Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2001-11-19
2002-05-28
Dees, Jose G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C514S167000
Reexamination Certificate
active
06395287
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to lotions stably containing maxacalcitol, which are useful as external medicines. More specifically, the present invention relates to lotions useful as external medicines wherein chemical stability and percutaneous absorption of maxacalcitol as an active ingredient can be controlled by regulating the composition of components.
BACKGROUND ART
Some classes of active vitamin D
3
derivatives such as 1&agr;,3&bgr;-dihydroxy-20&agr;-(3-hydroxy-3-methylbutyloxy)-9,10-seco-5,7,10(19)-pregnatriene (22-oxa-1&agr;, 25-dihydroxyvitamin D
3
; herein also referred to as maxacalcitol) have skin epidermal cell growth-inhibiting and differentiation-inducing effects and are expected to have pharmacological effects against psoriasis (JPA Nos. 267550/86 and 183534/88).
Maxacalcitol is known to be chemically unstable and rapidly decompose especially in aqueous solutions. Generally, the following techniques have been proposed to improve stabilization of vitamin D-related derivatives.
(1) stabilization by adding various amino acids (alanine, valine, lysine, etc.: JPA No. 17/87);
(2) stabilization by combination of ascorbic acid or a salt thereof with a chelating agent (JPA No. 44845/86);
(3) stabilization by adding ascorbic acid alone (JPA No. 238936/93); and
(4) stabilization by inclusion in cyclodextrin (JPA Nos. 83021/88 and 128417/76).
However, these techniques have disadvantages such as they involve a complex procedure or have an insufficient stabilization effect, and do not suffice to prepare a lotion stably maintaining maxacalcitol.
As to percutaneous absorption in the category of biological properties, the use of absorption promoters is recommended and the addition of unsaturated fatty acids such as oleic acid or the use of chemicals such as AZONEs has been reported (Morimoto et al. in the program and abstracts of lectures, p. 21, Proceedings of the eighth transdermal therapeutic system symposium, Tokyo, Feb. 21, 1996).
However, these absorption enhancers are not preferable for use in preparations that are often administered (applied) repeatedly, because their enhancing mechanisms depend on providing high absorption efficiency by damaging the skin.
Thus, the need to develop lotions stably maintaining maxacalcitol and having excellent percutaneous absorption continue to exist.
DISCLOSURE OF THE INVENTION
As for the behavior of its stability in aqueous solutions, maxacalcitol is known to remain stable if the pH of the solutions is shifted to an alkaline side. However, alkaline preparations are highly irritant to skin and side effects possibly increase. Therefore, when maxacalcitol is formulated in preparations for external medication, it is desirable to attain stabilization of maxacalcitol in a solution at or around neutral pH.
An object of the present invention is to provide a lotion wherein maxacalcitol as an active ingredient is stably maintained, especially a lotion having a pH at or around neutrality.
Another object of the present invention is to simply solve the problem of chemical stabilization of maxacalcitol, which could not be readily attained in the prior art, by a convenient method of adding a specific type of nonionic surfactant and a polyhydric alcohol.
Still another object of the present invention is to provide a lotion having particularly excellent percutaneous absorption by regulating the compounded amount of a less skin-irritating polyhydric alcohol to control the percutaneous absorption.
As a result of careful studies conducted to solve the above problems, we unexpectedly found that a lotion containing maxacalcitol as an active ingredient stably maintains the active ingredient even at or around neutral pH upon addition of a specific nonionic surfactant. The present invention successfully achieved not only solubilization of oil-soluble materials but also a high stabilization effect by using a specific type of nonionic surfactants among which have heretofore been used as solubilizers for materials that are slightly soluble in water. This was a quite unexpected discovery because no report had been made of the ability of any nonionic surfactants to simultaneously achieve both solubilization and stabilization of oil-soluble materials (maxacalcitol in the specification). Moreover, we succeeded in controlling both of heat stability and percutaneous absorption of the active ingredient maxacalcitol by selecting a polyhydric alcohol, a nonionic surfactant and a solubilizer as additives in a lotion, and also succeeded in establishing an optimal composition for both heat stability and percutaneous absorption in a lotion prepared from specific components. The present invention was completed based on these findings.
Accordingly, the present invention provides a lotion comprising maxacalcitol as an active ingredient and a nonionic surfactant as an additive.
According to a preferred embodiment of the present invention, an ether-type surfactant is used as a nonionic surfactant.
According to a more preferred embodiment of the present invention, a block copolymer-type nonionic surfactant or a polyoxyethylene alkyl ether is used as an ether-type surfactant.
According to a still more preferred embodiment of the present invention, a Pluronic-type or polyoxyethylene cetyl ether-type surfactant is used as an ether-type surfactant.
Preferably, Pluronic™ F-68 or Cetomacrogol™ 1000 is used as a Pluronic-type or polyoxyethylene cetyl ether-type surfactant, respectively.
More preferably, a lotion of the present invention contains 0.1-20% by weight of Pluronic F-68 or 0.1-2% by weight of Cetomacrogol 1000 as a surfactant.
Most preferably, a lotion of the present invention contains 1-5% by weight of Pluronic F-68 or 0.5-2% by weight of Cetomacrogol 1000 as a surfactant.
According to one embodiment of the present invention, there is provided a lotion which, besides a nonionic surfactant, further comprises a polyhydric alcohol and a solubilizer as additives.
Preferably, a lotion of the present invention contains a glycol as a polyhydric alcohol, an ether-type surfactant as a nonionic surfactant and a monohydric alcohol as a solubilizer.
More preferably, a lotion of the present invention contains propylene glycol and/or 1,3-butylene glycol as a polyhydric alcohol, a polyoxyethylene alkyl ether or a Pluronic-type surfactant as a nonionic surfactant and ethanol or isopropanol as a solubilizer.
More preferably, a lotion of the present invention contains propylene glycol and 1,3-butylene glycol as polyhydric alcohols, Cetomacrogol 1000 as a nonionic surfactant and ethanol as a solubilizer.
An especially preferred lotion of the present invention contains 1-70% by weight of propylene glycol, 1-45% by weight of 1,3-butylene glycol, 0.1-5% by weight of Cetomacrogol 1000, 1-20% by weight of ethanol, and the balance being water.
An especially preferred lotion of the present invention contains 50-70% by weight of propylene glycol, 1-20% by weight of 1,3-butylene glycol, 0.1-2% by weight of Cetomacrogol 1000, 1-20% by weight of ethanol, and the balance being water.
Most preferably, a lotion of the present invention contains 50-70% by weight of propylene glycol, 1-20% by weight of 1,3-butylene glycol, 1% by weight of Cetomacrogol 1000, 1% by weight of ethanol, and the balance is water.
PREFERRED EMBODIMENTS OF THE INVENTION
The present invention relates to lotions comprising maxacalcitol as an active ingredient and a nonionic surfactant as an additive, as well as lotions which, besides a nonionic surfactant, further contain a polyhydric alcohol and a solubilizer as additives.
1&agr;,3&bgr;-Dihydroxy-20&agr;-(3-hydroxy-3-methylbutyloxy) -9,10-seco-5,7,10(19)-pregnatriene (22-oxa-1&agr;,25-dihydroxyvitamin D
3
; herein also referred to as maxacalcitol) contained as an active ingredient in lotions of the present invention is a known vitamin D
3
derivative and can be synthesized by the process described in JPA No. 267550/86, for example.
The amount of maxacalcitol contained in lotions of the present invention is a therapeutically effective amount for the skin disease t
Miyauchi Eiichi
Sakai Yasuyuki
Sano Keiko
Browdy and Neimark , P.L.L.C.
Chugai Seiyaku Kabushiki Kaisha
Dees Jos,e G.
Haghighation Mina
LandOfFree
Lotions containing vitamin D3 derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Lotions containing vitamin D3 derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Lotions containing vitamin D3 derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2848182