AU776766B2

AU776766B2 - Phospholipin gel

Info

Publication number: AU776766B2
Application number: AU72767/00A
Authority: AU
Inventors: Ruland Fridrich; Bernd Ibscher
Original assignee: Merckle GmbH
Current assignee: Merckle GmbH
Priority date: 1999-08-25
Filing date: 2000-08-16
Publication date: 2004-09-23
Anticipated expiration: 2020-08-16
Also published as: EP1206245A2; HUP0203097A2; WO2001013887A3; DE19940227A1; NO20020768L; WO2001013887A2; AU7276700A; JP2003507408A; RU2261088C2; CA2381571A1; CZ2002561A3; NO20020768D0; HUP0203097A3; PL353215A1; SK2442002A3; ZA200201506B

Description

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 2 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, 50% of a C 2 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 2propanol.

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 3 pharmaceutical, buffer or salt, in particular if readily soluble substances, such as, for example, diphenhydramine HCL, 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 Al. 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.

The present invention thus seeks to provide 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 of salt.

According to the invention, it has now been found that S 20 this problem can be solved by incorporating into the S. phospholipid gel a tetra-, penta- or hexahydric alcohol, and/or sugar.

The present invention thus relates to a phospholipid 25 gel, comprising 5-60% by weight of at least one phospholipid; at least 1% by weight of at least one di- or trihydric C2- 4 -alcohol; 30 0.5-35% by weight of at least one tetra-, pentaor hexahydric alcohol and/or at least one sugar; optionally one or more additives and water to 100% by weight, with the exclusion of formulations consisting of 500mg egg yolk lecithin, 400mg ethylene glycol or prnnvylne glvyconl 100nm of glucose solution in water at 1000mg/ml, and 100mg SPAN per l.lg of the gel.

P AWPDOCSCRN\SETrSp.76697 10 dc.l15/07/04 3a 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 4 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 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® H. Phospholipon® 80 comprises approximately 76% of phosphatidylcholine and approximately 3% of lyuploupiciidyluioline, Phospholipon® 90 H, a hydrogenated phosphatidylcholine, comprises at least of phosphatidylcholine and at most 4% of lysophosphatidylcholine. Phospholipon® 80 is also obtainable as a 75% strength solution in ethanol (NAT 5 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 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 to 30% by weight, of at least one di- or trihydric C2_ 4 -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 C 2 4 -alcohol in the gel according to the invention can vary over a wide 6 range. A content of 1-40% 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 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/ 20 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 25 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 30 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 iLesent and the nature of buffer which y be employed and on further additives present.

Furthermore, the content of higher-hydric alcohol or 7 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 2-20% by weight and in particular 2.5-10% 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.

8 The pharmaceutical active compound can be selected, for example, from the group consisting of antiinflammatories, 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, diphenhydramine, calcitonin and indomethacin or their pharmaceutically acceptable salt. It 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 9 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 10% 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 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 0 C was 58%. In a gel which was 10 BISTRIS-buffered and otherwise of the same recipe, the decrease after 36 weeks at 410C, however, was only 44%.

Buffers which have proven particularly suitable are BISTRIS (2-(bis(2-hydroxyethylimino)-2-hydroxymethyl)- 1,3-propanediol) (pKa phosphate buffer (buffer range sec-phosphate about hydrogencarbonate buffer (buffer range about maleate buffer (buffer range about TRIS: (trishydroxymethylaminomethane), MOPS: (3-[N-morpholino]propanesulfonic acid) and HEPES (N-[2-hydroxyethyl]piperazine- N'[2-ethanesulfonic acid). On account of its pKa of 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 phosph lipid 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, 11 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 HC1 in an amount of approximately 1% by weight, hydrocortisone in an amount of approximately 0.25-1% 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 23.5% 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 100% 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 12 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 13 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 20.00C 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 6 as the phase delay between the oscillation requirement and response function as a function of the shear stress T.

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 r below the flow limit), the loss angle 6 of the substance does not depend on Tr (viscoelastic range). Under the influence of higher shear stress, 6 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. 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 6 is plotted against the shear 14 stress T, 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 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 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 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.

15 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 6 as a function of the shear stress T 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% NaCl were employed. From figure 1 A, it is evident that the shear stress T changes with increasing salt concentration.

Fig. 1 B shows the dependence of the storage modulus G' as a function of the shear stress T for a gel not according to the invention with addition of NaCl. Here, no NaCl NaCl NaCl and 0.8% NaCl 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 6 as a function of the shear stress T for a gel according to invention, to which various amounts of NaCl have been added. The symbols correspond to those of figure 1 A.

i'g. 2 B shows thaL in the gel cco rding theinvention 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.

16 Fig. 3 shows the dependence of the loss angle 5 (closed symbols) and the storage modulus G' (open symbols) as a function of the shear stress T for a gel not according to the invention with and without BISTRIS buffer.

Fig. 4 shows the dependence of the loss angle 6 (closed symbols) and the storage modulus G' (open symbols) as a function of the shear stress T 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 Nonhydrogenated lecithin 23.5% Propylene glycol 20.0% Ethanol 10.0% Sorbitol Phosph ate buffer 0.u05M Water to 100.0% Example 1.2 17 Diphenhydramine HC1 Nonhydrogenated lecithi Propylene glycol Ethanol Mannitol Water 20.0% 22.5% to 100.0% Example 1.3 Hydrocortisone Nonhydrogenated lecithin Propylene glycol Trehalose

BISTRIS

Water 0.25% 25.0% 27.5% 10.0% 0.075M to 100.0% Example 1.4 Calcitonin Nonhydrogenated lecithin Propylene glycol Glycerol Sucrose Water 100,000 I. U.

18.0g 25.0g to 100.Og Acyclovir is a substance which is poorly soluble in water. Diphenhydramine HC1 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 pharmaceuticals having properties, phospholipid invention can be obtained.

that, very gels with addition of different dissolving according to the 18 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 Sorbitol Heparin Na 60 000 23.5 22.5 5 1.57

I.U

Diclofenac Na 1% 23.5 22.5 5 1.57 Hydrocortisone 1% 23.5 22.5 5 1.57 Xylometazoline HC1 23.5 22.5 5 1.57 0.1% Indomethacin 1% 23.5 22.5 5 1.57 PL phospholipid (Phospholipon 80); glycol; EtOH ethanol PG propylene 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 19 recipe of the phospholipid gel had the following composition: 23.5% by weight of phospholipid 22.5% by weight of propylene glycol, 5% by weight of ethanol, 1.57% by weight of BISTRIS, remainder water.

0; 0.2; 0.4 and 0.8% by weight of NaCl were added to this base recipe and using the oscillation measurement generally described above, the loss angle 6 and the storage modulus G' was determined for each recipe (not according to the invention) as a function of the shear stress T. 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 falls 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, 2.5% 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.

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, 5.0% by weight of ethanol and water to 100.0% by weight without and in the presence of 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 aUnd thus the storability of this gel.

21 Example 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 PL 90 H 7.5 7.5 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 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 eah 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 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 (spreadability and hydro-/lipophilicity) or 11 subjects (remaining feeling) The evaluation was carried out according to the rank total test Sachs, 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 (1i- 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 23 6) Moreover, the standard deviation (sdv), the rank total (T total of all ranks) and the number of respective subjects are indicated in the table for each composition and each target criterion.

24 Table 3 Sub- ABcD EF j ect 1 3 4 4 2 3 2 1 1 1 4 2 3 6 6 6 5 5 2 3 6 4 4 6 3 2 2 5 5 1 1 3 4 6 4 3 5 1 1 4 3 2 2 5 6 3 2 5 1 6 4 3 4 4 2 2 2 5 5 5 4 3 3 6 6 6 1 1 1 4 6 6 3 4 3 2 2 4 6 5 5 5 3 2 1 1 1 6 1.5 2.5 2 1.5 2.5 3 4 5 1 6 4 6 5 6 5 3 1 4 7 1 1 1 5 2 2 6 6 6 4 3 5 1 5 3 3 4 4 2 8 2 2 2 5 3 6 4 6 4 3 5 5 6 4 1 1 1 3 9 3 1 5 4 2 3 5 5 2 1 3 4 6 4 6 2 6 1 2 2 4 3 5 4 3 5 6 6 1 1 11 4 3 6 2 2 5 3 6 3 1 1 2 5 4 1 6 5 4 12 6 2 4 1 6 1 2 5 5 3 4 6 4 3 3 5 1 2_ 25 13 4 6 5 5 5 4 3 4 3 2 3 6 6 2 2 1 1 1 sdv 1.33 1.96 1.35 1.33 1.34 1.79 1.76 1.55 1.4 1.61 1.39 1.72 0.66 1.42 2.01 1.96 1.96 1.79 T 40.5 45.5 47 38.5 43.5 36 47 56 35 40 44 46 71 55 37 36 29 j 13 13 11 13 13 11 13 13 11 13 13 11 13 13 11 13 13 11 For a better general view, the results from table 3 are given once more in table 4 and sorted according to the target criteria T rank total, j number of subjects).

Table 4 I. Spreadability II.Hydro-/lipophilicity III. Remaining feeling A B C D E F A B C D E F A B C D E F T 40.5 38.5 47 40 71 36 45.5 43.5 56 44 55 29 47 36 35 46 37 j 13 13 13 13 13 13 13 13 13 13 13 13 11 11 11 11 11 11 26 It is seen that the subjective feeling was preferred both for the spreadability on application and for the apcearance of the formulation for the gels according to the invention B, D and F) both compared with the sorbitol-free gel not according to the invention and compared with the conventional cream Although for the remaining feeling a composition according to the invention was also favored, overall, however, no uniform picture resulted.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.

Persons skilled in the art will appreciate that numerous variations and modifications will become apparent. All such variations and modifications which become apparent to persons skilled in the art, should be considered to fall within the spirit and scope that the invention broadly appearing before described.

*e The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia.

Claims

5-60% by weight of at least one phospholipid; at least 1% by weight of at least one di- or tri- hydric C 2 4 -alcohol; 0.5-35% by weight of at least one tetra-, penta- or hexahydric alcohol and/or at least on6 sugar; optionally one or more additives and water to 100% by weight, the by weight data in each case relating to the total gel, with the exclusion of formulations consisting of 500mg egg yolk lecithin, 400mg ethylene glycol or Spropylene glycol, 100mg of a glucose solution in water at 100mg/ml, and 100mg SPAN per l.lg of the gel. 2. A phospholipid gel as claimed in claim 1, characterized in that the sugar is mono-, di- and/or an 25 oligosaccharide. *999 3. The phospholipid gel as claimed in claim 3, in which the phospholipid has a phosphatidylcholine content of at least 70% by weight based on the phospholipid. 4. A phospholipid gel as claimed in claim 3, in which the phospholipid is a nonhydrogenated phospholipid having a phospahatidylcholine content of at least 70% by weight based on the phospholipid. 28
6. A phospholipid gel as claimed in claim 1 or 2, in which the phospholipid comprises a hydrogenated phospholipid which contains at least 90% by weight of phosphatidylcholine.
7. A phospholipid gel as claimed in one of the preceding claims, comprising 5-35% by weight, preferably 15-25% by weight, of at least one phospholipid.
8. A phospholipid gel as claimed in one of the preceding claims, in which the di- or trihydric C2-4- alcohol is propanediol, in particular propylene glycol, glycerol or a mixture of these alcohols.
9. A phospholipid gel as claimed in one of the preceding claims, comprising 1-40% by weight, preferably 15-40% by weight, of at least one di- or trihydric C2- 4 -alcohol. A phospholipid gel as claimed in claim 9, comprising 15-30% by weight of propylene glycol and 0-10% by weight, in particular 2.5-7.5% by weight, of glycerol.
11. A phospholipid gel as claimed in one of the preceding claims, in which the tetra-, penta- or hexa- hydric alcohol or sugar is selected from glucose, fructose, sucrose, trehalose, xylitol, maltitol, inositol, inositol, sorbitol and mannitol.
12. A phospholipid gel as claimed in one of the preceding claims, comprising 2-20% by weight, in particular 2.5-10% by weight, of at least one tetra-, penta- or hexahydric alcohol or sugar.
13. A phospholipid gel as claimed in one of the preceding claims, comprising a pharmaceutical active compound selected from the group consisting of anti- 29 inflammatories, nonsteroidal antirheumatics, corticoids, peptides, hormones, enzymes, nucleic acids, virustatics, vitamins, local anesthetics, antimycotics, antibiotics, circulation-promoting agents, a-sympatho- mimetics, antipsoriatics and nose drops.
14. A phospholipid gel as claimed in one of the preceding claims, comprising a pharmaceutical active compound selected from acyclovir, heparin, diclophenac, hydrocortisone, xylometazoline, diphenhydramine, calcitonin, cyclosporin, indomethacin and insulin. A phospholipid gel as claimed in one of the preceding claims, comprising up to 10% by weight of at least one alcohol selected from ethanol, 1-propanol and 2-propanol.
16. A phospholipid gel as claimed in one of the preceding claims, comprising at least one buffer having a high buffer capacity in the range from pH 5.5-8.0, preferably approximately pH
17. A phospholipid gel as claimed in claim 16, in which the buffer is selected from BISTRIS, phosphate buffer, hydrogencarbonate buffer, maleate buffer, HEPES, TRIS and MOPS.
18. A phospholipid gel as claimed in one of the preceding claims, which is free of other thickeners, emulsifiers, consistency-imparting agents and/or gel- forming agents.
19. A cosmetic or pharmaceutical formulation, comprising a phospholipid gel as claimed in one of claims 1-18. A cosmetic or pharmaceutical formulation as claimed in claim 19 for topical application. P XWPDOCS\CRNMSE1.Sp.\766971 doc-15/07104 30
21. A cosmetic or pharmaceutical formulation as claimed in claim 19, it being a lip gel, nasal gel, ophthalmic gel, vaginal gel or anal gel.
22. The use of a phospholipid gel as claimed in one of claims 1-18 for the production of a cosmetic or pharmaceutical formulation.
23. A process for the production of a phospholipid gel as claimed in one of claims 1-18 or of a cosmetic or pharmaceutical formulation as claimed in one of claims 19 to 21, in which the gel is prepared by mixing the constituents under vacuum or under an inert gas atmosphere.
24. Phospholipid gel, cosmetic or pharmaceutical formulation comprising said phospholipid gel, or process for the production of said phospholipid gel or cosmetic or pharmaceutical formulation, substantially as 20 hereinbefore described, with reference to the accompanying Examples. DATED this 14th day of July, 2004 MERCKLE GMBH by its Patent Attorneys DAVIES COLLISON CAVE