United States Patent:   5,985,296

Assignee:  Wacker-Chemie GmbH (Muchen, DE)

Filed:  March 20, 1998

Complexes of .gamma.-cyclodextrin and retinol or retinol derivatives, along with processes for their preparation and compositions for their use. The complexes are useful in cosmetic formulations and in pharmaceutical formulations.

SUMMARY OF THE INVENTION

The present invention relates to compositions containing complexes of .gamma.-cyclodextrin and retinol or retinol derivatives.

For the purposes of the invention, retinol derivatives are defined to mean retinyl esters (vitamin A esters) and vitamin A acid, (retinoic acid). Retinol derivatives are preferably defined to mean retinyl esters. In the following, the term complex includes retinol as well as retinol derivatives.

The complexes according to the invention have unexpectedly greater stability than known prior art cyclodextrin/retinol complexes.

Compared to the complexes of retinol with .beta.-cyclodextrin, the complexes of the present invention achieve markedly improved stabilization of the active substance. The vitamin A content of the .gamma.-cyclodextrin formulation of the invention following storage under atmospheric oxygen and irradiation with UVA light, was substantially greater than that of a corresponding .beta.-cyclodextrin formulation. The complexes according to the invention thus make it possible for retinol and also retinol derivatives to be widely used in cosmetics, in pharmaceuticals, and in food products.

Despite the prior art possibility of using .beta.-cyclodextrin or .beta.-cyclodextrin derivatives for the inclusion and stabilization of retinol and retinol derivatives, extra stabilizer substances must necessarily be used with these .beta.-cyclodextrin complexes. Thus, stabilizers preferentially have been added to these prior art formulations in order to increase the stabilization of retinol in the formulations.

This necessity for using extra stabilizers indicates that persons skilled in the art considered the possibility of increasing the stability of retinol using cyclodextrins or cyclodextrin derivatives to be nonexistant. Thus, these persons sought other ways for increasing the stability of retinol or its derivatives.

The novel complexes of .gamma.-cyclodextrin with retinol of the present invention can be prepared by known processes. For example, they can be prepared from solution, or by using the paste kneading procedure. The present invention thus further relates to processes which comprise complexing retinol or complexing a retinol derivative using .gamma.-cyclodextrin.

Surprisingly, it has been found that retinol can be complexed and stabilized in an excellent manner by .gamma.-cyclodextrin. The processes according to the present invention stabilize retinol and protect retinol from oxidative decomposition to a greater extent than the known prior art processes.

The preparation of the complexes according to the invention from concentrated, aqueous .gamma.-cyclodextrin solutions has been found to be advantageous. The .gamma.-cyclodextrin concentration in the aqueous solution ranges from 5% to 50% by weight, based upon the total solution weight. Preferably the .gamma.-cyclodextrin concentration in the aqueous solution ranges from 20% to 50% by weight, based upon the total solution weight. The weight ratio of retinol to .gamma.-cyclodextrin ranges between 1:20 and 1:1, and preferably ranges between 1:12 and 1:4.

The formulations are thoroughly mixed, for example, by vigorously stirring or kneading, depending on the consistency of the formulation.

The reaction temperature preferably ranges from 20^oC.-80^oC., particularly preferably ranges from 20^oC.-60^oC., and especially preferably ranges from 40^oC.-60^oC. The reaction time depends upon the temperature and is between one hour and several days. A reaction time of from 12 to 96 hours is preferred. The complexation reaction is preferably carried out under atmospheric pressure. The complexation reaction is preferably carried out under a protective gas atmosphere such as nitrogen or argon.

The complexes, which are sparingly soluble in water, can be used directly in the form of the reaction product mixture. They can, however, also be isolated and treated by filtration, centrifugation, drying, grinding, sieving, screening, granulation or tableting by the customary methods in each case.

Depending upon the application, for example, in cosmetic formulations, other suitable substances or additives can also be added to the .gamma.-cyclodextrin complexes. These other suitable substances include inert, non-toxic topically acceptable carrier materials. Thus, it is possible to add, for example, humectants, surfactants, detergent additives, skincare additives, self-tanning additives, thickeners, preservatives, stabilizers, emulsifiers, perfumes, dyes, antioxidants, vitamins, UV filters and silicone oils.

Inert means that the carrier does not react with the .gamma.-cyclodextrin complex. Non-toxic means that the carrier is not harmful when applied topically.

Thus, the invention further relates to cosmetic composition formulations which comprise a cosmetically effective amount of the complex. This effective amount ranges from 0.1% to 5% by weight, and preferably from 0.4% to 1% by weight based upon the total cosmetic composition formulation weight, of the .gamma.-cyclodextrin/retinol complex or the .gamma.-cyclodextrin/retinol derivative complex. The balance of the formulation up to 100% by weight is the above-mentioned additives which are customary for cosmetic formulations. Thus, the amount of these additives ranges from 95% to 99.9% by weight, and preferably from 99% to 99.6% by weight, based upon the total cosmetic composition formulation weight.

The invention further relates to pharmaceutical composition formulations which comprise a pharmaceutically effective amount of the complex. This effective amount ranges from 0.1% to 5% by weight and preferably from 0.4% to 1% by weight based upon the total pharmaceutical composition formulation weight, of the .gamma.-cyclodextrin/retinol complex or the .gamma.-cyclodextrin/retinol derivative complex. The balance of the formulation up to 100% by weight is additives customary for pharmaceutical formulations. The customary additives suitable for pharmaceutical formulations are those ingredients which are inert, non-toxic and pharmaceutically acceptable. Examples include thickeners, preservatives, stabilizers, emulsifiers, antioxidants and vitamins. The amount of these additives ranges from 95% to 99.9% by weight, and preferably from 99% to 99.6% by weight based upon the total pharmaceutical composition formulation weight.

Examples of other suitable substances include the following. Particularly preferred surfactants include nonionics such as polyethylene glycols, polypropylene glycols and mixtures thereof.

Particularly preferred as a detergent additive is sodium lauryl sulfate. Particularly preferred skincare additives include anti-acne agents such as benzoyl peroxide and resorcinol. Particularly preferred self-tanning additives include tannic acid and aluminum tannate. Particularly preferred thickeners include waxes, polyethylene glycol stearate, glyceryl stearate, kaolin, and almond bran. Particularly preferred preservatives include methylparaben and propylparaben. Particularly preferred stabilizers include sodium hydroxide and potassium hydroxide. Particularly preferred emulsifiers include polysorbates, stearic acid, cetyl alcohol, macadamia nut oil, jojoba oil and avocado oil. Particularly preferred as a dye additive is the hair dying agent hydrogen peroxide.

Particularly preferred antioxidants include zinc and selenium. Particularly preferred vitamins include vitamin B, vitamin C, and vitamin E. Particularly preferred UV filters include sunscreen agents such as octyl methoxycinnimate and butyl methoxydibenzoyl methane. Particularly preferred humectants include glycerin, isopropyl myristate, glycerin monomyristate, and isopropyl palmitate.

Both the cosmetic composition formulations and the pharmaceutical composition formulations are safe and effective.

Claim 1 of 12 Claims

1. A composition consisting of

a complex selected from the group consisting of .gamma.-cyclodextrin with retinol, and .gamma.-cyclodextrin with a retinol derivative selected from the group consisting of retinyl esters and retinoic acid;

wherein said retinol and retinol derivative and said .gamma.-cyclodextrin are present in a weight ratio of retinol to .gamma.-cyclodextrin ranging between 1:20 and 1:1.

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