WO1998031326A1

WO1998031326A1 - Aqueous composition comprising biotin-containing liposomes

Info

Publication number: WO1998031326A1
Application number: PCT/EP1998/000175
Authority: WO
Inventors: Ernst E. TEICHMÜLLER; Gabriele Blume
Original assignee: Rovi Gmbh Handelsgesellschaft Für Rohstoffe
Priority date: 1997-01-18
Filing date: 1998-01-14
Publication date: 1998-07-23
Also published as: DE69804971T2; CN1249678A; DE19701651A1; EP1006985A1; EP1006985B1; DE69804971D1

Abstract

The present invention relates to an aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated, characterised in that the weight ratio of phospholipids to biotin is in the range of from 50:1 to 1000:1. The present invention also concerns the use of an aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated, for the external cosmetic or medical treatment of cutaneous appendages on humans or animals, as well as a method for preparing one embodiment of the composition according to the present invention.

Description

AQUEOUS COMPOSITION COMPRISING BIOTIN-CONTAINING LIPOSOMES

The present invention relates to an aqueous composition comprising liposomes in which biotin is encapsulated, and the use of the composition for the treatment of cutaneous appendages, particularly to promote hair growth.

Hair loss, whether it be caused by ageing, a certain illness, or chemotherapy, is a widespread problem. The best-known means, the efficacy of which has been described in connection with the promotion of hair growth, are pyrimi ine derivatives such as enoxidile and hormones from the oestrogen group. Both substances are to be classified as pharmaceuticals, and are thus only available on prescription.

The hair growth promoting effects of biotin (vitamin H) has been known for a long time. In a study carried out, it was possible to demonstrate that, after a daily oral dose of 2.5 g of biotin, there was a significant reduction of hair loss and considerable improvement in the quality of the hair (G.L. Floresheim, "Behandlung brϋchiger Nagel mit Biotin", Zeitschrift fur Hautkrankheiten, 67 (3), 246-255 (1992)).

Biochemical examinations carried out in vitro on human epidermis cells have shown that after dosage with high concentrations of biotin (over and above the normal physiological value), the differentiation of the epidermis cells to the keratinocytes was stimulated (A. Fritsche, Inaugural Dissertation, University of Zurich (1990)). Biotin is of vital significance for the proliferation and differentiation of all cells. It is a coenzyme for carboxylase reactions, and obviously also plays a role in a whole series of further metabolic functions, though these have as yet hardly been researched. Biotin is of especially great significance for tissue with high metabolic activity. The positive effects on the metabolic processes of keratinocytes, which induce constant growth of the hair, are only achieved if there is a sufficient level of biotin in the deep hair root (papilla). This level is achieved via the blood circulation, after biotin has been taken orally. However, since orally ingested biotin can only partially be absorbed in the intestine, far higher quantities of biotin must always be ingested than actually reach the area where it has its effect. The high price of biotin makes the poor bio-availability of orally ingested biotin a distinct disadvantage. Equally disadvantageous is the risk of side effects, which are always a possibility with orally administered active substances.

Possibilities for the topical application of biotin with a view to promoting hair growth have also been investigated. As biotin is barely soluble in both water and ethanol (0.02 weight X, and 0.08 weight X respectively), the effect of biotin in normal cosmetic formulations is questionable. So far, it is not known whether sufficient quantities of biotin can be absorbed from a formulation by the scalp. On pages 511 - 515 of the SOFW Journal 122, edition 8/96, F. Noser and R. Bimczok describe the effects on hair structure of biotin applied epicutaneously to the scalp. Lotions with a biotin content of between 0.003 and 0.01 weight % were used by 60 men with fine, brittle and healthy hair for 6 months. Although a slight strengthening of the hair was observed, it was not possible to ascertain any significant reduction in hair loss.

DE-A-19509036 shows compositions with skin-penetrating carrier particles, the construction of which involves at least one amphiphilic physiologically acceptable substance, and which contain either biotin or one of its salts, and are for the treatment of various skin disorders. The carrier particles can be liposomes, and a preferred composition contains 0.25 weight X carrier particles, 0.25 weight X biotin and 1.5 weight X each of the vitamins A and E. There is no description in DE-A- 19509036 of an application for the liposomes loaded with biotin on cutaneous appendages such as hair and nails. EP-A-0665002 concerns a protective, nourishing and/or firming cosmetic composition for the simultaneous treatment of the skin's surface and deeper layers, made of a first emulsion of lipid vesicles capable of penetrating into the deeper skin layers and a second emulsion of lipid vesicles capable of penetrating the surface layers of the skin. Each emulsion contains at least one active ingredient, selected from a large group of various active substances. The lipid vesicles can be constructed from a number of substances, including phospholipids. From a wide range of possible active substances, vitamin H, D-panthenol, vitamin E and caffeine are mentioned. EP-A-0665002 gives no example of a composition containing phospholipid liposomes loaded with biotin.

It is the object of the present invention of provide a biotin-containing composition for the external treatment of cutaneous appendages, in which composition the bio-avai lability of the biotin is improved, compared to already known compositions for the treatment of cutaneous appendages.

The object is met by an aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated, characterised in that the weight ratio of phospholipids to biotin is in the range of from 50:1 to 1000:1.

Further, the invention concerns the use of an aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated, for the external cosmetic or medical treatment of cutaneous appendages on humans or animals, as well as a method for preparing one embodiment of the composition according to the present invention.

Preferred embodiments are described in the claims set out below. In the sense of the present invention, biotin is understood to be D(+)- biotin, also known as vitamin H, and its salts.

Liposomes are spherical forms (vesicles) with a cover of one or several double layers of lipids (bilayers), which form dispersions with aqueous systems. Liposomes can be loaded with various active substances, as in the case at hand. As the vesicles display amphiphilic characteristics, the encapsulated substances can select their own preferred surroundings. The particle size of the liposomes in the present invention is preferably 70 to 300 nm (diameter), more preferably 150 to 200 n .

The phospholipids used in the present invention are preferably of soy origin, and have a phosphatidyl choline content of at least 73 weight X; a phosphatidyl choline content of 73 - 79 weight X is especially preferred. It is possible, for example, to use phospholipid fractions from: a) 73 - 79 weight X phosphatidyl choline, 0 - 6 weight X lyso- phosphatidyl choline, about 8 weight X phosphatidic acid, about 4 weight X phosphatidyl ethanolamine, and about 9 weight X other lipids; or b) 90 - 96 weight X phosphatidyl choline and 0 - 6 weight X lyso-phosphatidyl choline; or c) at least 95 weight X phosphatidyl choline and a maximum of 2 weight X lyso-phosphatidyl choline. All these percentages are based on the total weight of phospholipids.

The fatty acid residues of soybean phospholipids are mainly derived from unsaturated fatty acids, with linoleic acid accounting for the main part. A typical fatty acid line up is: 61 - 71 X linoleic acid, 3 - 7 X linolenic acid, 6 - 7 X oleic acid, 10 - 15 X palmitic acid, and 1.5 - 4 X stearic acid. All these percentages are based on the total weight of fatty acid residues. Hydrogenated and partially hydrogenated phospholipids with a phosphatidyl choline content of at least 73 weight X, preferably 75 - 95 weight X can also be used.

The weight ratio of phospholipids to biotin in the composition of the invention preferably ranges from 50:1 to 1000:1, more preferably from 100:1 to 500:1.

A phospholipid content of 5 - 20 weight X, based on the total weight of the composition, is advantageous. A phospholipid content of 8 - 12 weight X is especially preferred.

The proportion of biotin in the composition according to the present invention is preferably 0.001 - 0.5 weight X, more preferably 0.002 - 0.09 weight X, based on the total weight of the composition

The aqueous composition according to the present invention can contain not just biotin, but also further active ingredients to promote hair growth and/or hair regeneration, either alone or in combination. If this is the case, these active ingredients are also encapsulated in the liposomes, and the weight of these additional actives should preferably account to no more than 10 X of the total weight of the composition. Suitable active ingredients are, for example, D-panthenol, vitamin E and caffeine. An especially preferred embodiment of the invention contains a combination of these three active ingredients just mentioned in addition to biotin.

D-panthenol (provitamin B5) is a multi -active substance, which among other things has the property of making the hair up to 10 X thicker and regenerating damaged hair. Preferably, the proportion of D-panthenol is from 0.1 to 10 X, based on the total weight of the composition. Vitamin E stimulates hair growth by increasing the micro-circulation. Furthermore, it works as an anti-oxidant, and slows down the photo- oxidative degradation processes of the keratin and hair pigments. Generally, vitamin E is used in the form of vitamin E acetate, and the preferred proportion of vitamin E acetate in the composition according to the invention is from 0.05 to 5 X, based on the total weight of the composition.

Caffeine is another substance that induces hair growth. This non- hormonal substance inhibits 5-α-reductase, an enzyme which is activated by hormonal hair loss. Preferably, the proportion of caffeine in the composition is from 0.05 to 3 X, based on the total weight of the composition.

In addition to the components already mentioned and water, which generally accounts for the greatest proportion of the weight of the formulation, the composition of the invention can contain one or more types of alcohol. Generally, the proportion of the alcohol(s) is from 1 to 20 X, preferably from 3 to 18 X, based on the total weight of the composition. Ethanol is a particularly suitable alcohol, though i- propanol , for instance, may also be used.

As well as, or instead of, alcohol, the composition of the invention can contain a preservative. Suitable preservatives are, for example, formaldehyde, parabens and Euxyl® K 400. If the preservative is present along with alcohol, then the alcohol proportion is usually only from 1 to 5 weight X.

The balance of the composition according to the present invention to one hundred percent is water. The previously described proportions of the individual components of the composition of the invention refer to a so-called concentrate, which is diluted at a ratio of 1:3 to 1:15 before final use. A dilution ratio of between 1:3 and 1:10 is preferred. In the diluted composition, the following proportions of biotin and any other optional active ingredients are preferred: biotin 0.006 - 0.009 weight X, D-panthenol 0.3 - 1 weight X, vitamin E 0.2 - 0.9 weight X, and caffeine 0.1 - 0.3 weight X, each based on the total weight of the diluted composition.

The compositions of the invention can be produced in accordance with any method for the preparation of liposome suspensions known to the person skilled in the art, for instance those in the book "Liposomes - a practical approach" published by R. C. New (Oxford University Press, 1990). Those compositions of the invention which contain alcohol can for example be produced by dissolving the phospholipids in alcohol, then adding biotin and any other alcohol -soluble actives and stirring until these have dissolved. The resulting lipid solution is slowly added to water in which any other actives have been dissolved, and the mixture is then stirred. The liposomes which develop spontaneously are then reduced in size by applying energy supply, e.g. by stirring at high speed, high- pressure filtration, ultrasound, extrusion or homogenisation, until the desired particle size is arrived at. If oxygen-sensitive phospholipids are being used, the production process can be carried out partially or entirely under protective gas or at reduced pressure.

The liposomes in which the biotin and any other optional actives are encapsulated act as a carrier system for these actives. This means that the actives, having been applied externally to the appropriate area, can be carried directly through the upper layers of the skin to the place where the hair or other keratin formation originates, where it can then develop its effect without any side effects. The liposomes in the present invention act as a carrier system, to ensure that an adequate level of biotin and, if applicable, other actives is present in the epidermis cells. One advantage of the present invention is that, due to the improved transportation to the point of activity, the biotin and any other optional actives can be used in lower concentrations than have so far generally been used in comparable compositions. On the other hand, the solubility of the biotin is increased in the composition of the invention, with the result that in some cases it can be used epicutaneously in higher concentrations than were previously usual.

An aqueous composition containing phospholipid liposomes in which biotin is encapsulated can be utilised for the external treatment of cutaneous appendages on human beings and animals. This external treatment can serve both cosmetic and medical ends. The term cutaneous appendages applies particularly to human hair and nails, but also covers all animal keratin formations such as scales, tortoiseshell, wool, threads, talons, hooves, claws, horns, antlers, and beaks. The present invention concerns particularly the cosmetic treatment to promote hair growth, and strengthen hair growth and/or regeneration. The advantageous effect of the present invention is achieved by applying the aqueous composition comprising biotin-containing liposomes to the scalp.

The invention will now be illustrated, using a number of examples. The following percentages are all based on weight.

Exampl e A B C

Phosphol ipids 10.00 * 10.00 * 10.00 *

Ethanol 16.00 X 16.00 * 3.33 X

Biotin 0.09 % 0.02 X 0.02 X

D-panthenol 10.00 X 3.00 % 3.00 *

Vitamin E acetate 2.50 X 2.50 % 2.50 *

Caffeine 3.00 X 0.50 * 0.50 X

Euxyl® K 400 - - 0.30 X

Distil led water ad. 100 X ad. 100 * ad. 100 *

Lipid/biotin 111: 1 500: 1 500 : 1

The phospholipids used are a phospholipid fraction consisting of: phosphatidyl choline (73 - 76 X) lyso-phosphatidyl choline (0 - 6 X) phosphatidic acid (< 8 X) phosphatidyl ethanol amine (< 4 X) and other lipids (approx. 9 X) (percentages refer to dry substance) .

All three compositions A, B, and C are produced by first dissolving the phospholipids in ethanol, then adding biotin and vitamin E acetate, and stirring until all the substances are dissolved. The other active ingredients, i.e. D-panthenol and caffeine are dissolved in water. The phospholipid solution which has been prepared is added to this aqueous solution drop by drop at reduced pressure, and the mixture is stirred at high speed for approx. 45 minutes. Size evaluation of the liposomes by means of dynamic light scattering resulted in a particle diameter of 150 to 200 nm. In the case of composition C, the preservative Euxyl® K 400 is added after this.

All three compositions are concentrates which are dissolved in water before use, the ratio being 10:1 (A), or 3:1 (B and C).

Claims

1. An aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated, characterised in that the weight ratio of phospholipids to biotin is in the range of from 50:1 to 1000:1.

2. The aqueous composition of claim 1, characterised in that the weight ratio of phospholipids to biotin is in the range of from 100:1 to 500:1.

3. The aqueous composition of claims 1 or 2, characterised in that the proportion of phospholipids is from 5 to 20 X, based on the total weight of the composition.

4. The aqueous composition of claim 3, characterised in that the proportion of biotin is from 0.001 to 0.5 X, based on the total weight of the composition.

5. The aqueous composition of claim 4, characterised in that the proportion of biotin is from 0.002 to 0.09 X, based on the total weight of the composition.

6. The aqueous composition of any of claims 1 to 5, characterised in that additionally D-panthenol is encapsulated in said liposomes.

7. The aqueous composition of claim 6, characterised in that the proportion of D-panthenol is from 0.1 to 10 X, based on the total weight of the composition.

8. The aqueous composition of any of claims 1 to 7, characterised in that additionally vitamin E is encapsulated in said liposomes.

9. The aqueous composition of claim 8, characterised in that the proportion of vitamin E as vitamin E acetate is from 0.05 to 5 X, based on the total weight of the composition.

10. The aqueous composition of any of claims 1 to 9, characterised in that additionally caffeine is encapsulated in said liposomes.

11. The aqueous composition of claim 10, characterised in that the proportion of caffeine is from 0.05 to 3 X, based on the total weight of the composition.

12. The aqueous composition of any of claims 1 to 11, characterised in that the composition additionally comprises one or more alcohols.

13. The aqueous composition of claim 12, characterised in that the proportion of alcohol (s) is from 1 to 20 X, based on the total weight of the composition.

14. The aqueous composition of any of claims 1 to 13, characterised in that the phospholipids are obtained from soybeans and comprise phosphatidyl choline at a proportion of least 73 X, based on the total weight of phospholipids.

15. The aqueous composition of any of claims 1 to 13, characterised in that the phospholipids are hydrogenated and comprise phosphatidyl choline at a proportion of least 73 X, based on the total weight of phospholipids.

16. An aqueous composition obtainable by diluting the composition of any of claims 1 to 15 with water or any aqueous system at a ratio in the range of from 1:3 to 1:15.

17. Use of an aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated, for the external cosmetic treatment of cutaneous appendages on humans or animals.

18. The use of claim 17, characterised in that the cutaneous appendages are human hair.

19. The use of claim 18, characterised in that the cosmetic treatment serves to promote hair growth, and/or strengthen and/or regenerate hair.

20. Use of an aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated, for the manufacture of a medicament for external treatment of cutaneous appendages on humans or animals.

21. The use of any of claims 17 to 20, characterised in that the aqueous composition is an aqueous composition according to any of claims 1 to 16.

22. A method for preparing an aqueous composition according to any of claims 12 to 15, comprising

(a) dissolving phospholipids, biotin and any optional alcohol - soluble ingredients in alcohol,

(b) dissolving any optional water-soluble ingredients in water,

(c) slowly adding the alcoholic solution of step (a) to water or the aqueous solution of stage (b),

(d) stirring of the mixture, and

(e) reducing the size of the liposomes that have developed spontaneously, by means of energy supply.

23. A method for medical treatment of cutaneous appendages on humans or animals by topically applying an aqueous composition comprising liposomes of phospholipids, in which liposome biotin is encapsulated.

24. The method of claim 23, characterised in that the aqueous composition is an aqueous composition according to any of claims 1 to 16.