Topical composition

Details Topical composition Topical composition

2001-10-26

2004-09-07

Hui, San Ming (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

C514S178000, C514S336000, C514S383000, C514S169000, C424S484000, C424S485000, C424S486000, C424S487000, C424S488000

Reexamination Certificate

active

06787529

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns topical compositions for application on skin which contain at least one vitamin D or vitamin D analogue and at least one corticosteroid.
BACKGROUND OF THE INVENTION
In the treatment of a number of conditions using dermal application, e.g. in the treatment of psoriasis, it is often indicated to employ a combination treatment incorporating two or even more different pharmacologically active compounds. Thus, in the treatment of e.g. psoriasis, it is known to use a combination treatment involving a steroid compound, such as a corticosteroid compound, and a vitamin D analogue such as calcipotriol, and where each of the active compounds are formulated in separate preparations due to the instability of corticosteroids at alkaline pH values and of vitamin D analogues at acid pH values.
Consequently, physicians have had to resort to letting patients under this type of two-component regimen perform sequential application of two creams/ointments, each containing one of the compounds formulated at its maximum stability pH. This may lead to incompatibility of the preparations so that patients must, e.g., apply one cream/ointment in the morning and the other in the evening. Needless to say, patient compliance as well as correct administration dosage is a problem under such circumstances. Richards, H. L. et al. report in
J Am Acad Dermatol
October 1999; 41(4):581-3 on a study of patients with psoriasis and their compliance with medication. They report that poor compliance with treatment advice in chronic conditions, such as psoriasis, represents a major challenge to health care professionals: Thirty-nine percent of participants reported that they did not comply with the treatment regimen recommended. The noncompliant group had a higher self-rated severity of psoriasis, were younger, and had a younger age at onset than those who were compliant. The noncompliant group reported that psoriasis had a greater impact on daily life.
WO 00/64450 describes a pharmaceutical composition for dermal use comprising a combination of a vitamin D analogue and a corticosteroid, which composition alleviates the inconveniences of a two-component or multi-component regimen for the treatment of psoriasis and related skin diseases. This composition, however, tends to be rather oily and to leave, on application, a greasy film of non-absorbed excipients on the skin.
SUMMARY OF THE INVENTION
It is therefore the object of the present invention to provide a composition comprising both active components in a formulation exhibiting improved skin absorption (and less oily appearance) and ease of application, both qualities leading to improved patient compliance.
Accordingly, the present invention relates to a pharmaceutical gel composition for application on skin, said composition comprising at least one vitamin D or vitamin D analogue and at least one corticosteroid, said composition further comprising a viscosity-increasing excipient in an amount resulting in a viscosity which, on the one hand, is sufficient to substantially prevent the corticosteroid from sedimenting during application and storage of the composition and, on the other hand, is sufficient to facilitate an even distribution of the composition on an affected skin area,
The gel composition of the invention has been found to be particularly favourable for application on the scalp due to the ease with which it may be applied and to the considerably less oily appearance which makes the composition more acceptable to patients suffering from psoriasis of the scalp.
In another aspect, the invention relates to the use of a gel composition as defined above for the manufacture of a medicament for the topical treatment of psoriasis and related conditions, e.g. sebo-psoriasis of the scalp, in humans.
DETAILED DESCRIPTION OF THE INVENTION
In the present context, the term “sufficient”, when used in connection with viscosity, is understood to indicate a viscosity which, on the one hand, is sufficiently high to ensure that the corticosteroid (which is present in the composition in the form of dispersed particles) does not sediment from the composition which would, of course, result in an uneven application of the corticosteroid over the affected area. On the other hand, the viscosity of the application should be sufficiently low to enable the patient to readily remove the required dose of the composition from the container in which it is available (e.g. a tube or the like) and apply it evenly over the affected area to ensure an even dosing of the active components.
For application of the present composition on the scalp, it is particularly important to ensure that the viscosity is sufficiently high to substantially prevent “leakage” of the composition from the area where it is applied to other areas, in particular the face. It is equally important that the composition is readily applied on an area of skin covered by hair to ensure correct dosing of the active components.
In practical terms, this means that the viscosity should preferably be in the range of from about 5 mPa.s to about 500 mPa.s, in particular from about 10 mPa.s to about 250 mPa.s, such as from about 20 mPa.s to about 100 mPa.s. The viscosity may suitably be determined by the cup/rotor method involving an NV1 device on a Haake VT 550 viscosimeter at 700 s
−1
and 20° C.
In a currently favoured embodiment, a suitable viscosity of the composition may be obtained by including a thixotropic gelling agent as the viscosity-increasing excipient such that the composition, on standing, is in the form of a gel. A thixotropic agent has the advantage of being readily applied while, on standing, such as after application, the viscosity increases so that the composition will typically not leak from affected areas of skin on which it is applied to unaffected areas. An example of a suitable thixotropic gelling agent is hydrogenated castor oil.
In an alternative embodiment, the viscosity-increasing excipient may be selected from a wax, e.g. Cera Alba (white wax) or Cera Flava (yellow wax), polyethylene or a microcrystalline wax such as Esma-P®.
When the composition is an emulsion, it may be a water-in-oil or oil-in-water emulsion comprising a suitable emulsifier which may, for instance, be selected from polyoxyethylene cetyl ether, polyoxyethylene stearyl ether or polyoxyethylene oleyl ether, or polyethyleneglycol dipolyhydroxystearate.
In order to circumvent the problem of instability of certain vitamin D analogues in an acid environment (they have a maximum stability at pH values above about 8) and instability of corticosteroids in an alkaline environment (they have a maximum stability at a pH of about 4-6), it is furthermore preferred that the composition is substantially non-aqueous. The term “substantially non-aqueous” is intended to indicate that the composition has a water content below about 5%, preferably below about 2%, such as below about 1.5%.
Consequently, the composition preferably comprises at least one substantially non-aqueous solvent selected for its ability to dissolve or solubilise the vitamin D analogue. The solvent may suitably be selected from the group consisting of:
(i) compounds of the general formula R
3
(OCH
2
C(R
1
)H)
x
OR
2
(I) wherein x is in the range of 2-60, R
1
in each of the x units independently is H or CH
3
, R
2
is straight chain or branched C
1-20
alkyl or benzoyl, and R
3
is H or phenylcarbonyloxy;
(ii) di-(straight or branched)-C
4-10
alkyl esters of C
4
-C
8
dicarboxylic acids;
(iii) straight or branched C
12-18
-alkyl benzoates;
(iv) straight or branched C
2-4
-alkyl esters of straight or branched C
10-18
-alkanoic or-alkenoic acids;
(v) propylenglycol diesters with C
8-14
-alkanoic acids; and
(vi) branched primary C
18-24
alkanols.
It has been found that in such combination compositions containing a solvent selected from one of the group indicated above and in a substantially non-aqueous environment, the active components can co-exist without degradation, despite their different pH/stability profiles. The tend

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