WO1995001776A1

WO1995001776A1 - Phospholipid composition and use of a composition of this kind

Info

Publication number: WO1995001776A1
Application number: PCT/DE1994/000732
Authority: WO
Inventors: Jörg-Christian Hager; Wolfgang Bentheimer; Evelyn Brock; Ursula Schmidt
Original assignee: Rhone-Poulenc Rorer Gmbh
Priority date: 1993-07-03
Filing date: 1994-06-20
Publication date: 1995-01-19
Also published as: DE4322158C2; DE4322158A1

Abstract

Described is a phospholipid composition containing at least one phospholipid plus water and, optionally, an organic solvent. The composition includes a mixture of liposomes and spherical or near-spherical lipid vesicles, the lipid vesicles containing, in addition to at least one phospholipid, at least one lipophilic substance and the ratio by weight of the phospholipid in the liposomes to the lipid vesicles lying between 5:1 and 1:5.

Description

Phospholipidic composition and use of such a composition

The present invention relates to a phospholipid composition with the features of the preamble of claim 1 and its use as a pharmaceutical or cosmetic preparation.

Phospholipidic compositions have been known for a long time and are also used in cosmetic or pharmaceutical preparations. For example, H.P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and neighboring areas, Verlag Editio Kantor, Eulendorf, 1989, page 744-746 a corresponding overview of phospholipids, their use and their structure.

Lautenschläger et al in their publication (Seifen-Öle-Fette-Wwachs, 114 (1988), 531 ff) emphasize the importance of soy phospholipids in cosmetics, while Skoza and Papahadjopoulos provide a detailed description of the manufacture special phospholipids (Ann. Rv. Biophys. Bioeng. 1980, 9, 467-476).

The aforementioned phospholipids, in particular soybean phospholipids, are often offered for pharmaceutical and / or cosmetic use in aqueous systems, such aqueous systems then containing liposomes. Liposomes represent vesicles with a wide variety of structures, with a distinction being made between unilamellar, oligolamellar, multilamellar or fused bodies, depending on the respective production process becomes. These liposomes have a hollow body structure, in which the shell of the hollow body is formed by a phospholipid membrane. Their diameter varies between approximately 15 nm and 3,500 nm.

Similar to the biological cells, liposomes can store water-soluble substances in their vesicular inner areas and / or amphiphilic and / or lipophilic substances in their membranes, such liposomes then being referred to as loaded liposomes.

However, the storage capacity of the known liposomes for lipophilic substances described above is low. Depending on the chemical composition of the phospholipids used for the production of the liposomes, the known liposomes can absorb up to a maximum of about 30% of their weight special lipophilic substances, such as triglycerides, which means nothing else that even a extremely highly concentrated liposome system, which contains about 10% by weight of phospholipid, contains a maximum of about 3% by weight of lipophilic substance. This relatively low storage capacity of the known liposome systems is further illustrated by the fact that comparable oil-water emulsions have concentrations of lipophilic substances which vary between 10% by weight and 20% by weight.

The present invention has for its object to provide a phospholipid composition of the type specified, which has a significantly improved storage capacity for hydrophilic and / or lipophilic substances.

According to the invention, this object is achieved by a phospholipid composition having the characterizing features of patent claim 1.

The phospholipid composition according to the invention, which in addition to water and optionally an organic solvent contains at least one phospholipid, has a mixture of liposomes and spherical or spherical lipid vesicles, the lipid vesicles also containing at least one lipophilic substance in addition to the at least one phospholipid and the mass ratio of the

Phospholipids in the liposomes to the lipid vesicles varied between 5: 1 and 1: 5. In other words, the composition according to the invention is an aqueous system which, in addition to liposomes, also has those spherical or spherical lipid vesicles which, from the at least one phospholipid which must necessarily contain the phospholipid composition according to the invention, furthermore also from at least one lipophilic Substance is formed.

The phospholipid composition according to the invention has a number of advantages.

First of all, it should be noted that the phospholipid composition according to the invention has a significantly increased storage capacity for lipophilic substances compared to a conventional composition containing liposomes, so that the composition according to the invention in particular also for the topical use of cosmetic and / or pharmaceutical compounds suitable is. This significantly improved storage capacity for lipophilic substances is not only attributed to the presence of the spherical or spherical lipid vesicles. Rather, it is assumed that the simultaneous presence of liposomes and lipid vesicles in the mass ratio given above causes a synergistic effect which leads to a corresponding increase in the storage capacity for lipophilic substances. Furthermore, the composition according to the invention permits the simultaneous absorption of lipophilic substances in the lipid vesicles and of hydrophilic substances which are embedded or attached within the liposomes or on their membrane walls. By such a simultaneous Absorption of hydrophilic and lipophilic substances, the cosmetic and / or pharmaceutical applications of the composition according to the invention are duplicated. Furthermore, it was found that the composition according to the invention penetrates the skin excellently when applied topically. This also applies in particular to those embodiments of the composition according to the invention which at the same time have hydrophilic and lipophilic substances, in particular hydrophilic and lipophilic pharmaceutical and / or cosmetic active ingredients. In these embodiments of the preparation according to the invention, the hydrophilic substances are then in liposomally packaged form, the phospholipid representing the outer lipid double membrane. The lipophilic substances comprise the lipid vesicles described above, these lipid vesicles being stabilized by coating them with phospholipid molecules. This in turn means that both the appropriately loaded liposomes and the lipid vesicles have an outer membrane made of at least one phospholipid, which in turn means that when applied topically to the skin it is only a natural product that is which is at least one phospholipid, comes into contact. This explains that the composition according to the invention has a high level of skin tolerance and thus enables gentle application to the skin, so that skin irritations do not occur even with those hydrophilic or lipophilic substances which, as pure substances, cause considerable skin irritation when used topically - call. Furthermore, the preparation according to the invention and in particular due to the outer phospholipid membrane makes the penetration of hydrophilic and / or lipophilic substances provided in the composition according to the invention considerably easier, as already mentioned above. Surprisingly, it was also found that particles were present when hydrophilic and lipophilic substances, in particular hydrophilic and lipophilic active substances, were present at the same time Form (liposomes or lipid vesicles loaded with the respective substance), each having a size that is particularly suitable for penetration into the skin. In the composition according to the invention, the hydrophilic and / or lipophilic substances are also particularly well protected against external influences, in particular chemical influences, so that the composition according to the invention gives the lipophilic and / or hydrophilic substances provided therein a high durability.

A first, particularly suitable embodiment of the composition according to the invention has a mass ratio of the phospholipid in the liposomes to the lipid vesicles of between 5: 2 and 5: 4. This embodiment is distinguished by a particularly good penetration capacity through the human skin when the phospholipid composition according to the invention is applied topically.

With regard to the solvent which can be contained in the composition according to the invention, it can generally be stated that this is a solvent which is non-toxic and does not cause skin irritation. The composition according to the invention preferably has propylene glycol and / or ethanol as solvent.

Another embodiment of the composition according to the invention has lipid vesicles which consist of at least one lipophilic substance and in particular at least one lipophilic pharmaceutical and / or cosmetic active substance as the core, this lipophilic substance or this lipophilic active substance is stabilized on its surface by at least one phospholipid as a membrane-like shell. Of course, such a lipid vesicle can also consist of at least one lipophilic substance as the core, this lipophilic core substance then being loaded with at least one lipophilic pharmaceutical and / or cosmetic active ingredient. which is then enclosed by the membrane-like, at least one phospholipid shell. Here, such embodiments of the composition according to the invention have a high penetration capacity with respect to human skin, as has already been explained above. Furthermore, the at least one phospholipid present in the shell prevents such a stabilized substance or active ingredient from aging during storage, so that very stable compositions can be produced in this way.

With regard to the at least one phospholipid provided in the composition according to the invention, it should generally be stated that any phospholipid is suitable for this. In particular, however, the composition according to the invention has a soy phospholipid as phospholipid, i.e. thus a phospholipid mixture which is isolated from soy beans by methods known per se.

A particularly good storage capacity for lipophilic and hydrophilic substances, in particular pharmaceutical and / or cosmetic active ingredients, is ensured if the composition according to the invention comprises a phospholipid mixture which in particular contains phosphatidylcholine. Depending on the respective field of application, a soy-phospholipid mixture of this type is used for this, which is highly pure and contains 93 ± 3% by weight phosphatidylcholine and 3 +, 3% by weight lysophosphatidylcholine. Furthermore, a soy-phospholipid mixture which has 76 + 3% by weight phosphatidylcholine and 3rd + 3% by weight lysophosphatidylcholine can also be used in the composition according to the invention.

In a preferred embodiment, the acyl residues in the phospholipid mixture are composed of the following acyl residues: 61-73% by weight of linoleic acid residues, 10-14% by weight of palmitic acid residues, 8-12% by weight of oleic acid residues, 4-6% by weight of linoleic acid residues and 2% by weight of other fatty acid residues.

With regard to the at least one phospholipid that is also provided in the composition according to the invention, it should be noted that two possibilities are conceivable here in principle. Thus, the first possibility provides that the composition according to the invention has those liposomes and lipid vesicles which consist of the same phospholipid or the same phospholipid mixture. This first option is then particularly easy to manufacture.

In the second possibility, the composition according to the invention has liposomes and lipid vesicles, but the phospholipid or phospholipid mixture forming the liposomes is different from the phospholipid or phospholipid mixture which together with the at least one lipophilic substance and / or the at least one lipophilic pharmaceutical and / or cosmetic active ingredient that forms lipid vesicles. In this embodiment it is possible, by varying the phospholipid or phospholipid mixture, to adapt the properties of the liposomes or lipid vesicles specifically to the hydrophilic substance or lipophilic substance used in each case.

If the composition according to the invention is used for cosmetic and / or pharmaceutical use, it is advisable to design the average particle size of the liposomes in such a way that they have a value between 100 nm and 350 nm, in particular between 150 nm and 250 nm ¬ points.

With regard to the average particle size of the lipid vesicles, it should be noted that this preferably varies between 50 nm and 200 nm, in particular between 80 nm and 100 nm. The reason for the preferred mean particle sizes of the liposomes and lipid vesicles reproduced above is to be seen in the fact that those embodiments of the composition according to the invention which have the specific above-mentioned mean particle size are particularly rapid when applied topically through human skin penetrate. For example, after applying such an embodiment of the composition according to the invention to the skin, it can be observed that it is immediately absorbed by the skin, so that after a short rub on the skin surface no residues of the composition can be found.

Depending on the particular field of application of the composition according to the invention, the composition according to the invention can be solid, liquid, creamy or gel-like. If the composition according to the invention is used in the cosmetic and / or pharmaceutical field, it makes sense to provide a liquid to cream-like consistency, the viscosity of which varies between 150 mPa • s and 5,000 mPa • s. Such embodiments of the composition according to the invention can then be handled particularly easily in a topical application.

With regard to the water content in the composition according to the invention, it should be noted that this water content varies between 40% by weight and 60% by weight. Distilled water and / or purified water (DAB 10) are understood to be water in the sense of the present invention. Furthermore, the term water includes all aqueous solutions, in particular physiological saline solutions, or buffer solutions, in particular phosphate buffer.

With regard to the organic solvents already mentioned above, which may possibly be present in the composition according to the invention, it should be noted that their Concentration varies between 5% and 20% by weight. In addition to the solvents already mentioned (ethanol and propylene glycol), propanol-1, propanol-2 or mixtures of the solvents listed are also suitable.

The presence of the aforementioned organic solvents in the composition according to the invention has the additional advantage that these solvents or solvent mixtures of the composition according to the invention have a preservative effect, so that opened units have a longer shelf life.

With regard to the at least one phospholipid or phospholipid mixture contained in the composition according to the invention, it should be noted that its concentration preferably varies between 5% by weight and 40% by weight.

The concentration data (% by weight) given in the present application all relate to the ready-to-use composition according to the invention, unless another reference is expressly disclosed.

As has already been mentioned several times above, the composition according to the invention preferably has a pharmaceutical and / or a cosmetic active ingredient. It was found here that a pharmaceutical and / or cosmetic composition of this type, when applied topically, produces very good and reproducible treatment effects.

A particularly suitable development of the composition according to the invention has a mixture of active substances, in particular such a mixture which contains at least one hydrophilic active substance and at least one lipophilic active substance. The at least one hydrophilic active ingredient is then preferably encapsulated in the liposomes, while the lipophilic active ingredient in particular is embedded in the lipid vesicles and / or is attached to the lipid vesicles. Compositions constructed in this way can be stored over a longer period of time, even over a period of several years, without the cosmetic and / or pharmaceutical properties deteriorating as a result.

In principle, all the hydrophilic or lipophilic active substances which are taken up or incorporated by the liposomes or lipid vesicles present in the composition according to the invention can be used in the composition according to the invention. However, it is particularly suitable if the composition according to the invention has allantoin, biohyaluronic acid and / or panthenol as the hydrophilic active ingredients, such hydrophilic active ingredients then preferably being incorporated into the liposomes or attached to the lipid membrane of the liposomes.

With regard to the concentration of the aforementioned hydrophilic active ingredients, it should be noted that the composition according to the invention preferably contains 0.05% by weight to 0.3% by weight of allantoin, 0.0005% by weight to 0.01% by weight of biohyaluronic acid and / or 0.1 wt% to 1 wt% panthenol.

If the composition according to the invention is used for the therapy and / or prophylaxis of skin diseases, in particular neurodermatitis or psoriasis, a further embodiment of the composition according to the invention has a lipophilic active ingredient which is selected from the group vitamin A, vitamin C, vitamin E and / or derivatives of the aforementioned vitamins is selected. In this case, this lipophilic active ingredient is provided in the lipid vesicles contained in the composition according to the invention, with such a composition then preferably between 1.5% by weight and 3% by weight of vitamin A, 0.01% by weight to 0.1 % By weight of vitamin C and / or 5% by weight to 15% by weight of vitamin E. In particular when the composition according to the invention contains the aforementioned hydrophilic active ingredients (allanoin, biohyaluronic acid and / or panthenol) in the concentrations listed therein as well as the preferred lipophilic active ingredients (vitamin A, vitamin C, vitamin E and / or derivatives of these vitamins) in the mass ratios also given, such an embodiment of the composition according to the invention is eminently suitable for the prophylaxis or therapy of skin diseases, in particular any form of neurodermatitis and psoriasis. Likewise, the composition according to the invention can be used in the cosmetic field, in which case such cosmetic preparations then preferably have the aforementioned hydrophilic and / or lipophilic active ingredients. The concentration of these active ingredients is then usually reduced in cosmetic preparations in comparison to pharmaceutical preparations, ie corresponding cosmetic embodiments then have active ingredient concentrations which are approximately 30% to 50% below the concentrations which are previously specified for pharmaceutical preparations.

Further hydrophilic active substances which can be provided in the composition according to the invention include heparin sodium, chlorhexidine (as gluconate or as hydrochloride), urea, hexamidine isethionate and / or resorcinol.

Depending on the active substance selected, compositions containing such active substances are suitable for the treatment of superficial venous diseases, for disinfection, for moisture retention in the skin or as a preparation with itching-reducing activity.

In addition to the aforementioned lipophilic active ingredients or instead of the aforementioned lipophilic active ingredients, the composition according to the invention can also contain retinoids, steroids, contain vegetable and / or animal oils, linoleic acid, radical scavengers and / or UV absorbers, the selection of these active substances being based on what the composition according to the invention is to be used for.

As already mentioned above, the composition according to the invention can be in the form of creams, gels, pastes or ointments, it being very easy to produce appropriate aqueous systems from these by adding water, which can then be applied topically. Systems diluted in this way are then also particularly suitable for cosmetic use.

Advantageous developments of the composition according to the invention are specified in the subclaims.

The composition according to the invention is explained in more detail below using exemplary embodiments.

Embodiment 1

507.0 g of purified water were placed in a beaker. The compounds listed below were dissolved in this water:

5.0 g dexpanthenol

2.0 g allantoin

0.01 g of biohyaluronic acid and

0.25 g trometamol

The solution thus prepared was referred to as solution A.

A second solution B was prepared in a beaker, this solution containing 0.5 g ascorbyl palmitate and 26.7 g propylene glycol. For this it was necessary to heat the propylene glycol to 50 ° C. Having a clear 333.3 g of a phospholipid solution were added to the solution.

The phospholipid solution listed above was composed of 60% by weight of a phospholipid preparation in propylene glycol, the phospholipid preparation being composed as follows:

80% by weight phosphatidylcholine 8% by weight phosphatidic acid

4% by weight of phosphatidylethanolamine and 8% by weight of further phospholipids.

The solution thus prepared was stirred until this solution was clear.

210.5 g of solution B were removed and 25 g of retinol palmitate and 100 g of tocophenol acetate were dissolved therein. In order to obtain a clear yellow solution, solution C had to be heated to approx. 40 ° C. The solution thus prepared was referred to as Solution C.

Solution A (514.26 g) was placed in a batch container. 150 g of solution B were sucked into this solution by vacuum, stirring being carried out continuously at 300 rpm.

Then 333.5 g of solution C were sucked in and stirred at 1,000 rpm for 15 minutes. This resulted in a cream-white, firm, homogeneous gel. After the stirring speed had been reduced again to 300 rpm, the pH was adjusted to 6.7 using an aqueous solution containing 0.25 g of trometamol. The gel obtained after that was designated Gel I.

Embodiment 2

A solution A was prepared as described in Example 1 above. To prepare solution B, 0.5 g of ascorbyl palmitate was dissolved in 26.7 g of ethanol. In order to prepare solution C, in addition to 100 g of tocopheroacetate, 333.3 g of a 60% by weight phospholipid solution in ethanol were added to the clear solution, the phospholipid fraction selected for this having the composition as described above in the exemplary embodiment 1 is described. The further processing with the formation of a gel II was carried out as described above in exemplary embodiment 1. The gel so produced was named Gel II.

Embodiment 3

A gel III was produced as described in Example 1 above. Deviating from this, however, a different phospholipid fraction was used, this phospholipid fraction having the following composition:

93% by weight phosphatidylcholine

3% by weight of lysophosphatidylcholine and

4% by weight of other phospholipids.

Otherwise, the preparation of gel III was analogous to the preparation of gel I.

Embodiment 4

A gel IV was produced from the components of embodiment 3, but in contrast to embodiment 3 mentioned above, ethanol IV was used instead of propylene glycol in the case of the gel IV. Otherwise, the preparation of gel IV corresponded to the preparation of gel III.

The gels I to IV described above were tested for psoriasis and neurodermatitis with regard to their effectiveness. continuous For this purpose, a target group was selected, each consisting of 20 subjects, of whom 10 subjects were treated with gels I to IV and 10 subjects with a blind pattern, which differed from gels I to IV in that the Blind patterns showed no panthenol, alantoin, no biohyaluronic acid and no ascorbyl palmitate, tocophenol acetate and retinol palmitate.

For treatment, defined amounts of gel were applied to a precisely marked area of skin, the application of 0.2 g / 10 cm ^{2 being carried out} three times a day.

After 8 days and 14 days, a subjective evaluation was carried out by 3 physicians who were not involved in the experiment, and the table below shows the percentage healing.

10 subjects each psoriasis atopic dermatitis treated with% healing% healing in days 8 14 8 14

Gel I 80 92 75 90

Gel II 83 97 76 91

Gel III 87 96 79 93

Gel IV 91 98 83 100

Blind test 10 15 18 21

(without active ingredients)

Claims

claims

1. Phospholipidic composition which, in addition to water and optionally an organic solvent, contains at least one phospholipid, characterized in that the composition comprises a mixture of liposomes and spherical or spherical lipid vesicles, the lipid vesicles in addition to the at least one phospholipid further contain at least one lipophilic substance and the mass ratio of the phospholipid in the liposomes to the lipid vesicles varies between 5: 1 and 1: 5.

2. Composition according to claim 1, characterized in that the mass ratio of the phospholipid in the liposomes to the lipid vesicles varies between 5: 2 and 5: 4.

3. Composition according to claim 1, characterized gekennzeich¬ net that the organic solvent is propylene glycol and / or ethanol.

4. Composition according to one of the preceding claims, characterized in that the composition comprises those lipid vesicles which consist of lipophilic active substances which are stabilized on the surface by phospholipids.

5. Composition according to one of the preceding claims, characterized in that the composition has a soy phospholipid as Phos¬ pholipid.

6. Composition according to .Anspruch 5, characterized gekennzeich¬ net that the soy phospholipid

76 +.3% by weight phosphatidylcholine and 3 + 3% by weight lysophosphatidylcholine

contains.

7. The composition according to claim 5, characterized in that the soy phospholipid

93 ± 3% by weight phosphatidylcholine and 3 ± 3% by weight lysophosphatidylcholine

contains.

8. Composition according to one of the preceding claims, characterized in that the liposomes and the Lipidve¬ sicles contain the same phospholipid.

9. Composition according to one of the preceding claims, characterized in that the liposomes have an average particle size between 100 nm and 350 nm, preferably between 150 nm and 250 nm.

10. Composition according to one of the preceding claims, characterized in that the lipid vesicles have an average particle size between 50 nm and 200 nm, in particular between 80 nm and 150 nm.

11. Composition according to one of the preceding claims, characterized in that the composition has a viscosity between 150 and 5,000 mPa.s.

12. Composition according to one of the preceding claims, characterized in that the composition comprises between 40% by weight and 60% by weight of water.

13. Composition according to one of the preceding claims, characterized in that the composition contains between 5% by weight and 20% by weight of organic solvent.

14. Composition according to one of the preceding claims, characterized in that the composition has the phospholipid in a concentration between 5% by weight and 40% by weight.

15. Composition according to one of the preceding claims, characterized in that the composition contains at least one pharmaceutical active ingredient or one cosmetic active ingredient.

16. Composition according to one of the preceding claims, characterized in that the composition comprises a mixture of active ingredients.

17. The composition according to claim 16, characterized in that the composition comprises a mixture of a hydrophilic active substance with a lipophilic active substance, the hydrophilic active substance being encapsulated in the liposomes and the lipophilic active substance being contained in the lipid vesicles.

18. Composition according to one of the preceding claims, characterized in that the hydrophilic active ingredient comprises allantoin, biohyaluronic acid and / or panthenol.

19. The composition according to claim 18, characterized in that the composition of hydrophilic active ingredients in a concentration of 0.05% by weight to 0.3% by weight of allantoin, 0.0005% by weight to 0.01% by weight of biohyaluronic acid and / or 0.1% by weight to 1% by weight of panthenol.

20. Composition according to one of claims 18 to 19, characterized in that the composition contains a lipophilic active ingredient selected from the group vitamin A, vitamin C, vitamin E and / or derivatives thereof.

21. The composition according to claim 20, characterized in that the composition 1.5% by weight to 3% by weight of vitamin

A, 0.01 to 0.1% by weight of vitamin C and / or 5% by weight to 15% by weight of vitamin E.

22. Use of the composition according to one of the preceding claims for the prophylaxis or therapy of skin diseases.

23. Use of the composition according to one of the preceding claims as a cosmetic preparation.