphatidyl choline 80 wt. % .+-. 10 wt. %
Lysophosphatidyl choline 3 wt. % .+-. 3 wt. % Phosphatidic acid
.ltoreq.8 wt. % Phosphatidyl ethanolamine .ltoreq.4 wt. % Other
oily components max. 6 wt. % Acid number 2 Peroxide number 6
[0143] The phospholipid foaming agent B used above in examples 3
and 18 has the following composition, with the following values
referring to the dry substance.
TABLE-US-00019 Phosphatidyl choline 85 wt. % .+-. 10 wt. %
Lysophosphatidyl choline 3 wt. % .+-. 3 wt. % Tocopherol max. 0.3
wt. % Acid number 1 Peroxide number 5
[0144] The above indicated peroxide number indicates the
milliequivalents of oxygen which are contained in 1000 g of a
sample (dry substance). This value, after reacting the sample with
potassium iodide in a mixture of chloroform and acetic acid, is
determined by titrating the iodine produced in this way with sodium
thiosulfate and a potentiometric determination.
[0145] The acid number indicates how many mg of potassium hydroxide
are needed to neutralize the free, nonesterified fatty acids that
are contained in 1 g of phospholipid foaming agent (dry substance).
This value is determined by titration of a corresponding dissolved
sample with potassium hydroxide solution, using phenolphthalein as
indicator.
* * * * *