Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITION, ESPECIALLY IN THE FORM OF A LUBRICANT GEL
COMPRISING A LOCAL ANAESTHETIC AND POLYHEXAN1DE
The present invention relates to the field of medicine
or medical technology. More particularly, the present
invention relates to the field of medically useful
catheters which can be especially in the form of
bladder catheters and/or fistula catheters, and to the
area of compositions or lubricants especially useful
for facilitating or improving catheterization. The
present invention also relates to the area of
endoscopy, especially in connection with the medical
use of endoscopies or medical probes.
More particularly, the present invention relates to a
composition, more particularly a pharmaceutical
composition, preferably, in the form of a lubricant gel
and/or lubricant, which can be used as a (local)
antiseptic and/or (local) anesthetic, and which can he
used in diagnostic and/or therapeutic (surgical)
procedures, preferably in catheterizations, probings,
endoscopies, intubations and/or obstetrical procedures
or the like.
Furthermore, the present invention relates to the use
of the composition according to the invention as a
(local) antiseptic and/or (local)
anesthetic,
especially in diagnostic and/or therapeutic (surgical)
procedures, preferably in catheterizations.
Lastly, the present invention relates to containers,
catheters, packaging units and kits which comprise the
composition according to the invention.
As part of medical procedures for diagnostic,
therapeutic or prophylactic purposes, it is frequently
necessary to insert medical instruments, such as
catheters, into the human or animal body via preferably
natural body openings, but also via artificial or
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surgically established body openings. Examples of such
procedures include catheterizations of the bladder, it
being possible to carry out said catheterizations in a
transurethral manner or a percutaneous or suprapubic
manner, probings, endoscopies, intubations and
obstetrical procedures.
In the area of urology, catheters are frequently used
as part of diagnostic and therapeutic methods, for
example in order to drain urine from the bladder or the
kidneys or in order to introduce medicaments or
contrast agents into the urogenital tract. A
distinction is made here between percutaneous,
especially suprapubic, catheters, which are guided
through the skin into the bladder or into the renal
pelvis, and transurethral catheters, which are inserted
along the urethra or through the urethra into the body
or into the bladder. Percutaneous or suprapubic bladder
and kidney catheters are primarily used for a prolonged
catheter retention time or in cases in which the use of
a transurethral catheter is too risky. By contrast,
transurethral catheters are preferably used as
disposable catheters in diagnostic methods or as long-
term catheters generally with a retention time of a few
days.
The advantage of transurethral catheters is that, when
used properly, they are substantially more gentle for
the patient, especially since injuries associated with
the placement of the catheter are minimized.
Nevertheless, placement of a transurethral catheter -
known as catheterization - is a process which is
frequently described as very unpleasant or as even
painful and in which there is additionally the risk of
urogenital tract injuries. In the prior art,
catheterization is facilitated by using auxiliary
agents, such as lubricants for example. However, these
are frequently merely unsatisfactory with respect to
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the improvement in catheterization that is sought after
and with regard to ensuring lower adverse effects
during the retention of the catheter in the body.
In order also to achieve a reduction in friction
between medical instruments, such as catheters or
probes or endoscopes, and skin or mucosa or the body
opening, it has been found to be advantageous to use
lubricants or lubricant gels as auxiliary agents, so as
to prevent skin irritations, pain and injuries due to
the procedure or the catheterization. Furthermore, in
connection with procedures of the aforementioned type,
it is advantageous when a disinfection of the skin or
mucosa in the treated area is carried out
simultaneously in order to prevent infections and
inflammations.
In this connection, first-generation lubricants are
predominantly based on fatty or oily substances, though
this is disadvantageous in many respects, especially
with respect to sterility and wetting properties.
Lubricants meanwhile typically consist of a fat-free
gel which may optionally contain an antiseptic active
ingredient and/or antiseptic ingredient for reducing
the microbial count. Furthermore, it is possible for
lubricants or lubricant gels to contain a local
anesthetic in order to alleviate the pain during the
procedure.
Although the lubricants or lubricant gels known from
the prior art sometimes have improved wetting or
lubricating properties with respect to oil- and fat-
based lubricants used in the first-generation
lubricants, they are not always optimal with regard to
their action and use, especially with respect to
efficacy or onset of action and tolerability.
Especially the action of the optionally used local
anesthetic is not always sufficient, and so there is no
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satisfactory or sufficient alleviation of pain. In
particular, there is frequently no optimal coordination
with the other components of the lubricant, and so the
efficiency of action of the local anesthetic as such is
not always optimized especially with respect to its
efficacy or availability at the site of action.
With respect too to antimicrobial or antiseptic
properties, the lubricants of the prior art are not
always satisfactory, this being linked especially to
the antiseptic active ingredients and/or antiseptic
ingredients that are typically used. For instance,
chlorhexidine or octenidine are frequently used in the
prior art as antiseptic components in lubricant gels or
lubricants. However, a disadvantage in this case is the
not always optimal tolerability. Although efficacy is
altogether at least sufficient, it is not always
optimal, since the onset of action is sometimes delayed
and is, furthermore, frequently not sufficiently long-
lasting.
Furthermore, especially the use of chlorhexidine is,
under certain circumstances, associated with a
development of resistances with respect to various
microorganisms, and this is disadvantageous in many
respects in view of the hospital microbes that
frequently emerge. Sometimes, the mere use of
chlorhexidine is enough to promote the development of
further resistant microorganisms, and there is
furthermore no effective protection against pathogens
or microorganisms that are already resistant.
Chlorhexidine in particular exhibits no action or
virtually no action in the case of certain microbes of
the species Staphylococcus aureus, and this cannot be
compensated for even by an increase in concentration of
the active ingredient. Moreover, it is also barely
possible to effectively control or break up biofilms
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using chlorhexidine Or octenidine. Furthermore,
chlorhexidine and octenidine exhibit a certain
cytotoxicity especially in the event of a high
concentration or misuse, and this can be problematic
especially with respect to wound healing or wound
antisepsis. Wound healing in particular will be slowed
by octenidine and chlorhexidine under such
circumstances.
Therefore, the lubricants or lubricant gels known in
the prior art are not always optimal with regard to
their tolerability and their efficiency of action,
especially in terms of wound antisepsis or antiseptic
action and also pain alleviation.
Embodiments of the present invention provide improved
compositions for use as lubricants or lubricant gels
which are capable of preventing or at least reducing
the above-described disadvantages of the lubricants or
lubricant gels known in the prior art.
Embodiments of the present invention provide improved
compositions in the form of lubricants or lubricant
gels, which, with respect to the compositions of the
prior art, exhibit improved antiseptic properties and
also no adverse effects or at least reduced adverse
effects and an improved or quickened onset of action.
Embodiments of the present invention provide
compositions which exhibit improved pain-alleviating
properties.
Embodiments of the claimed invention pertain to a
composition in the form of a lubricant gel and/or a
lubricant for use in catheterizations, probings,
endoscopies, intubations and/or obstetrical procedures,
wherein the composition comprises: (a) a
pharmaceutically effective amount of at least one local
anesthetic as "component (a)- and (b) a
pharmaceutically effective amount of polyhexanide
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and/or salts thereof as "component (b)", wherein the
composition is at least substantially free of
(poly)alkylene glycols; and wherein the composition has
a physiologically compatible pH within the range from 5
to 7.5.
Embodiments of the claimed invention also pertain to a
container containing a composition as disclosed herein.
Embodiments of the claimed invention also pertain to a
packaging unit, containing such a container, wherein
the container has been introduced into outer packaging
providing protection against contamination.
Embodiments of the claimed invention also pertain to a
catheter, wherein the catheter is provided with a
composition as disclosed herein, and wherein the
composition is applied to a segment of the catheter
that is insertable and/or introducible into a body
lumen.
Embodiments of the claimed invention also pertain to a
kit comprising, as spatially separated components, a
catheter and a composition as disclosed herein.
It is self-evident that, hereinafter, special designs,
embodiments or the like which are only described in
connection with one aspect of the invention, also apply
accordingly with regard to the other aspects of the
invention, without this requiring an explicit mention.
Furthermore, in the case of all below-mentioned
relative or percentage amounts, especially weight-based
amounts, it should be noted that they are to be
selected by a person skilled in the art in the context
of the present invention in such a way that the sum of
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the particular ingredients, active ingredients,
additives or excipients or the like is always 100% or
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100% by weight. This, however, is automatically
understood by a person skilled in the art.
Apart from that, it is possible for a person skilled in
the art to deviate from the below-specified numbers,
ranges or amounts on the basis of the application or as
determined by the individual case without departing
from the context of the present invention.
Moreover, all below-stated parameter values or the like
can be fundamentally determined or ascertained using
standardized or explicitly specified methods of
determination or else using methods of determination
that are familiar per se to a person skilled in the
art.
The present invention therefore provides - in a
first aspect of the present invention - a
composition, more particularly a pharmaceutical
composition, preferably in the form of a lubricant gel
and/or lubricant, preferably for use as a (local)
antiseptic and/or (local) anesthetic, especially for
use in diagnostic and/or therapeutic (surgical)
procedures, preferably for use in catheterizations,
preferably transurethral or suprapubic
catheterizations, probings, endoscopies, intubations
and/or obstetrical procedures, wherein the composition
contains in each case in effective amounts, more
particularly in pharmaceutically effective amounts, (a)
at least one local anesthetic ("component (a)") and (b)
polyhexanide and/or the salts thereof ("component
(b)"), more particularly as antiseptic active
ingredient and/or antiseptic ingredient (disinfectant).
This is because, in the context of the present
invention, the applicant has found that, surprisingly,
the specific combination of polyhexanide as antiseptic
active ingredient and/or antiseptic ingredient
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(disinfectant) together with at least one local
anesthetic leads to compositions, preferably for use as
lubricant or lubricant gel in catheterizations or the
like, which have significantly improved properties
compared with lubricant or lubricant gels of the prior
art, especially with respect to tolerability and to a
rapid onset of action coupled with prolonged duration
of action and, simultaneously, excellent pain-
alleviating or analgesic properties.
Moreover, the inventive compositions as such are
especially suited for prophylactic or therapeutic
mucosa/skin disinfection, especially in connection with
catheterizations, endoscopies or the like preferably
carried out in the diagnosis and/or therapy.
The terms "pharmaceutical composition", "pharmaceutical
preparation" or the like, as used in the context of the
present invention, are to be understood in a very broad
manner and do not refer only to pharmaceutical
preparations or pharmaceuticals or drugs as such or in
the narrower sense, but also to so-called medical
devices, homeopathic substances, foodstuffs, food
supplements or the like.
Moreover, the term "mucosa/skin disinfection" used
according to the invention refers especially to a
disinfection or microbe reduction of body regions in
particular, such as skin or mucosa, wherein said
disinfection or microbe reduction is present or is
carried out during the preferably therapeutic or
diagnostic use of catheters, endoscopes or the like and
wherein said body regions are in contact with the
catheters or endoscopes used, specifically especially
for avoiding or reducing the formation of biofilms, for
preventing infections or for preventing the
transmission of, in particular, pathogenic microbes or
pathogens from a medical instrument that is used, such
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as a catheter, to the skin or mucosa in contact
the
As will be explained below, the composition according
to the invention has further numerous advantages and
particularities:
The compositions according to the invention dispense
with the additional use of preservatives - especially
as a result of the distinctly improved antiseptic or
antimicrobial properties substantially caused by the
use of polyhexanide. This further increases the
tolerability of the compositions according to the
invention, and so undesired systemic reactions or
irritations and allergic reactions to any preserving
agents can be ruled out or minimized.
In one embodiment according to the invention, the
composition according to the invention is formed
without any preserving agents or preservatives or is at
least substantially free of preserving agents or
preservatives.
Furthermore, the application and efficacy studies
carried out by the applicant clearly show that the
antiseptic or disinfectant polyhexanide, on the one
hand, and the local anesthetic used according to the
invention, more particularly lidocaine, on the other,
are supplemented or intensified in a synergistic manner
in terms of their efficacy. Firstly, an excellent
antimicrobial performance action, more particularly a
rapid onset of action and a long-lasting duration of
action, is achieved; secondly, the use of the
compositions according to the invention can also
significantly alleviate or reduce pain during
procedures, such as catheterizations, probings,
endoscopies, intubations or obstetrical procedures.
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Furthermore, the use as such of polyhexanide as
antiseptic or as antiseptic active ingredient and/or
antiseptic ingredient (disinfectant) is also
advantageous in many respects. More particularly, the
efficiency of action can be significantly improved
because polyhexanide allows a particularly rapid onset
of action, though the action additionally also lasts
for an extremely long time. Furthermore, when using
polyhexanide as mucosa disinfectant, there is no
appreciable systemic resorption of the active
ingredient, and so the risk of adverse effects
occurring can be distinctly lowered. In this
connection, it should also be emphasized that
polyhexanide does not act cytotoxically, and this
further increases the tolerability of the overall
composition.
Moreover, the antiseptic or the antiseptic active
ingredient and/or antiseptic ingredient (disinfectant)
used according to the invention in the form of
polyhexanide has a particularly broad spectrum of
activity, i.e., it acts both against Gram-positive
pathogens and against Gram-negative pathogens. This is
particularly advantageous in that polyhexanide also has
a good efficiency of action toward the so-called
hospital microbes, such as Staphylococcus aureus.
Without wishing to be restricted to this theory here,
the nonspecific mode of action or interaction of
polyhexanide with the acidic membrane phospholipids of
bacteria or microorganisms prevents resistances to
polyhexanide from being able to be developed.
Moreover, the storage stability of the compositions
according to the invention is increased by the
purposeful use of polyhexanide, since this antiseptic
active ingredient and/or antiseptic ingredient
(disinfectant) as such already has an excellent
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microbial stability, and so a use of (additional)
preserving agents is not required.
Furthermore, it is advantageous that the use of
polyhexanide does not negatively influence wound
healing; on the contrary, wound healing is even
promoted as a result of the high antimicrobial activity
of polyhexanide.
Furthermore, in the context of the present invention,
it has been shown that, surprisingly, the compositions
according to the invention can be improved in terms of
their tolerability when the use of glycols, more
particularly propylene glycol, is dispensed with, since
they or it can lead to intolerabilities, such as mucosa
irritations and allergic reactions. Therefore, in one
embodiment according to the invention, the composition
according to the invention can be at least
substantially free of glycols, more particularly free
of propylene glycols.
Moreover, the composition according to the invention
has a specifically coordinated or adjusted viscosity
and excellent lubrication or gliding properties, and so
the composition according to the invention adheres to
and wets the mucosa in an outstanding manner, allowing
a problem-free gliding or insertion of medical
instruments, such as catheters, probes, endoscopes or
ultrasound probes. The body region in contact with the
medical instrument, such as skin or mucosa, is thus
protected from injuries to the greatest possible
extent. The additional local anesthetic in
conjunction with or in addition to the extraordinarily
good adhesion and lubrication properties of the
composition according to the invention - additionally
results in the underlying procedures for the patients
proceeding in an extremely gentle and pain-free manner.
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The compositions according to the invention in the form
of lubricants or lubricant gels are designed in such a
way that they wet and adhere to the mucosae in an
optimal manner and moreover have excellent lubricant
properties. This makes it possible to carry out
diagnostic or therapeutic procedures very much more
easily and rapidly, and the risk of mucosa injuries in
the region of the examined tissue or body part is
simultaneously minimized, as mentioned above.
In the case of the below-specified substances which may
be present in the composition according to the
invention, reference is always made to the compounds
which can be mixed into or added to the composition. It
is possible here that the compounds are converted into
other substances owing to reactions; more particularly,
acid/base reactions are possible, i.e., the substances
used may, for example, be protonated or deprotonated.
However, this is known per se to a person skilled in
the art.
The polyhexanide used according to the invention has an
antiseptic or antimicrobial action. Chemically, the
active ingredient polyhexanide is generally
polyhexamethylene biguanide (PHMB), which can be
synonymously also referred to as
poly(iminocarbonimidoyliminocarbonimidoylimino-1,6-
hexanediyl) hydrochloride or polyhexanide and has in
particular the molecular formula C81-117N5 and a molecular
weight of 183.25 g/mol.
An advantage of polyhexanide is in particular its broad
spectrum of activity, which is also directed against
the difficult-to-treat hospital microbes, such as
Staphylococcus aureus for example. Furthermore,
polyhexanide acts even in extremely low concentrations,
since it binds directly to the bacterial cell wall and
damages said wall in such a way that the result is
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typically cell death. This makes possible the effective
use of this antiseptic even in low concentrations,
lowering accordingly the risk of the occurence of
adverse effects. Furthermore, polyhexanide has a low
systemic resorption, leading equally to a minimization
of adverse effects.
The term "local anesthetics", as used according to the
invention, is generally understood in the context of
the present invention to mean anesthetics having a
locally confined action or for the purpose of local
pain relief or anesthesia, and in particular the local
anesthetics used in the context of the inventive use
should not have any euphorigenic or habit-forming
action. The chemical structure of the underlying local
anesthetics is fundamentally similar. It generally
comprises a lipophilic aromatic ring structure, an
intermediate chain and a hydrophilic amino group.
Depending on the intermediate chain, a distinction is
made between amino esters ("ester type") and amino
amides ("amide type"). The amino esters are metabolized
in tissue by a cholinesterase; the degradation of the
amino amides takes place in the liver by N-dealkylation
or hydrolysis. In particular - without wishing to be
restricted to this theory - local anesthetics develop
their action on the cell membrane of nerve cells, with
the formation and conduction of sensations, such as
temperature, pressure or pain, being attenuated or
completely interrupted in a local manner.
With regard to the local anesthetic used according to
the invention, it is possible in the context of the
present invention to use a range of substances which
are effective as local anesthetic and which are well
known per se to a person skilled in the art. However,
according to the invention, it is preferred when the
local anesthetic is selected from the group of local
anesthetics of the ester type, more particularly amino
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esters, and local anesthetics of the amide type, more
particularly amino amides, and also the mixtures or
combination thereof, more particularly from lidocaine,
mepivacaine, prilocaine, bupivacaine, articaine and
ropivacaine and also the mixtures or combination
thereof, particularly preferably lidocaine.
In the context of the present invention, particularly
good results are achieved when the local anesthetic is
lidocaine. In this case, the local anesthetic is one of
the amide type, which has a good efficacy coupled with,
simultaneously, a rapid onset of action. For further
explanations regarding lidocaine, reference can, for
example, be made to Rompp Chemielexikon [Rompp
dictionary of chemistry], 10th edition, volume 3, 1997,
Georg Thieme Verlag Stuttgart/New York, keyword:
"Lidocaine" and also to the particular literature cited
therein, the entire content of which is hereby
incorporated by reference.
Concerning the amount used of the local anesthetic or
of component (a), this can vary within wide ranges.
However, in the context of the present invention, a
particularly good efficacy has been demonstrated when
the composition contains component (a) in an amount
within the range from 0.1 to 10% by weight, more
particularly within the range from 0.5 to 8% by weight,
by preference within the range from 0.7 to 6% by
weight, preferably within the range from 1 to 3% by
weight, based on the composition.
Equally, it can be envisaged that the composition
contains component (a) in an amount of at least 0.01%
by weight, more particularly at least 0.1% by weight,
by preference at least 0.5% by weight, preferably at
least 1% by weight, based on the composition. In this
connection, it can also be envisaged that the
composition contains component (a) in an amount of not
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more than 15% by weight, more particularly not more
than 10% by weight, by preference not more than 8% by
weight, preferably not more than 5% by weight,
particularly preferably not more than 3% by weight,
based on the composition.
The amount too of the polyhexanide used according to
the invention as antiseptic can vary within wide
ranges. In terms of the antiseptic or antimicrobial
action, the best results are achieved according to the
invention when the composition contains polyhexanide
and/or the salts thereof in an amount within the range
from 0.05 to 10% by weight, more particularly within
the range from 0.1 to 8% by weight, by preference
within the range from 0.5 to 5% by weight, preferably
within the range from 0.75 to 3% by weight,
particularly preferably within the range from 1 to 2%
by weight, based on the composition.
It can also be envisaged in the context of the present
invention that the composition contains polyhexanide
and/or the salts thereof in an amount of at least 0.05%
by weight, more particularly at least 0.1% by weight,
by preference at least 0.5% by weight, preferably at
least 0.75% by weight, particularly preferably at least
1% by weight, based on the composition. It can be
equally envisaged with regard to the amount used of
polyhexanide that the composition contains the
polyhexanide in an amount of not more than 10% by
weight, more particularly not more than 8% by weight,
by preference not more than 5% by weight, preferably
not more than 3% by weight, particularly preferably not
more than 2% by weight, based on the composition.
Furthermore, in the context of the present invention,
it has been demonstrated that, surprisingly, it is not
only the active-ingredient amount of the two active
ingredients as such that are used which is of
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importance in terms of an optimization of action, but
also the ratio used of the two active ingredients in
relation to one another. A particularly good efficiency
of action in terms of the antiseptic action, on the one
hand, and the pain-alleviating action, on the other, is
achieved in the context of the present invention when
the composition contains component (a) and component
(b) in a weight-based ratio of [(a): (b) within the
range from 1:50 to 50:1, more particularly within the
range from 1:20 to 20:1, by preference within the range
from 1:10 to 10:1, preferably within the range from 1:5
to 5:1, particularly preferably from 1:3 to 3:1. This
is because, by using the two active ingredients in a
defined ratio in relation to one another, the action of
local anesthetic, on the one hand, and antiseptic, on
the other, during combined use goes beyond the
particular individual action of the active ingredients
during sole administration, and this can be judged to
be evidence of the presence of a synergistic effect.
The composition according to the invention can be
configured in an altogether variable manner. Preferred
embodiments will be explained in detail below.
In one embodiment preferred according to the invention,
it can be envisaged that the composition is water-based
or water/alcohol-based, preferably water-based.
In this connection, it is advantageous when the
composition contains water, more particularly purified
water, in an amount within the range from 30 to 99% by
weight, more particularly within the range from 40 to
98% by weight, preferably within the range from 50 to
97% by weight, particularly preferably within the range
from 60 to 96% by weight, based on the composition.
Furthermore, it can be envisaged in the context of the
present invention that the composition according to the
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invention contains at least one preferably polyhydric
alcohol, especially selected from the group of
polyvinyl alcohols, glycerol, glycols and the
combinations thereof, preferably glycerol. However, in
the context of the present invention, it has been found
to be advantageous when the composition is at least
substantially free of glycols, more particularly
(poly)alkylene glycols. In particular, it can be
envisaged in this connection that the composition
according to the invention comprises at least
substantially no propylene glycol. This is because
(poly)alkylene glycols, especially propylene glycol,
can lead to skin irritations and to reactions due to
intolerability, and this is disadvantageous especially
with respect to use on the mucosa, since the mucosa is
particularly sensitive. Furthermore, dispensing with
(poly)alkylene glycols, especially propylene glycol, at
least substantially avoids a systemic resorption,
especially an excessive systemic resorption, of the
active ingredients used, i.e., of the local anesthetic
and of the antiseptic, and this further increases the
tolerability of the composition according to the
invention.
Concerning the amounts used of the preferably
polyhydric alcohol, these can vary within wide ranges.
Particularly good results are obtained according to the
invention when the composition contains the preferably
polyhydric alcohol in an amount within the range from 1
to 80% by weight, more particularly within the range
from 5 to 70% by weight, by preference within the range
from 10 to 60% by weight, preferably within the range
from 15 to 50% by weight, based on the composition.
In a further embodiment according to the invention, it
can be envisaged that the composition comprises a mix
or a mixture of water and at least one preferably
polyhydric alcohol. In this connection, it has been
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found to be advantageous when the proportion of water
is at least 10% by weight, more particularly at least
30% by weight, by preference at least 50% by weight,
based on the mix or the mixture. Equally, it can be
envisaged with regard to this embodiment according to
the invention that the weight-based ratio of water to
alcohol in the composition is within the range from 9:1
to 1:5, more particularly within the range from 3:1 to
1:3, by preference within the range from 2:1 to 1:2,
preferably within the range from 1.5:1 to 1:1.5.
Concerning, in addition, the role of the composition
according to the invention as lubricant, it is
preferred according to the invention when the
composition is viscous or gel-like or is in the form of
a lubricant gel or lubricant. The viscous or gel-like
consistency ensures the suitability of the compositions
according to the invention for reducing friction, i.e.,
the resistance between skin or mucosa, on the one hand,
and medical instruments, on the other, is reduced,
making an easy insertion possible without injuries or
skin irritations occurring.
In this connection, it is advantageous when the
composition comprises at least one gel-forming agent.
In the context of the present invention, the gel-
forming agent can be selected from the group of
bentonites, silicic acids, polyacrylic acids,
carbomers, polyvinylpyrrolidones, cellulose
and
cellulose derivatives, xanthans and the mixtures
thereof, by preference cellulose and cellulose
derivatives, preferably modified celluloses,
particularly preferably chemically modified celluloses,
very particularly preferably
methylcellulose,
carboxymethylcellulose and/or hydroxyethylcellulose,
even more preferably hydroxyethylcellulose.
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Concerning the amount used of the gel-forming agent,
this can be varied within wide ranges. In particular,
the amount of gel-forming agent is selected depending
on the viscosity that the composition according to the
invention is to have. In the context of the present
invention, it has been found to be advantageous when
the composition comprises the gel-forming agent in an
amount within the range from 0.01 to 20% by weight,
more particularly within the range from 0.1 to 10% by
weight, by preference within the range from 0.5 to 5%
by weight, preferably within the range from 1 to 3% by
weight, based on the composition.
Particularly effective gel-type structures or
properties are obtained when the composition according
to the invention has, at a temperature of 20 C, a
dynamic viscosity within the range from 20 to 20 000
mPa-s, more particularly within the range from 50 to
15 000 mPars, by preference within the range from 100
to 10 000 mPa.s, preferably within the range from 500
to 8000 mPa.s, particularly preferably within the range
from 1000 to 7000 mPa-s, even more preferably within
the range from 2000 to 6000 mPa-s.
In the context of the present invention, it is thus
possible, on the basis of the selected gel-forming
agents and the usable amounts of the gel-forming agent,
to specifically set the rheological properties of the
composition according to the invention and to be able
to tailor said properties so to speak.
Concerning the methods or procedures for determining
the viscosity of the composition according to the
invention, these as such are known to a person skilled
in the art, and so no further information regarding
this is required here. In particular, it is possible to
use measuring instruments such as capillary
viscometers, rotational viscometers, falling ball
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viscometers or Brookfield viscometers to determine the
viscosity. In particular, the above-specified viscosity
values are based on a determination in accordance with
DIN 53015 at room temperature (20 C) (e.g., using a
falling ball viscometer, e.g., RheoTec Messtechnik
GmbH, Germany).
Furthermore, the composition according to the invention
typically has a physiologically compatible pH. In this
connection, it is advantageous according to the
invention when the composition has a pH within the
range from 3 to 8.5, more particularly within the range
from 4 to 8, by preference within the range from 5 to
7.5, preferably within the range from 6 to 7.
Furthermore, it is preferred in the context of the
present invention when the composition has a
physiologically compatible electrical conductivity,
more particularly within the range from 1 to 20 mS/cm,
by preference within the range from 2 to 15 mS/cm,
preferably within the range from 3 to 13 mS/cm,
particularly preferably within the range from 5 to
10 mS/cm.
Furthermore, it can be envisaged in the context of the
present invention that the composition also contains at
least one acid and/or base, more particularly for
setting the pH, by preference for setting a
physiologically compatible pH, preferably for forming a
buffer system. The relevant buffer systems are well
known to a person skilled in the art, and so there is
no need for any further explanations in relation to
this.
Moreover, it has been found to be advantageous when the
composition preferably comprises at least one base. In
this connection, it can be envisaged that the base is
selected from the group of amines, carboxylates, alkali
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metal hydroxides and/or alkaline earth metal hydroxides
and the mixtures and combinations thereof, more
particularly alkali metal hydroxides and/or alkaline
earth metal hydroxides, preferably sodium hydroxide.
The addition of acids or bases, especially of bases,
allows the pH to be specifically set, and so the
compositions according to the invention are
physiologically highly compatible and, at the same
time, the preferably used local anesthetic, preferably
of the amide type, is present in protonated form,
improving or ensuring the local action of the local
anesthetic. Likewise, buffer systems are formed, and as
a result, the pH of the composition according to the
invention remains stable even during application.
Furthermore, according to a preferred embodiment of the
present invention, it is envisaged that the composition
according to the invention comprises at least
substantially no preserving agent or no preservative.
More particularly, in the context of the present
invention, it can be envisaged that the composition is
at least substantially free of preserving agents or of
preservatives. By dispensing with preserving agents, it
is possible to even further increase the tolerability
of the compositions. It is completely surprising here
that the composition according to the invention has an
excellent long-term stability even without the use of
preserving agents, and that there is no microbiological
infestation of the compositions even after a storage
time of at least two years.
Furthermore, the composition according to the invention
can contain at least one further active ingredient
and/or ingredient, especjaliy selected from the group
of skin protectants, antiseptics, local anesthetics,
vitamins, trace elements, minerals, micronutrients and
the combinations thereof.
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It can be equally envisaged that the composition
according to the invention contains at least one
customary pharmaceutical additive and/or excipient,
which is preferably selected from the group of
processing aids, stabilizers, emulsifiers,
antioxidants, preservatives, humectants, pH setters, pH
buffer substances, thickeners, antiseptics, dyes,
buffer substances, odorants, fragrances, extenders,
binders, wetting substances and/or preservatives and
the combinations thereof.
In general, the composition according to the invention
is suitable for use in the area of medicine, medical
technology, pharmacy and cosmetics.
More particularly, the composition according to the
invention is suitable for use as a (local) antiseptic
and/or (local) anesthetic, especially in diagnostic
and/or therapeutic (surgical) procedures, preferably in
catheterizations, preferably transurethral
or
suprapubic catheterizations, probings, endoscopies,
intubations and/or obstetrical procedures.
Equally, the composition according to the invention is
suitable for use in prophylactic or therapeutic
(mucosa) disinfection, especially in the context of
catheterizations, preferably transurethral
or
suprapubic catheterizations, endoscopies, probings,
intubations and obstetrical procedures.
In summary, it should be emphasized that it is possible
for the first time according to the invention, with
respect to the composition according to the invention,
to provide lubricants or lubricant gels as aids for
therapeutic or diagnostic or prophylactic procedures,
such as catheterizations, endoscopies, probings,
intubations or obstetrical procedures, which lubricants
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or lubricant gels are distinctly superior to the
lubricants or lubricant gels of the prior art. The
composition according to the invention has altogether
an improved efficacy, more particularly an increased
antiseptic action, specifically both with respect to
the spectrum of activity and with respect to a rapid
onset of action. Furthermore, the composition is
improved in terms of its tolerability, since especially
the antiseptic used has at least substantially no
cytotoxic action and the risk of undesired adverse
reactions or effects is thus minimized. Furthermore,
the local anesthetic used, on the one hand, and the
antiseptic, on the other, are complementary to one
another in a synergistic manner, i.e., the combined use
of both active ingredients, especially in defined
ratios to one another, leads to a significant increase
in action with regard to both active ingredients.
Furthermore, the composition according to the invention
has viscosity and adhesion properties which are
tailored or which are optimized with respect to the
particular area of use, and so medical procedures, more
particularly catheterizations, endoscopies,
intubations, probings and obstetrical procedures, can
be carried out more easily and more gently - especially
with a reduced risk of injury.
The present invention further provides for - in a
secondaspect of the present invention - the use
of the composition according to the invention, as
described above, as a (local) antiseptic and/or (local)
anesthetic, especially in diagnostic and/or therapeutic
(surgical) procedures, preferably in catheterizations,
preferably transurethral or suprapubic
catheterizations, probings, endoscopies, intubations
and/or obstetrical procedures.
Therefore, the present invention relates to the
composition according to the invention as such, as
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described above, for use as a (local) antiseptic and/or
as a (local) anesthetic, especially in diagnostic
and/or therapeutic (surgical) procedures, preferably in
catheterizations, preferably transurethral
or
suprapubic catheterizations, probings, endoscopies,
intubations and/or obstetrical procedures.
For further details concerning this aspect of the
invention, reference can be made to the above
explanations in relation to the first inventive aspect,
said explanations also applying accordingly with regard
to this aspect of the invention.
Equally, the present invention also relates to the use
of the composition according to the invention for
prophylactic and/or therapeutic mucosa/skin
disinfection, especially in the context of
catheterizations, preferably transurethral
or
suprapubic catheterizations, probings, endoscopies,
intubations and/or obstetrical procedures.
Therefore, the present invention also relates to the
composition according to the invention as such, as
described above, for use in prophylactic and/or
therapeutic mucosa/skin disinfection, especially in the
context of catheterizations, preferably transurethral
or suprapubic catheterizations, endoscopies, probings,
intubations and/or obstetrical procedures.
In particular, the present invention also relates to
the use of the composition according to the invention,
as defined above, as lubricant and/or as lubricant gel
especially in catheterizations, especially for a
bladder catheter, probings, endoscopies, intubations
and/or obstetrical procedures.
Therefore, the present invention also relates to the
composition according to the invention as such, as
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defined above, for use in catheterizations, probings,
endoscopies, intubations and/or obstetrical procedures,
especially as a lubricant and/or as a lubricant gel in
catheterizations, probings, endoscopies, intubations
and/or obstetrical procedures, especially for a bladder
catheter.
The use of the composition according to the invention
especially in catheterization allows not only a
comparatively gentle catheterization and lowers the
risk of injuries in catheterization; on the contrary, a
distinctly reduced occurrence of infections during the
catheter retention time is also observed.
Moreover, the present invention relates to the use of
the composition according to the invention, as defined
above, for the curative and/or prophylactic treatment
of infections, inflammations and/or pain which are
associated with Or linked to catheterizations,
probings, endoscopies, intubations and/or obstetrical
procedures and which, in the case of catheterizations,
occur especially in the region of the ureter and/or
bladder.
Consequently, the present invention also relates to the
composition according to the invention as such, as
defined above, for use in the curative and/or
prophylactic treatment of infections, inflammations
and/or pain which are associated with or linked to
catheterizations, probings, endoscopies, intubations
and/or obstetrical procedures and which, especially in
the case of catheterizations, occur in the region of
the ureter and/or bladder.
In general, the composition according to the invention
can be applied in the case of or in connection with
catheterization, especially in the installation of a
catheter, especially a bladder catheter.
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It has been found to be particularly advantageous when
the composition is applied into a body lumen,
especially into the urethra, in the case of
catheterization, especially before the installation of
a catheter, especially a bladder catheter. Typically,
it is envisaged that the composition according to the
invention is installed before placement of the catheter
into the urethra, though it is also possible to wet the
catheter additionally during catheterization using the
composition according to the invention.
Furthermore, it is possible according to the invention
for the composition, in the case of catheterization, to
be applied on the catheter before and/or during the
installation of a catheter, especially a bladder
catheter. It can be envisaged here that the composition
is applied to the segment of a catheter that is
insertable and/or introducible into a body lumen,
especially into a urethra.
In turn, the present invention further provides - in a
third aspect of the present invention - a
container, especially an application apparatus,
preferably in the form of a preferably sterile syringe,
which contains the above-described composition
according to the invention.
In the context of the present invention, it can be
envisaged in this connection that the container is
designed to accommodate a single dose of the
composition.
In a preferred embodiment of the present invention, the
container has a defined volume of from 3 to 30 cm3, more
particularly from 3.5 to 20 cm3, preferably from 4 to
15 cm3, particularly preferably from 4.5 to 12 cm3, for
accommodating the composition, especially for
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accommodating the composition according to the
invention.
In a particular embodiment of the present invention,
the container of the invention also comprises an
application unit, especially in the form of a piece of
tubing, for the application or administration of the
composition to body lumen accommodating or adjacent to
a catheter, especially a bladder catheter or kidney
catheter, especially for the application and/or
administration of the composition to the urethra or
bladder.
For further details concerning this aspect of the
invention, reference can be made to the above
explanations in relation to the other inventive
aspects, said explanations also applying accordingly
with regard to this aspect of the invention.
Moreover, the present invention further provides - in a
fourth aspect of the present invention - a
catheter, especially a bladder catheter or fistula
catheter, the catheter being provided with or
comprising the above-described composition according to
the invention. It can be envisaged here that the
composition is also applied to a segment of the
catheter that is insertable or introducible into a body
lumen, especially into the urethra.
With regard to further details concerning this aspect
of the invention, reference can be made to the above
explanations in relation to the other inventive
aspects, said explanations also applying accordingly
with regard to this aspect of the invention.
In turn, the present invention further provides - in a
fifthaspect of the present invention -apackaging
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unit, containing at least one container, as described
above, and/or one catheter, as described above.
It can be envisaged here that the container or the
catheter has been introduced into outer packaging
providing protection against contamination.
With regard to further details concerning this aspect
of the invention, reference can be made to the above
explanations in relation to the other inventive
aspects, said explanations also applying accordingly
with regard to this aspect of the invention.
Lastly, the present invention further provides - in a
sixth aspect of the present invention - a kit,
especially a catheterization system, comprising, on the
one hand, a catheter, especially a bladder catheter or
fistula catheter, as spatially separate components and,
on the other hand, the above-described composition.
In the context of the present invention, it can be
envisaged here that the composition has been introduced
into a container according to the invention, as defined
above.
In the kit according to the invention, the relevant
components or constituents are spatially separate, but
are functionally connected.
With regard to further details concerning this aspect
of the invention, reference can be made to the above
explanations in relation to the other inventive
aspects, said explanations also applying accordingly
with regard to this aspect of the invention.
Further designs, modifications and variations of the
present invention are readily identifiable and
realizable for a person skilled in the art upon reading
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the description, without said person departing from the
context of the present invention.
The present invention will be illustrated on the basis
of the following exemplary embodiments, which, however,
are intended in no case to limit the present invention.
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Exemplary embodiments:
1. Providing
compositions according to the invention
and comparative compositions
The efficacy of the compositions according to the
invention is investigated by comparing
compositions according to the invention that are
provided by the applicant with various comparative
compositions. Tables 1 and 2 show the recipes for
compositions A and B according to the invention
that are provided.
Table 1: Recipe of composition A according to the
invention
Component Amount in % by weight
(based on the composition)
Purified water 92-96
Lidocaine hydrochloride 1.5-3
Polyhexanide (0.3%) 0.5-3
Hydroxyethylcellulose 0.5-2.5
Sodium hydroxide solution 0.01-0.15
Table 2: Recipe of composition B according to the
invention
_____________
Component Amount in % by weight
(based on the composition)
Purified water 92-96
Benzocaine hydrochloride 1.5-3
Polyhexanide (0.3%) 0.5-3
Hydroxyethylcellulose 0.5-2.5
Sodium hydroxide solution 0.01-0.15
Comparative composition C differs from composition
A according to the invention in that octenidine
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hydrochloride is used as antiseptic instead of the
polyhexanide used according to the invention.
Comparative composition D differs from composition
A according to the invention in that chlorhexidine
is used as antiseptic instead of the polyhexanide
used according to the invention.
As described below, the four compositions provided
are investigated in the context of application or
efficacy studies with regard to their application
properties and their efficacy in catheterizations.
2. Physical properties/stability properties of the
compositions according to the invention:
After their preparation, compositions A and B
according to the invention are investigated with
regard to their physical properties both before
and after sterilization. The relevant results are
shown in Tables 3 and 4 below.
Table 3: Properties of composition A according to the
invention
Composition A Before After
sterilization
sterilization
Appearance Virtually Virtually
colorless, clear, colorless, clear,
viscous liquid viscous liquid
pH 6.59 6.57
Viscosity [mPa-s] 2.764
(20 C)
Polyhexanide 1.567 1.531
content (mg/100 ml)
Lidocaine 2.031 2.000
hydrochloride
content (mg/100 ml)
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Unknown Not detectable Not detectable
contaminants
Table 4: Properties of composition B according to the
invention
Composition B Before After sterilization
sterilization
Appearance Virtually Virtually
colorless, clear, colorless, clear,
viscous liquid viscous liquid
pH 6.66 6.63
Viscosity [mPa-s] 2.770
(20 C)
Polyhexanide 1.543 1.510
content (mg/100 ml)
Benzocaine 2.021 2.016
hydrochloride
content (mg/100 ml)
Unknown Not detectable Not detectable
contaminants
As shown by the above specifications, the
compositions according to the invention have a
good stability. Even after sterilization, there is
virtually no change in appearance, pH and active-
ingredient content. The compositions according to
the invention also exhibit after sterilization a
viscosity within the range envisaged according to
the invention, said viscosity being optimal for
the application due to said viscosity being
unchanged.
Furthermore, the compositions according to the
invention are investigated with regard to their
long-term stability, i.e., their stability over a
period of two years. It is apparent here that,
even after a storage over a period of two years,
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the optical properties remain unchanged, that
especially no clouding or crystallization can be
observed. Furthermore, the active-ingredient
contents also remain at least substantially
constant.
It has also been demonstrated in the context of
the investigation of long-term stability that the
compositions according to the invention do not
exhibit any microbiological infestation or any
bacterial contamination, even though the
compositions according to the present invention
are free of preserving agents. Altogether, the
compositions according to the invention thus have
an excellent long-term stability or storage
stability.
3. Application and efficacy studies:
In the context of efficacy studies carried out by
the applicant, the excellent action of
compositions according to the present invention
based on the inventive active-ingredient
combination of polyhexanide, on the one hand, and
a local anesthetic, on the other (cf. following
"Composition A" (local anesthetic: lidocaine) and
"Composition B" (local anesthetic: benzocaine)) is
demonstrated with respect to comparative
compositions based on octenidine and lidocaine as
active-ingredient combination (cf. "Composition
C") and based on chlorhexidine and lidocaine (cf.
following "Composition D"). In this connection, a
distinctly improved efficacy both with respect to
the reduction of infections and with respect to
the pain-relieving properties is observed for the
inventive combination based on the following
composition A and composition B.
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The efficacy study carried out is ascertained on
the basis of various investigation methods (i.e.,
subjective well-being of the patients, pathogen or
bacterial content in a sample from the test
subject after removal of the catheter).
In the context of the investigations explained
below, to the test subjects prior to placement of
the catheter, corresponding catheterization gels
based on the above compositions are applied in
each case to the ureter and the corresponding
catheters are subsequently placed. For each
investigation group or composition, ten test
subjects are investigated, with the test subjects
distributed across the groups ranging from 40 to
69 years of age. Each investigation group consists
of 5 male and 5 female test subjects.
a) In the context of the first line of
investigation, the test subjects give their
subjective feeling on the basis of a grading
system with grades from 1 to 6 (1 = very good
to 6 = unsatisfactory). This investigation
focuses especially on pain during placement
of the catheter and on the sensation of pain
at time t - 6 hours, 12 hours or 24 hours
after catheterization.
With compositions A and B according to the
invention, it is possible to observe a
distinct improvement in pain symptoms. Both
in the case of placement of the catheter and
at the later times after catheterization, the
pain symptoms can be significantly improved
for the test subjects. In this connection,
the use of lidocaine as local anesthetic is
found to be slightly superior with respect to
the use of benzocaine. Nevertheless, even
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with the use of benzocaine, an excellent
alleviation of pain can be achieved
altogether. With comparative compositions C
and D, poorer results are achieved. The
results ascertained for all groups are shown
in Table 5 below:
Table 5: Results of the assessment of pain symptoms
A(invention) B(invention) C(comparison) D(comparison)
t = Oh 1.2 0.1 1.3 0.2 1.6 0.4 2.0 0.3
t = 6 h 1.4 0.3 1.5 0.1 1.9 0.5 2.6 0.1
t = 12 h1.7 0.1 1.8 0.3 2.2 0.3 2.9 0.5
t - 24 h2.0 0.2 2.1 0.2 2.4 0.6 3.3 0.2
h) In a second line of investigation, the
catheter is removed after 72 hours and a
sample from each test subject is subsequently
investigated with respect to any
microbiological infestation. The
classification is likewise carried out on the
basis of the above-described grading system
with grades from 1 to 6 (1 = very low or no
microbiological infestation to 6 = very
severe microbiological infestation in the
acquired sample). Corresponding mean values
and the associated standard deviations are
ascertained. Table 6 below shows the results
ascertained for all groups. With regard to
compositions A and B according to the
invention, there is a significant reduction
in microbiological infestation.
With
comparative compositions C and D, especially
composition D, poorer results are achieved.
Table 6: Results of the assessment of microbiological
infestation
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A(invention)B(invention) C(comparison) D(comparison)
t = 72 h1.1 0.2 1.2 0.1 1.4 0.1 2.9 0.4
c) In a third line
of investigation, the extent
to which the various tested compositions
cause skin irritations or intolerabilities is
assessed. In this connection too, the
classification is done on the basis of the
above-mentioned grading scale from 1 to 6 (1
= no irritation or intolerabilities to 6 -
very severe intolerabilities or irritations).
The corresponding mean values and the
associated standard deviations are
ascertained. Table 7 shows the relevant
results ascertained for all groups. With
regard to compositions A and B according to
the invention, no intolerabilities whatsoever
are observed. Comparative compositions C and
D are, on average, tolerated less well by the
test subjects.
Table 7: Assessment of tolerability
A (invention) B (invention) C(comparison) D(comparison)
1.2 0.2 1.3 0.1 2.3 0.3 3.2 0.4
The above series of experiments show altogether
the excellent efficacy of the compositions
according to the invention based on polyhexanide,
on the one hand, and a local anesthetic,
especially lidocaine hydrochloride, on the other,
with respect to the stated comparative
compositions. In particular, in the context of the
present invention, it has been demonstrated that
using polyhexanide as antiseptic can significantly
improve the tolerability of lubricants Or
lubricant gels. Furthermore, an excellent
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antimicrobial action and an efficient pain
alleviation are achieved.
Moreover, the compositions according to the
invention have an excellent (storage) stability.
Even over a storage period of two years, there are
no relevant changes in physical properties.
Concerning, in addition, specifically the
microbial stability of the compositions according
to the invention, this is ensured even without the
use of an additional preserving agent.
