Note: Descriptions are shown in the official language in which they were submitted.
CA 02381571 2002-02-08
,
August 16 2000
K/T/sm
Merckle GmbH
Ludwig-Merckle-Str. 3
D-89143 Blaubeuren
Phospholipid gel
The present invention relates to a phospholipid gel,
and to cosmetic and pharmaceutical formulations which
contain these gels.
Phospholipid gels are known in the prior art. These
gels have found interest as pharmaceutical vehicles.
The phospholipid is not only a vehicle for the active
substance here, but also controls the bioavailability
of the pharmaceutical. The reason for this is the
special molecular arrangement of the phospholipids,
which can form stable liposomes consisting of bilayers.
The active compound is better absorbed, since the
phospholipids make possible an easier absorption of the
active compound into the target cells.
A process for the preparation of liposome solutions
which can contain a pharmacological active compound is
disclosed, for example, in EP-B-0 069 307. In the
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preparation of these solutions, liposome gels are
firstly obtained which can be used, for example, as an
ointment base. In order to suppress gelling of the
liposome solutions obtained, EP-B-0 069 307 proposes
adding an electrolyte such as, for example, a
physiological buffer system or a sugar.
A liposomal composition for medicinal or cosmetic
purposes which comprises 0.5-10% of phospholipids, 20-
50% of a C2-4-alcohol, 0-30% of glycol, at least 20% of
water and at least one active compound is disclosed in
WO 95/35095.
DE 195 20 659 discloses a pharmaceutical preparation
which, in addition to the active compound acyclovir,
contains 5-35% by weight of a phospholipid, 15-50% by
weight of an alcohol and 79-0% by weight of water, the
alcohol being a di- and/or trihydric C2_5-alcohol on its
own or as a mixture with ethanol, 1-propanol and/or 2
propanol.
US patent no. 5,820,848 discloses liposome-containing
gels which can contain a short-chain alcohol such as
methanol, ethanol, propanol, isopropanol or n-butanol
or polyols such as glycerol and ethylene glycol.
The phospholipid gels known in the prior art have the
disadvantage that they easily liquefy on application to
the skin. Liquefaction of the gel strand is all the
more strongly pronounced the higher the perspiration
content on the skin. This is particularly
disadvantageous in the case of gels which are intended
for application to the mucous membranes. Patients
frequently feel the liquefaction and consequently the
watery feeling on application of the conventional
phospholipid gels to be unpleasant.
Moreover, known phospholipid gels have the disadvantage
that they can liquefy even on incorporation of a
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pharmaceutical, buffer or salt, in particular if
readily soluble substances, such as, for example,
diphenhydramine HC1, are incorporated. In these cases,
the preparations may flow even under their own weight.
This effect is known, for example, from
DE 40 03 783 A1. In this, a phospholipid-containing
gel is disclosed which is preserved using alcohols such
as ethanol or 2-propanol. According to examples 7 and
9-12, the gels obtained liquefy on addition of a buffer
or salt solution.
An object of the present invention thus consists in
making available a phospholipid gel which, compared
with known phospholipid gels, has a higher stability on
application to the skin and in the presence of an
incorporated pharmaceutical, buffer or salt.
According to the invention, it has now been found that
this problem can be solved by incorporating into the
phospholipid gel a tetra-, penta- or hexahydric
alcohol, and/or sugar.
The present invention thus relates to a phospholipid
gel, comprising
5-60o by weight of at least one phospholipid;
at least 1°s by weight of at least one di- or tri-
hydric CZ_4-alcohol;
0.5-35% by weight of at least one tetra-, penta-
or hexahydric alcohol and/or at least one sugar;
optionally one or more additives and water to 100
by weight,
the % by weight data in each case relating to the
entire gel.
The phospholipid preparation according to the invention
contains phospholipids which are preferably of natural
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origin. In particular, phospholipids from plants, such
as, for example, soybean lecithin, are suitable. The
phospholipids can be characterized by means of the
phosphatidylcholine content, which is the main
ingredient of phospholipids.
In principle, according to the invention either
hydrogenated and/or nonhydrogenated phospholipids can
be employed. In the case of the nonhydrogenated
phospholipids, the phosphatidylcholine content is at
least approximately 70% by weight based on the
phospholipid, preferably the phosphatidylcholine
content is at least approximately 75% by weight. In
the case of the hydrogenated phospholipids, the
phosphatidylcholine content is a least approximately
90% by weight.
The phospholipid used according to the invention can
also be a mixture of various phospholipids and in
particular a mixture of phosphatidylcholine and
lysophosphatidylcholine. In such a mixture, the weight
ratio of phosphatidylcholine to lysophosphatidylcholine
should be between 97:3 and 40:60, higher
phosphatidylcholine contents of at least 75% by weight
(in the case of nonhydrogenated phospholipids) and
preferably at least 90% by weight (in the case of
hydrogenated phospholipids) based on the total
phospholipid being preferred.
Known phospholipids which fulfill these properties are
obtainable, for example, from Nattermann Phospholipid
GmbH under the names Phospholipon° 80 and Phospholipon~
90 H. Phospholipon° 80 comprises approximately 76% of
phosphatidylcholine and approximately 3% of
lysophosphatidylcholine, Phospholipon° 90 H, a
hydrogenated phosphatidylcholine, comprises at least
900 of phosphatidylcholine and at most 4% of
lysophosphatidylcholine. Phospholipon° 80 is also
obtainable as a 75% strength solution in ethanol (NAT
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8539) and as a 60% strength solution in propylene
glycol (NAT 8450). Phospholipids from other
manufacturers, however, can also be used for the gel
according to the invention.
In one embodiment, hydrogenated phospholipids are
employed. An advantage of this embodiment is that
smaller amounts of phospholipids can be added. Thus,
for example, approximately 20% of nonhydrogenated
phospholipids can be replaced by approximately 10% of
hydrogenated phospholipids so that a cost-saving
results.
The content of phospholipids in the gel should be
between 5 and 60% by weight. Below 5%, no gel
formation is possible, and above 60%, acceptable gel
can no longer be formulated. Preferably, the
phospholipid content in the gel according to the
invention is 5-35% by weight and particularly
preferably 15-25% by weight.
As a further constituent, the gel according to the
invention comprises at least 1% by weight, preferably
20 to 30% by weight, of at least one di- or trihydric
CZ-9-alcohol. In higher concentrations, this alcohol
acts as a preservative. Moreover, this alcohol acts
as a solvent for the phospholipid and can also serve as
a solubilizer for the active compound. Furthermore,
this constituent can serve as a penetration enhancer.
Finally, the moistness of the skin can also be
increased. A suitable dihydric alcohol is in
particular a propanediol, propylene glycol
(1,2-propanediol) having proven particularly
advantageous. A trihydric alcohol which can be
employed is, for example, glycerol. The gel can also
contain mixtures of various types of these alcohols.
The content of the di- or trihydric CZ_4-alcohol in the
gel according to the invention can vary over a wide
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range. A content o~ 1-90$ by weight is preferred,
particularly preferably 15-30~ by weight,
~-~-- ,~°~ ~ If propylene glycol is employed on its
own as the alcohol component, the propylene glycol
content in the gel should preferably be between 25 and
30$ by weight. If glycerol is employed on its own as
the alcohol component, the glycerol content in the gel
should be between 20 and 30$ by weight. However,
mixtures of, for example, 15-30~ by weight of propylene
glycol and 0-10$ by weight, in particular 2.5-7.5~ by
weight, of glycerol can also be present in the gel
according to the invention.
As an essential constituent which decreases the
proneness to liquefaction of the phospholipid gel, the
gel according to the invention contains 0.5-35$ by
weight of at least one tetra-, penta- or hexahydric
alcohol or sugar. The term "sugar" is understood
according to the invention as meaning mono-, di- and/
or oligosaccharides. The tetra-, penta- or hexahydric
alcohols are preferably sugar alcohols. These include,
for example, glucose, fructose, sucrose, trehalose,
xylitol, maltitol, inositol, sorbitol and mannitol.
Mixtures of the additives mentioned, namely mixtures of
various alcohols and/or various sugars, such as, for
example, a mixture of sorbitol and glucose, can also be
used.
In order to decrease the proneness of the phospholipid
gel to liquefaction, the content of the polyhydric
alcohol or sugar in the preparation can be varied over
a wide range. The amount to be employed depends, for
example, on the presence of other preservatives, the
liquefying action of a pharmaceutical which may be
present and the nature of a buffer which may be
employed and on further additives present.
Furthermore, the content of higher-hydric alcohol or
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sugar should be tailored to the intended use of the gel
according to the invention. If the gel according to
the invention is intended, for example, for application
to the nasal mucous membranes, it should be taken into
account that in the nose, on the one hand, increased
moistness is present and on the other hand salts are
present which, as electrolytes, favor liquefaction of
the gel. If the gel according to the invention,
however, is to be applied, for example, only to dry
skin, the liquefying action is smaller on account of a
lower moisture and salt content. on the skin. The
alcohol, sugar or sugar alcohol content in the gel can
be tailored according to these requirements. In the
case of gels which can come into contact with the
gastrointestinal tract, such as, for example, gels for
lips and/or oral mucous membranes, it is to be taken
into account that certain sugars produce a sweet taste.
On the other hand, however, it may be preferred not to
use sugars if the gel is also to be suitable for
diabetics. Sugar alcohols are then preferred.
A polyhydric alcohol or sugar content in the range from
2-20o by weight and in particular 2.5-loo by weight has
proven advantageous.
If the gel according to the invention is to be employed
as a pharmaceutical formulation, it additionally
comprises one or more pharmaceutical active compounds.
The gel according to the invention is particularly
advantageous for active compounds which are readily
water-soluble substances, since these regularly already
lead to liquefaction of conventional gels on
incorporation. Advantageously, the gel according to
the invention, however, is also suitable for poorly or
nonsoluble pharmaceutical active compounds, since it
then displays its liquefaction-inhibiting action on
application, for example to the skin or mucous
membrane.
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The pharmaceutical active compound can be selected, for
example, from the group consisting of anti-
inflammatories, nonsteroidal antirheumatics,
corticoids, peptides, hormones, enzymes, nucleic acids,
virustatics, vitamins, local anesthetics, antimycotics,
antibiotics, antipsoriatics, circulation-promoting
agents, a-sympathomimetics and nose drops. Preferably,
virustatics, in particular acyclovir, corticoids,
hormones and in particular peptides, can be
incorporated into the gel according to the invention.
Pharmaceutical active compounds which may be mentioned
are, for example, acyclovir, heparin, diclofenac,
hydrocortisone, xylometazoline, cyclosporin, diphen-
hydramine, calcitonin and indomethacin or their
pharmaceutically acceptable salt. Lt is an advantage
of the composition according to the invention that not
only the active compounds, but also pharmaceutically
acceptable salts can be incorporated without problems.
The phospholipid gel preparation according to the
invention also makes possible a topical application of
those medicaments which cannot be administered orally
and otherwise have to be administered parenterally.
These active compounds are, for example, insulin, which
can be absorbed, for example, via the nasal mucous
membrane.
However, it is also possible, with the aid of the
phospholipid gels according to the invention, to
administer vaccines, hormones or nucleic acids
(preferably for inoculation). On account of the
phospholipids, the gels according to the invention make
possible a good penetration of the skin. The
phospholipid gel according to the invention therefore
makes possible a noninvasive administration form of
those pharmaceuticals which cannot be administered
orally, such as, for example, peptides or nucleic acids
(for example for inoculation). The gel structure which
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can be achieved by means of the phospholipid gels
according to the invention makes it possible, for
example, to apply the gel preparation to the nasal
mucous membranes in such a way that the active compound
can readily penetrate the mucous membrane.
Instead of or in addition to pharmaceutical active
compounds, the gel according to the invention, however,
can also include constituents having a cosmetic action.
Examples of these are vitamins, sunscreen filters or
a-hydroxy acids.
As a further constituent, the gel according to the
invention can contain up to 10o by weight of at least
one alcohol selected from ethanol, 1-propanol and
2-propanol. These monohydric alcohols, however, are
incorporated into the gel only in addition to the
abovementioned di- and trihydric alcohols.
A significant advantage of the gel according to the
invention consists in the fact that, on account of the
stabilization of the phospholipid gel by the polyhydric
alcohol, and/or sugar, present, a buffer system can be
incorporated into the preparation without liquefaction
of the gel occurring. The buffer should be chosen here
such that it has a high buffer capacity in the range of
the stability optimum of the phosphatidylcholine. The
stability optimum of phosphatidylcholine is at pH 6.5,
so that the buffer should have a high buffer capacity
in the range from pH 5.5-8.0 and preferably
approximately pH 6.5. As a result of the buffering of
the gel in the range of the stability optimum of the
phosphatidylcholine, the storage stability of the gel
can be increased. This is to be attributed to a
slowing of the hydrolysis of the phosphatidylcholine to
lysophosphatidylcholine. For example, in a nonbuffered
gel the decrease in the phosphatidylcholine content
after 25 weeks at 41°C was 58s. In a gel which was
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BISTRIS-buffered and otherwise of the same recipe, the
decrease after 36 weeks at 41°C, however, was only 44~.
Buffers which have proven particularly suitable are
BISTRIS (2-(bis(2-hydroxyethylimino)-2-hydroxymethyl)-
1,3-propanediol) (pKa 6.5), phosphate buffer (buffer
range sec-phosphate about 6.2-8.2), hydrogencarbonate
buffer (buffer range about 5.4-6.9), maleate buffer
(buffer range about 6.0-6.8), TRIS: (trishydroxymethyl-
aminomethane), MOPS: (3-[N-morpholino]propanesulfonic
acid) and HEPES (N-[2-hydroxyethyl]piperazine-
N'[2-ethanesulfonic acid). On account of its pKa of
6.5, BISTRIS has proven particularly advantageous.
The amount of the buffer added is not particularly
critical, but should be chosen to be so high that an
adequate buffer action is achieved. For example, a
BISTRIS concentration of approximately 0.075M (1.57 by
weight) in the gel is particularly suitable.
If desired, a prespecified pH of the gel can, however,
also be set by addition of an acid or alkali, such as,
for example, NaOH.
The gel according to the invention can also contain
further additives, such as, for example, preservatives,
colorants, deodorants and taste enhancers. The taste
enhancers can in particular play a role if the
substances per se are otherwise not pleasant-tasting.
The phospholipids obtained from soybeans are in some
cases also not felt to be pleasant as regards taste.
Unlike other gel preparations, the semisolid
phospholipid gel preparation according to the invention
preferably contains no further thickeners, emulsifiers,
consistency-imparting agents or other gel-forming
agents in the conventional sense. In particular, the
gel preferably contains no further gel-forming agents,
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such as acrylates, cellulose derivatives, starch and
starch derivatives, gelatin and alginates.
In addition to the constituents mentioned, the gel
according to the invention contains water to 100 by
weight. For pharmaceutical preparations, purified
water according to pharmacopeia should be used.
The gel according to the invention is particularly
suitable for the production of cosmetic or
pharmaceutical formulations. The amount of the
cosmetic substance or pharmaceutical to be incorporated
into the phospholipid gel for this purpose can be
varied over a wide range and depends on the substance.
The person skilled in the art can easily determine
suitable concentrations, for example as a function of
the efficacy of the active compound and of the intended
purpose of use of the gel obtained. Acyclovir can be
incorporated into the preparation, for example, in an
amount of approximately 5~ by weight, diphenhydramine
HCl in an amount of approximately 1% by weight,
hydrocortisone in an amount of approximately 0.25-to by
weight, heparin Na in an amount of 60 000 I.U. and
calcitonin in an amount of 100 000 I.U. Further
possible active compounds and amounts of active
Compound can be taken from the examples.
A preferred base recipe according to the invention for
pharmaceutical formulations comprises approximately
23.50 by weight of phospholipid, approximately 22.5 by
weight of propylene glycol, approximately 5% by weight
of ethanol, approximately 2.5~ by weight of sorbitol, a
BISTRIS concentration of approximately 1.57% by weight,
an active compound in suitable amount and water to 1000
by weight.
The cosmetic and pharmaceutical formulations according
to the invention are suitable for application to the
skin or mucous membrane, such as, for example, the skin
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of the lip or the oral mucous membranes. Preferably,
the phospholipid gel-containing formulations according
to the invention, however, can also be applied to the
nasal mucous membranes. Here, the effect according to
the invention of the suppression of the liquefaction of
the gel is particularly advantageous, since in the
nose, on the one hand, increased moistness is present
and on the other hand salts are also present which, as
electrolytes, can lead to an increased liquefaction
with conventional gels.
The phospholipid gels according to the invention can
also be applied, however, even in the case of other
mucous membranes. An appropriate cosmetic or
pharmaceutical formulation can be, for example, a lip
gel, nasal gel, ophthalmic gel, vaginal gel or anal
gel, such as a hemorrhoid gel or a gel for the
treatment of anal fissures.
The phospholipid gels according to the invention
primarily serve for use in humans. However, it is also
possible to employ these phospholipid gels in animals,
such as, for example, for veterinary medical purposes,
in particular for the treatment of dogs, cats or
horses.
The gel according to the invention and the cosmetic or
pharmaceutical formulation according to the invention
can be prepared by mixing the constituents under vacuum
or under an inert gas atmosphere. The mixing of the
constituents and the gel formation can be carried out
according to conventional processes known in the prior
art. The absence of oxygen, which can be achieved by
working under vacuum or an inert gas atmosphere, is
advantageous here.
The gel according to the invention is preferably a gel
having a semisolid consistency. The consistency of the
gel can be determined using a' rotary viscometer. For
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the present invention and in particular also in the
following examples, a rotary viscometer (RheoStress
RS 150) from HAAKE was used. The measurements were
carried out at 20.0°C using measuring plates having a
diameter of 35 mm. The measuring gap was 0.5 mm. The
measurements were carried out as oscillation
measurements with shear stress requirement at constant
frequency (1.0 Hz). For this, the sample was
introduced into the measuring gap and the measuring
body was set into an oscillating motion (oscillation
requirement) and the response function of the sample
was measured. An accurate description of this method
is found in the HAAKE publication "Characterization of
Contact Adhesives (PSA systems)" by D. Eidman.
In this measuring process, the storage modulus G' can
be determined as a component of the strain energy which
can be stored elastically by the system, the loss
modulus G" as a component of the strain energy which is
irreversibly converted into viscous flow by the system,
and the loss angle 8 as the phase delay between the
oscillation requirement and response function as a
function of the shear stress i.
The flow limit of a substance or of a composition is
not precisely defined. One possibility for the
determination of the flow limit consists, however, in
the oscillation measurement described above. With
small amplitudes (shear stress i below the flow limit),
the loss angle 8 of the substance does not depend on i
(viscoelastic range). Under the influence of higher
shear stress, 8 increases greatly, which allows a
rather viscous behavior to be concluded. The critical
shear stress value on the transition from the linear
viscoelastic to the viscous range can be interpreted as
the flow limit (cf. H.-M. Petri in the HAAKE
publication "Determination of the Flow Limit in
Foodstuffs"). This value can be read off from a graph
in which the loss angle b is plotted against the shear
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stress i, at the transition of the resulting curve from
its virtually horizontal part to the steeper part.
An increased flow limit, that is an increased value for
the critical shear stress, confirms an increased
stability of the measurement sample with respect to
liquefaction. Qualitatively, such an increased
stability can also be recognized from an increase in
the maximum storage modulus G' in a plot of G' against
i.
As guidance for the assessment of the liquefaction, a
division can be used according to which a cosmetic milk
has a flow limit at a critical shear stress of < 10 Pa,
a lotion a flow limit at a critical shear stress of 10-
Pa and a cream a flow limit at a critical shear
stress of usually > 100 Pa. The flow limit of the gels
according to the invention is preferably at a critical
shear stress of above 20 Pa and particularly preferably
20 between 20 and 200 Pa. Gels having a flow limit at a
critical shear stress of below about 20 Pa begin
according to experience to flow under their own weight.
Semisolid gels are mainly understood in particular as
meaning those gels which do not flow under their own
weight.
However, it must be stressed that the above-described
critical shear stress at the flow limit of the gels
according to invention is of minor importance as an
absolute value for the present invention, since this
essentially depends on the determination method.
Moreover, according to the invention it is rather
significant that the sugar- or alcohol-containing gel
has a higher stability to liquefaction compared with
conventional, that is sugar- or alcohol-free, gels.
This effect is marked by a relative increase in the
critical shear stress at the flow limit or a relative
increase in the maximum storage modulus G' in
comparison with conventional gels.
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The phospholipid gels according to the invention are
distinguished in particular by the stability of their
consistency to the incorporation of additives, such as
pharmaceuticals or buffers, and in their application to
the skin or mucous membrane. The consistency of the
gels is stabilized in such a way that even on
incorporation of additives the semisolid state is
retained. Moreover, the properties of spreadability on
application to the skin or mucous membrane are also
retained.
Fig. 1 A shows the dependence of the loss angle 8 as a
function of the shear stress i for a gel not according
to the invention with addition of NaCl. Sometimes no
NaCl (~), sometimes 0.2~ NaCl (~), sometimes 0.4$ NaCl
(~) and sometimes 0.8~ NaC1 (~) were employed. From
figure 1 A, it is evident that the shear stress
changes with increasing salt concentration.
Fig. 1 B shows the dependence of the storage modulus G'
as a function of the shear stress i for a gel not
according to the invention with addition of NaCl. Here,
no NaCl (0),0.2$ NaCl (O),0.4~ NaCl (D) and 0.8~ NaCl
(O) were employed in the experiment. From figure 1 B,
it is evident that the maximum storage modulus G'
decreases with increasing salt concentration.
Fig. 2 A shows the dependence of the loss angle 8 as a
function of the shear stress i for a gel according to
invention, to which various amounts of NaCl have been
added. The symbols correspond to those of figure 1 A.
Fig. 2 B shows that in the gel according to the
invention the values hardly change even on addition of
NaCl. The meaning of the symbols of figure 2 B
corresponds to that of figure 1 B. The fact that the
values hardly change due to addition of NaCl shows the
superiority of the gel according to invention.
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Fig. 3 shows the dependence of the loss angle 8 (closed
symbols) and the storage modulus G' (open symbols) as a
function of the shear stress i for a gel not according
to the invention with and without BISTRIS buffer.
Fig. 4 shows the dependence of the loss angle b
(closed symbols) and the storage modulus G' (open
symbols) as a function of the shear stress i for a gel
according to the invention with and without BISTRIS
buffer.
The invention is illustrated in more detail by the
following examples without being restricted to these.
Example 1
In this example, various pharmaceutical-containing gels
according to the invention are prepared. Examples 1.1
to 1.4 show that various pharmaceuticals having
different solubility properties and in different
concentrations can be incorporated into the preparation
according to the invention.
Gels having the following compositions were prepared
(details in % by weight, if not stated otherwise):
Example 1.1
Acyclovir 5.0~
Nonhydrogenated lecithin 23.50
Propylene glycol 20.0
Ethanol 10.0
Sorbitol 2.50
Phosphate buffer 0.05M
Water to 100.0
Example 1.2
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Diphenhydramine HC1 1.0~
Nonhydrogenated lecithi 20.0
Propylene glycol 22.5s
Ethanol 5.0°s
Mannitol 5.0%
Water to 100.0
Example 1.3
Hydrocortisone 0.25
Nonhydrogenated lecithin 25.0
Propylene glycol 27.5
Trehalose 10.0%
BISTRIS 0.075M
Water to 100.0
Example 1.4
Calcitonin 100,000 I. U.
Nonhydrogenated lecithin 18.0g
Propylene glycol 25.0g
Glycerol 5.0g
Sucrose 6.0g
Water to 100.0g
Acyclovir is a substance which is poorly soluble in
water. Diphenhydramine HCl is a hydrophilic substance
which is very readily soluble in water as a salt.
Hydrocortisone is a lipophilic substance which is more
soluble in lipophilic solvents than in water.
Calcitonin is a hydrophilic protein which is soluble in
water.
This example shows that, with addition of
pharmaceuticals having very different dissolving
properties, phospholipid gels according to the
invention can be obtained.
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Example 2
Table 1 below contains a listing of the compositions of
further gels according to the invention. In addition
to a favorite base recipe, these gels contain various
pharmaceuticals in various concentrations. The
quantitative data of the individual constituents are
stated in % by weight based on the overall composition.
Table 1
Pharmaceutical PL PG EtOH BISTRIS Sorbi-
tol
Heparin Na 60 000 23.5 22.5 5 1.57 2.5
I.U
Diclofenac Na 1~ 23.5 22.5 5 1.57 2.5
Hydrocortisone l0 23.5 22.5 5 1.57 2.5
Xylometazoline HCl 23.5 22.5 5 1.57 2.5
0.1%
Indomethacin 1s 23.5 22.5 5 1.57 2.5
PL - phospholipid (Phospholipon 80); PG - propylene
glycol; EtOH = ethanol
Example 3
When incorporating pharmaceuticals or additives into
phospholipid gels, electrolytes are frequently
introduced into the preparations. Moreover, when
applying the gels to the skin, in particular the mucous
membrane, electrolytes such as, for example, salts from
the perspiration are dissolved in the gels. These
electrolytes can lead to a liquefaction of the gels.
This example shows the action of an addition of salt on
a phospholipid gel with and without sorbitol. The base
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recipe of the phospholipid gel had the following
composition: 23.5% by weight of phospholipid PL80,
22.50 by weight of propylene glycol, 5% by weight of
ethanol, 1.570 by weight of BISTRIS, remainder water.
0; 0.2; 0.4 and 0.8o by weight of NaCl were added to
this base recipe and using the oscillation measurement
generally described above, the loss angle 8 and the
storage modulus G' was determined for each recipe (not
according to the invention) as a function of the shear
stress i. The result of these measurements is shown in
figure 1 A and 1 B. It is seen that the critical shear
stress, that is the shear stress value at which the
curves shown climb steeply from their virtually
horizontal course, falls with increasing salt
concentrations. Moreover, the maximum storage modulus
G' falls with increasing salt content. This shows that
the flow limit of the gels falis with increasing salt
content and the gels thus liquefy more easily with
increasing salt concentration.
Figures 2 A and 2 B show the result of the same
measurement, 2.5o by weight of sorbitol and 0.2; 0.4
and 0.8% by weight of NaCl in each case being added to
the base recipe. It is seen that as a result of the
addition of sorbitol the influence of the electrolyte
on the flow limit and the maximum storage modulus G' of
the gel is virtually suppressed.
This experiment shows that the consistency of
phospholipid gels according to the invention is
retained despite addition of electrolytes such as NaCl.
Analogous measurements were carried out with addition
of various pharmaceuticals, such as acyclovir, heparin
Na and diclofenac Na, and various sugar alcohols and
sugars, such as glucose, sucrose, trehalose, xylitol
and fructose, comparable results being obtained.
CA 02381571 2002-02-08
- 20 -
Example 4
In this example, a buffer was added to a base recipe of
23.5% by weight of phospholipid, 22.5 by weight of
propylene glycol, 5.0o by weight of ethanol and water
to 100.0% by weight without and in the presence of 2.5°s
of sorbitol and the effect of this addition on the
proneness of the composition to liquefaction was
investigated.
BISTRIS was added to the recipe as a buffer. The
buffer concentration was 1.57 by weight.
The result for the oscillation measurement as described
above for the sorbitol-free gels (not according to the
invention) with and without BISTRIS is shown in figure
3. It is seen that the level of the storage modulus G'
is lowered in the presence of BISTRIS, just as the
critical shear stress, which is a measure of the flow
limit.
The result of the oscillation measurement using the
sorbitol-containing gels according to the invention
with and without BISTRIS is shown in figure 4. It is
seen that no lowering of the level of the storage
modulus G' or of the critical shear stress takes place.
The measured courses of the curves are virtually
identical.
This example shows that the addition of sorbitol to a
phospholipid gel virtually abolishes the proneness of
the gel to liquefaction on addition of a buffer. By
means of this, it is possible by incorporation of a
buffer into a phospholipid gel to increase
significantly the stability of this gel and thus the
storability of this gel.
CA 02381571 2002-02-08
- 21 -
Example 5
In this example, the subjective feeling on the topical
application of phospholipid gels according to the
invention and not according to the invention is
investigated. The compositions of the gels
investigated are shown in table 2, the compositions A,
B, D and F being compositions according to the
invention and the sorbitol-free composition C serving
as a comparison composition not according to the
invention. As an additional comparison composition, a
conventional acyclovir cream (composition E) was
included in the test.
Table 2
A B C D F
NAT 8450 20.0 20.0 20.0 5.0 -
PL 90 H 7.5 - - 7.5 6.0
Propylene glycol 20.0 30.0 20.0 30.0 20.0
Glycerol - 7.5 12.5 - -
Sorbitol 5.0 10.0 - 10.0 10.0
Acyclovir 5.0 5.0 5.0 5.0 5.0
PL 90 H = Phospholipon~ 90 H (hydrogenated)
NAT 8540 - 60% solution of Phospholipon 80 in propylene
glycol
The quantitative data in table 2 are in % by weight
based on the total composition, these in each case
being made up to 100% by weight with water.
The study was carried out as follows. Before the start
of the experiment, both lower arms and, before each
application, the index finger of each patient, were
wiped with Kleenex~. After each application cycle (all
six bases are applied), the application sites were
wiped with Kleenex~. A total of three cycles were
CA 02381571 2002-02-08
- 22 -
carried out. Per cycle, the subject once wore a strip
of 1 cm length on the inside of the lower arm and
spread this with the index finger. Per lower arm,
three formulations were applied.
The diameter of the base spread along the arm should be
at most 5 cm. The individual application sites should
not intersect.
After each application cycle, the subjects were ordered
to assess the spreadability on application
(consistency, cosmetic feel, etc), the appearance of
the formulation (hypo-/lipophilicity) and the remaining
feeling after the application (stickiness, skin
tautness, etc) and to assign the formulations to a rank
according to their popularity. Rank 1 had the best
assessment, rank 6 the worst.
The test was carried out with 13 subjects (spreacl
ability and hydro-/lipophilicity) or 11 subjects
(remaining feeling).
The evaluation was carried out according to the rank
total test (L. Sacks, Statistical Methods, Planning and
Evaluation, p. 85 ff). For this, the ranks which had
been assigned to a composition by each subject for each
investigated criterion (target criterion) were summed
(rank total) and compared with one another. A lower
rank total shows a greater popularity of a composition
in comparison and conversely.
The results of this investigation are shown in table 3.
For each composition A-F, for each target criterion (I
- spreadability, II - hydro-/lipophilicity, III -
remaining feeling), the rank to which each subject (1-
13) has assigned this is indicated. The subject 1 has,
for example, favored composition C (rank 1) in the
assessment of the spreadability (target criterion I)
and assessed the composition E to be the worst (rank
CA 02381571 2002-02-08
- 23 -
6). Moreover, the standard deviation (sdv), the rank
total (T - total of all ranks) and the number of
respective subjects (j) are indicated in the table for
each composition and each target criterion.
CA 02381571 2002-02-08
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- 26 -
It is seen that the subjective feeling was preferred
both for the spreadability on application and for the
appearance of the formulation for the gels according to
the invention (A, B, D and F) both compared with the
sorbitol-free gel not according to the invention (C),
and compared with the conventional cream (E). Although
for the remaining feeling a composition according to
the invention (F) was also favored, overall, however,
no uniform picture resulted.
