Title:  Creams containing vitamin D3 derivatives

United States Patent:  6,491,936

Issued:  December 10, 2002

Inventors:  Yasukawa; Satoshi (Tokyo, JP); Uchio; Takashi (Tokyo, JP); Sano; Keiko (Tokyo, JP)

Assignee:  Chugai Seiyaku Kabushiki Kaisha (Tokyo, JP)

Appl. No.:  162109

Filed:  June 5, 2002

The present invention aims to provide an O/W type creams showing improved skin absorption and heat stability of maxacalcitol as an active ingredient. The present invention provides O/W type creams containing maxacalcitol in the oil phase and/or water phase, more specifically O/W creams containing maxacalcitol and an emulsifier wherein maxacalcitol exists in the oil phase as well as O/W creams wherein maxacalcitol exists in the water phase.

DISCLOSURE OF THE INVENTION

Preparations for topical application may be presented in such dosage forms as ointments, creams or lotions. Dosage forms vary with the application site. Ointments are applied over the whole body, especially under clothing. Creams are applied on parts exposed to the air such as the face or the hands, and lotions are applided to the scalp or the like. Especially, creams which are exposed to the air are required to have benefits such as non-tackiness after application and inconspicuous appearance at the treated site.

In the development of creams as one dosage form for topical application, O/W type creams containing a large amount of water in an outer water phase are thought to be most advantageous for seeking such benefits as non-tackiness after application and inconspicuous appearance at the treated site. O/W type creams containing maxacalcitol as an active ingredient may include two types, depending on whether the active ingredient exists in the oil phase or the water phase.

Maxacalcitol is known to be slightly soluble in water and to be unstable in aqueous solutions; it is also known to be highly soluble and have dramatically improved stability in organic solvents such as ethanol and chloroform and also to have very high stability in base materials such as petrolatum. Therefore, O/W type creams containing maxacalcitol in an inner oil phase have been supposed to be preferable for maintaining an advantageous creamy form and for stably containing the active ingredient maxacalcitol.

However, it is also important in development of creams to ensure chemical stability of the active ingredient, as well as physical stability of the emulsion. It is regarded that the physical stability of the emulsion depends on the concentrations of surfactants and co-surfactants; as both concentrations become higher and as the ratio of the concentrations becomes closer to a proper value, more stable emulsification is achieved.

As for the skin absorption of the active ingredient, the following are regarded as contributing to low skin absorption of the active ingredient:

1) high affinity of maxacalcitol for the oil phase base material, 2) low delivery or access rate of oil phase to skin, and 3) inhibition release of the maxacalcitol from the oil phase during transfer of maxacalcitol to skin. More specifically, transfer of maxacalcitol to skin may be inhibited by the presence of surfactants and co-surfactants at the oil/water interface or the presence of crystalline structures around oil-phase particles. Namely, when a drug is contained in the inner oil phase, the surfactant phase existing at the oil/water interface or the crystalline structures existing around the oil-phase particles during the release process may further hinder the release of the drug.

In order to eliminate the above disadvantages and enhance skin transfer by removing rate-limiting factors during the release process, we tried to develop a cream containing the drug maxacalcitol in the outer water phase and concurrently a cream containing maxacalcitol in the oil phase.

As described above, an object of the present invention is to provide a cream maintaining a creamy form, showing high skin absorption of the active ingredient maxacalcitol and stably maintaining said active ingredient for a long time-period.

As a result of careful studies conducted to find a cream showing high skin absorption of the active ingredient maxacalcitol and stably maintaining said active ingredient for a long time-period, we obtained the following finding. In O/W type creams wherein maxacalcitol exists in the oil phase, stability of the emulsion dramatically improved, however the skin transfer rate of the active ingredient decreased when the concentrations of surfactants and co-surfactants increased. In order to increase the skin transfer rate, it seemed necessary to decrease those factors which are regarded to be responsible for the absorption inhibition, in other words, the amount of surfactants existing at the oil/water interface or the amount of crystalline structures produced around oil-phase particles. Thus, we attempted to decrease the loading of surfactants and co-surfactants in so far as a stable emulsion would be maintained. As a result, we found that an excellent cream is provided when the total concentration of surfactants and co-surfactants in the cream is within the range of from 2 to 7% by weight. We also found that absorption can be controlled by incorporation of maxacalcitol in the oil phase, whereby an optimal level in skin can be maintained. A part of the present invention was accomplished on the basis of these findings.

As a result of careful studies to improve the skin absorption and the storage stability of creams containing maxacalcitol in the water phase, we also found that a homogeneous dispersion of maxacalcitol in the outer water phase ensures the storage stability of maxacalcitol and also remarkably improves the skin absorption to approximately twice as compared with creams containing maxacalcitol in the inner oil phase. A part of the present invention was accomplished on the basis of these findings.

As described above, we accomplished the present invention on the basis of the findings that incorporating maxacalcitol in the water phase can remarkably improve absorption and that incorporating maxacacitol in the oil phase can control absorption.

Moreover, we also found that the maxacalcitol level in skin can be controlled over a wide range, from low to high levels, by incorporation of maxacalcitol in both of oil and water phases.

Accordingly, the present invention provides an O/W type cream containing maxacalcitol in the oil phase and/or water phase.

According to an aspect of the present invention, there is provided an O/W type cream containing maxacalcitol and an emulsifier, wherein maxacalcitol exists in the oil phase.

In creams of the present invention, the emulsifier is preferably a mixture of a surfactant and a co-surfactant.

In creams of the present invention, the ratio between surfactants and co-surfactants is preferably within the range of from 1:1 to 1:11.

In creams of the present invention, the total concentration of surfactants and co-surfactants in a cream is preferably within the range of from 2 to 7% by weight.

In creams of the present invention, the surfactant is preferably an ether-type surfactant.

In creams of the present invention, the surfactant is more preferably a polyoxyethylene alkyl ether.

In creams of the present invention, the co-surfactant is preferably a higher alcohol.

In creams of the present invention, the co-surfactant is more preferably stearyl alcohol, cetyl alcohol or cetostearyl alcohol.

In creams of the present invention, the ratio of oil phase in an O/W type cream is preferably within the range of from 30 to 50% by weight.

According to another aspect of the present invention, there is provided an O/W type cream, wherein maxacalcitol exists in the water phase.

According to an embodiment of the O/W type cream wherein maxacacitol exists in the water phase, there is provided an O/W cream wherein crystalline maxacalcitol is pulverized and contained in the water phase.

According to another embodiment of the O/W type cream wherein maxacalcitol exists in the water phase, there is provided an O/W cream wherein crystalline maxacalcitol is dissolved in an organic solvent and contained in the water phase.

According to still another embodiment of the O/W type cream wherein maxacalcitol exists in the water phase, there is provided an O/W cream containing an alcohol and/or a nonionic surfactant in the water phase.

Claim 1 of 7 Claims

What is claimed is:

1. An O/W cream comprising maxicalcitol as an active ingredient, wherein the maxacalcitol is present in the water phase, and the cream comprising from 2 to 7% by weight of a mixture of a surfactant and a cosurfactant.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.