Compositions for the treatment of psoriasis

A topical anthralin cream composition in which the anthralin demonstrates improved stability, comprises from about 0.05% to about 5% by weight of anthralin in a water: fluid hydrocarbon emulsion having a weight ratio of at least about 5:1, at least one anionic emulsifying agent, at least one oil soluble anti-oxidant, at least one water soluble acidic material, and at least one bifunctional sequestering agent.

DETAILED DESCRIPTION 
1,8,9-Trihydroxyanthracene, also known as dithranol or anthralin, is one of 
the few effective agents available for the treatment of psoriasis. The 
compound, however, exhibits high irritancy to skin which is not afflicted 
with psoriasis, undesirable staining properties, and a tendency to be 
oxidized, leading to product instability. Historically, the compound has 
been formulated in heavy pastes and ointments such as Lassars paste and 
emulsifying ointments. 
The utilization of oxalic acid to stabilize anthralin composition is 
described in U.S. Pat. No. 4,367,224. Such compositions are however 
anhydrous and take the form of a congealed yellow ointment. 
The topical composition described in U.S. Pat. No. 4,203,969 represents a 
cosmetically more elegant anthralin formulation than prior formulations. 
Moreover, the spreadable composition described in that patent appears to 
satisfy some stability criteria in that excessive decomposition is not 
discernible upon U.V. analysis. More sophisticated analysis of this 
formulation, however, indicates that it is subject to undesirable 
transformations with the passage of time. In particular, high performance 
liquid chromatography (HPLC) has shown that although the overall 
pharmaceutical formulation appears to retain its stability, the anthralin 
dispersed in the oil phase undergoes unacceptable chemical change, not 
only reducing its effective concentration but also producing degradation 
products of unknown efficacy. While the structure of anthralin break-down 
product(s) has not yet been fully elucidated, current evidence strongly 
suggests dimer formation; see e.g. Caron et al., Brit J. Derm., (1981) 
105, Suppl. 20, 57. 
The present invention pertains to improved aqueous anthralin formulations 
which are cosmetically acceptable and which exhibit significantly reduced 
chemical degradation of active ingredient, as compared with the prior art 
formulation. 
The formulation described herein has certain features in common with the 
prior formulations of U.S. Pat. No. 4,203,969. In particular, it utilizes 
a two phase system of water and a hydrocarbon material. Moreover, the 
desirability of a water soluble acidic component such as citric acid or 
sodium bisulfite has been confirmed. 
The present formulation, however, rather than utilizing a large proportion 
of hydrocarbon material as the anthralin-carrying phase, employs a 
predominantly aqueous vehicle, the ratio of water to hydrocarbon being at 
least on the order of 5:1. Secondly, the hydrocarbon, rather than being of 
the nature of the semi-solid petrolatum employed in the prior art, is 
largely fluid. Thirdly, the formulation includes at least one anionic 
emulsifier. Notwithstanding the high water content, the foregoing produces 
a high internal phase emulsion having an oil continuous phase and a water 
disperse phase. Fourthly, rather than utilizing a water-soluble, 
oil-insoluble antioxidant, the present composition employs precisely the 
opposite, namely an antioxidant which is oil soluble. Fifthly, the present 
composition includes a bifunctional sequestering agent. 
In particular, the present invention pertains to an anthralin cream 
composition which comprises: 
(a) 
(i) from about 0.05% to about 5% by weight of the composition, of anthralin 
in 
(ii) a water: fluid hydrocarbon emulsion wherein the weight ratio of water 
to fluid hydrocarbon is at least about 5:1 but which has an oil continuous 
phase; 
(b) an emulsifying amount, up to about 3%, by weight of the composition, of 
at least one anionic emulsifier; 
(c) from about 0.02% to about 2% by weight of the composition of at least 
one oil-soluble antioxidant; 
(d) from about 0.5% to about 1%, by weight of the composition, of at least 
one acidic material; and 
(e) from about 0.02% to about 2% by weight of the composition of at least 
one bifunctional sequestering agent. 
In addition to the foregoing components, the present composition 
advantageously can include one or more polyols such as glycerol, propylene 
glycol, sorbitol and the like, one or more hydroxybenzoic acid or alkyl 
(C.sub.1 -C.sub.4) hydroxybenzoate preservatives such as salicylic acid, 
methylparaben, ethylparaben, and propyl paraben, and up to about 6% of an 
emulsifying agent which may be either, or preferably both, of a fatty 
alcohol and a non-ionic emulsifier. 
The desirability of incorporating an antioxidant has been recognized in the 
prior art, but its role appears to have been directed towards curtailing 
oxidation of lipophobic components of the emulsifying agent. The 
requirement that the antioxidant be water soluble and oil-insoluble 
precluded that component from exerting its properties in the discontinuous 
hydrocarbon (oil) phase where the anthralin was primarily distributed. 
Although not wishing to be bound by any particular theory, it is believed 
that the large proportion of hydrocarbon material in the prior art 
composition reduced (but did not eliminate) decomposition by providing a 
high dilution factor for the anthralin. This, coupled with the semi-solid 
nature of the hydrocarbon, would result, by simple chemical kinetic 
principles, in a reduced incident of the reaction(s) involved in 
decomposition of active compound, whether the reaction was mediated by 
oxygen or otherwise. The relatively high content of hydrocarbon which 
consequently remained on the skin upon evaporation of the water phase, 
however, necessarily limited the effective concentration of active 
ingredient and moreover produced an oily, difficultly spreadable 
composition. 
The present invention is based in part on the discovery that while the 
presence of an antioxidant is important to the stability of such anthralin 
emulsion formulations, it must be soluble in the hydrocarbon phase if the 
decomposition of the anthralin itself is to be inhibited. Unexpectedly, 
this discovery also has permitted a significant reduction in the 
proportion of hydrocarbon material (relative to the aqueous phase), as 
well as the use of more fluid hydrocarbon material. 
Despite this significant reduction in the hydrocarbon content, the 
hydrocarbon component(s) constitutes the continuous phase of the emulsion. 
The hydrocarbon continuous phase is achieved by utilizing one or more 
anionic emulsifers, preferably fatty acid metal soap emulsifiers such as 
aluminum, calcium or magnesium stearate and/or a phosphonic ester salt of 
a mono- or diglyceride. The amount of emulsifier present will be at least 
that necessary to provide a stable emulsifying effect, which amount 
generally need be no more than about 3%, often less. 
The use of such emulsifers in high internal phase water-in-oil emulsions in 
cosmetic formulations is described in U.S. Pat. No. 4,104,403. However, 
anionic emulsifiers prima facie would not appear to lend themselves to 
anthralin formulations since trace amounts of metals catalyse or initiate 
the decomposition of anthralin. However by incorporating an oil-soluble 
antioxidant in the formulation and by further providing at least one 
bifunctional sequestering agent, it is possible to formulate a high 
internal phase oil emulsion formulation of anthralin which not only 
demonstrates improved stability of both overall composition and active 
ingredient, but also has an esthetically pleasing cream-like cosmetic 
consistency permitting it to be easily spread and readily absorbed. 
Suitable oil soluble antioxidants include such material as ascorbyl 
palmitate, alpha tocopherol, butylated hydroxytoluene, hydroxyquinone, and 
butylated hydroxyanisole. The amount included will depend upon the 
antioxidant potency of the material employed but generally a range from 
about 0.02 to about 2% by weight is satisfactory. It is not only possible 
but often desirable to employ several antioxidants in which case the 
content of each can be reduced. For example, satisfactory stabilization 
can be achieved by utilizing a three component oil soluble antioxidant 
mixture of approximately equal amounts of tocopherol, BHT and ascorbyl 
palmitate; e.g., 0.07% tocopherol, 0.05% BHT and 0.05% ascorbyl palmitate. 
Desirably the formulation will contain other emulsifying agents such as 
higher alkanols; e.g., octyldecanol, particularly 2-octyldecanol and 
non-ionic surfactants such as polyglycerol oleate, glycerol oleate, 
propylene glycol cocoate, polyoxyethylene and 25 polyoxypropylene ethers 
and esters such as polyoxypropylene stearyl ether. The amount of such 
additional emulsifying agents which can be present will vary depending 
upon the effectiveness of the particular agent or combination. 
Significantly, however, because of the reduction of the hydrocarbon 
material which has been achieved and the use of the metal soap, the total 
amount of non-ionic emulsifers can be significantly reduced and seldom 
need exceed about 5% by weight. In fact in the preferred embodiment, the 
amount will be below 5%, e.g., from about 1 up to about 4.5%. 
The hydrocarbon material typically will include one or more light mineral 
oils. Semi-solid hydrocarbons and paraffin can be dissolved therein but 
the proportion of these relative to the liquid hydrocarbon should not be 
so great that the overall hydrocarbon component loses its fluid nature. 
The hydrocarbon component acts as a solubilizer for the anthralin and its 
fluid nature permits the active ingredient to be easily spread and to 
penetrate the involved area. Typically, the total content of the fluid 
hydrocarbon in the composition, which includes normally solid hydrocarbon 
dissolved in normally liquid hydrocarbon, will be on the order of 10 to 
15% by weight whereas the water content will be at least about 75% by 
weight and preferably about 80%. Hence a typical formulation could have 
10.6% of a 2.3:3.3:6.0 mixture of petrolatum, paraffin and light mineral 
oil and 81% water, the ratio of water to hydrocarbon being about 7.6:1. 
In addition to the foregoing components, there will be one or more water 
soluble components which satisfy at least one of the categories of an 
acidic material in an amount of from about 0.5% to about 1% by weight of 
the composition; and at least one bifunctional sequestering agent in an 
amount of from about 0.02% to about 2% by weight of the composition, both 
of said functional categories being satisfied. 
Acidic materials are typically topically acceptable weak organic acids and 
weak inorganic acids and acid salts; e.g., malic acid, citric acid, 
salicylic acid, and sodium metabisulfite. Two or more such materials can 
be used in amounts of from 0.5% to 1% of the composition. 
The bifunctional sequestering agent component includes such materials as 
disodium ethylenediamine tetraacetic acid and related chelating agents, 
thiourea, thioacetic acid, cysteine, tyrosine, nicotinic acid and 
sarcosine. Again, two or more such sequestering agents can be employed, 
the total content of which will range from about 0.02 to about 2% by 
weight. 
Both functional categories must be satisfied but can be satisfied by the 
same compound. Thus some substances theoretically can fall within both 
categories of components and serve two functions. For example, malic, 
salicylic and citric acids, while acidic substances, can also serve as 
sequestering agents. (Salicylic acid also can functions as a hydroxylated 
benzoic acid derivative). The acidic material sodium metabisulfite, on the 
other hand, is not a sequestering agent so that a further component to 
satisfy this second functional category must be present. Several materials 
in each category can be present. 
The composition is prepared by forming a hydrocarbon phase and an aqueous 
phase into which phases are added the various components. The selection of 
the phase to which a component is to be added is made on the basis of the 
component's preferential solubility; i.e., whether it is predominatly 
hydrophobic or hydrophilic. Heat can be utilized to facilitate production 
of homogenous individual phases and the homogenizing of the combined two 
phases to produce the emulsion. Any materials which are sensitive to 
excessive heat, such as tocopherol or tocopherol acetate, can be added 
subsequently.

Typical formulations utilizing the principles of this invention are as 
follows: 
EXAMPLE 1 
To 120 g of light mineral oil are added 46 g of 30 petrolatum and 46 g of 
paraffin. Fourteen grams of aluminum stearate are added to this 
hydrocarbon mixture as emulsifier, together with 30 g of polyglyceryl 
oleate and 60 g of 2-octyldodecanol. There then are added 4.8 g of 
anthralin and 0.4 g of ascorbyl palmitate as one oil soluble antioxidant. 
Finally 8 grams of salicylic acid are added and the whole is thoroughly 
blended at 90.degree. C. This hydrocarbon phase will weigh approximately 
330 g and will constitute approximately 16.5% of the final composition. 
Separately, 1,646 g of deionized water are heated to approximately 
90.degree. C. and 18 g of citric acid are dissolved therein. To this is 
added 1.2 g of disodium ethylenediamine tetracetic acid and 5g of a 1.5:1 
mixture of methylparaben and ethylparaben. When this aqueous mixture, 
which will weigh about 1,670 g and will constitute approximately 83.5% of 
the final composition, is homogenous, it is combined with the above 
hydrocarbon component in a homogenizer. When the emulsion is thoroughly 
blended, it is cooled to 50.degree. C. and 0.6 g of tocopherol acetate are 
added. This mixture is further blended to produce 2,000 g of a 0.2% 
homogenous anthralin cream which maintains its formulation stability and 
in which the anthralin does not appear to undergo excessive degradation, 
e.g. less than 10% as determined by HPLC. 
EXAMPLE 2 
A 0.2% anthralin formulation is prepared according to the procedure of 
Example 1 utilizing the following components: 
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Oil phase: 
mineral oil 6.0% 
paraffin 2.3% 
petrolatum 2.3% 
aluminum stearate 
0.7% 
glyceryl oleate 1.5% 
anthralin .22% 
ascorbyl palmitate 
.02% 
octyldodecanol 3.0% 
salicylic acid 0.4% 
Water phase: 
deionized water 68.82% 
citric acid 0.9% 
Na.sub.2 EDTA 0.06% 
sorbitol (70%) 13.5% 
methyl paraben 0.15% 
propyl paraben 0.10% 
Alpha tocopherol 0.03% 
______________________________________ 
EXAMPLE 3 
A formulation is prepared following the procedure of Example 1, utilizing 
however 180 g of light mineral oil, 1556 g. of deionized water and 10 g. 
of Emulsynt 1055 (polyglycerol-4-oleate and polyethyleneglycol-8 propylene 
glycol cocoate). 
EXAMPLE 4 
A 0.4% anthralin formulation is prepared according to the proportions and 
procedure of Example 1, adding however a total of 1 g. of ascorbyl 
palmitate and 1.4 g. tocopherol together with 1 g. of butylated 
hydroxytoluene. The content of anthralin which is added is increased to 
8.8 g. and the water to 1629 g. Finally, 2.09 g. of sodium bisulfite and 
12 g. of disodium ethylenediamine tetraacetic acid are added to the water 
phase prior to emulsification. 
EXAMPLE 5 
Formulations of the following compositions are prepared in accordance with 
the procedure set forth in Example 1. 
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% of Composition 
Formulations: 5A 5B 5C 5D 
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Oil phase: 
mineral oil 6.0 6.0 6.0 6.0 
paraffin 2.3 2.3 2.3 2.3 
petrolatum 2.3 2.3 2.3 2.3 
aluminum stearate 
0.7 0.7 0.7 0.7 
glyceryl oleate 
1.5 1.5 1.5 1.5 
anthralin 0.12 0.22 0.44 
1.1 
ascorbyl palmitate 
0.05 0.05 0.05 
0.05 
octyldodecanol 3.0 3.0 3.0 3.0 
salicylic acid 0.4 0.4 0.4 0.4 
butylated hydroxy- 
0.05 0.05 0.05 
0.05 
toluene 
Water phase: 
deionized water 
81.66 81.56 81.34 
80.68 
citric acid 0.9 0.9 0.9 0.9 
Na.sub.2 EDTA 0.60 0.60 0.60 
0.60 
sodium bisulfite 
0.10 0.10 0.10 
0.10 
Preservatives: 
propyl paraben 0.15 0.15 0.15 
0.15 
methyl paraben 0.10 0.10 0.10 
0.10 
Tocopherol 0.07 0.07 0.07 
0.07 
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