Pharmaceutical compositions for the treatment of skin

Pharmaceutical compositions for the treatment of skin have been prepared in a carrier which contains 40 to 60% of liquid paraffin, 40 to 60% of solid paraffin, and 0.5 to 5% of microcrystalline wax. The new carrier is especially suitable for readily oxidizable drugs such as dithranol and its derivatives. From the compositions of the invention it is possible to prepare sufficiently thin and hard, yet non-brittle sticks by means of which the drug can be applied at precisely the desired point of the skin.

The present invention is concerned with new paraffin-based pharmaceutical 
compositions to be applied to the skin. The invention is particularly 
concerned with compositions containing readily oxidizable drugs such as 
dithranol and its derivatives. 
One of the drawbacks of the ointment bases used in the treatment of skin 
diseases is a tendency to spread from the affected skin to the surrounding 
healthy skin and to clothes. This is particularly detrimental when poorly 
penetrating ointments are used which contain vaseline, paraffin oil, and 
soft waxes and which mainly affect the horny layer and the epidermis. It 
is almost impossible to direct such ointments to the affected skin areas 
only, and dosage is difficult and extremely variable. This causes 
problems, especially if the ointment includes agents which irritate the 
skin or which colour the skin and clothes. One substance that affects the 
colours healthy skin is dithranol, or anthranil, still the most commonly 
used pharmaceutical for the topical treatment of psoriasis. 
P. G. Unna was the first scientist to develop ointment sticks containing 
dermatological agents in an attempt to reduce the above drawbacks 
/Monatschefte fur Praktische Dermatologi 1886:5 157-167/. According to 
Unna, dry, localised, spot-like skin diseases, such as psoriasis, dry 
eczemas, and spotty fungal skin diseases are best suited for treatment 
with ointment sticks. He suggests that the consistency of the ointment 
stick be sufficiently soft so that little force is needed to apply a 
stripe of ointment to the skin but, on the other hand, sufficiently hard 
so that the stick is not deformed when used or when exposed to high 
temperatures. According to him, these requirements, though dependent on 
the pharmaceutical used, could be satisfied by mixtures of olive oil and 
wax. Unna used colophonium as a hardening agent in addition to wax. Unna 
used yellow beeswax (cera flava). Of the ointment stick formulae suggested 
by Unna, almost all of which had stick bases of similar compositions, the 
following two deserve mention: "Stilus acid. salicyl. unguens 10%" (Acid. 
salicyl. praec. 10.0, Colophoni 5.0, Cerae flavae 45.0, Ol. oliv. prov. 
40.0) and "Stilus Chrysarobini unguens 30%" (Chrysarobini 30.0, Colophoni 
5.0, Cerae flavae 35.0, Ol. oliv. prov. 30.0). 
Unna also developed a paraffin ointment stick (Paraffini solid. 50.0, 
Paraffini liquid. 50.0), but, owing to the softness of the stick he did 
not mix any pharmaceutical into the stick, but used the stick for oiling 
dry, horny skin in the way a lip pomada is used. 
Since Unna's pioneering work, there have been very few papers on ointment 
sticks in the treatment of skin diseases. 
In 1941, F. Dietel mentioned the chrysarobin ointment stick for the 
treatment of psoriasis /Deutsche medizinische Wochenschrift 1941:9 237-9/. 
The composition of the stick was: Chrysarobin 30.0, Cerae flav. 20.0, 
Adipis lanae 50.0. 
In 1962 and 1966, there were two papers in which a close relative of 
chrysarobin, cignolin (or dithranol) was used in ointment sticks/Weber, 
G., Medizinische Welt 1962:35 1839-40 and Schafe, M. K., Zeitschrift fur 
Hautund Geschlechtskrankheiten 1966 XL 347-51/. In both papers, the same 
commercial preparation "Psoriacid" was used. The exact composition of the 
ointment base was not given, but it included Vaselinium album, Adeps 
lanae, Paraff. solidum suffanita and Cera alba. 
In 1970, F. Novotny used the following ointment stick base in his study: 
Oleum ricini 1.0, Paraffinum liquidum 4.0, Cera flava 43.0, Oleum cacao 
52.0, /Cs. Derm. 45 (1970):1 20-22/. 
At present, only one ointment stick is available as a commercial 
preparation in the Nordic countries. This is an "Anthraderm" stick 
containing 0.5, 1.0 or 2.0% dithranol (Pharma-medica). The composition of 
the ointment base has not been given as a percentage, but the base 
contains wool alcohols, cocoa oil, white beeswax, whale wax (cetaceum), 
and peanut oil (oleum arachidis) as well as 0.5% salicylic acid and 0.02% 
butylated hydroxytoluene as stabilizers. 
Even though stick-shaped preparations would be a good dosage form for 
several dermatological medicines in view of the treatment, they have not 
obtained a position of major importance in practice. This is because the 
ointment stick bases so far developed have been too soft and have 
contained oxidizable vegetable oils and animal fats. Rancid, peroxidating 
oils and fats, in turn, oxidize many pharmaceutical substances such as 
dithranol and chrysarobin resulting in ineffective compounds. Unna stated 
in his monography discussing dithranol that, in the presence of oxygen, 
the most important fatty acid in olive oil--oleic acid--converts both 
chrysarobin and dithranol into dark, coloured compounds. It has also been 
noticed that the oxidation of dithranol is faster, the more double bonds 
the fatty acid molecule contains. 
Some sticks also have the drawback that they contain wool grease, which can 
cause contact allergy. 
These problems are associated with the "Anthraderm" stick. The unsaturated 
fatty acids included in peanut oil and cocoa oil oxidize after the opening 
of the package and oxidize the dithranol into a dark, ineffective dimer. 
In spite of the antioxidants in the stick it must be stored in a cool 
place and used within 6 months of opening. 
It has now been discovered that a paraffin ointment base which contains 
about 40 to 60% of liquid paraffin (white vaseline), about 40 to 60% of 
solid paraffin, and about 0.5 to 5% of microcrystalline paraffin wax is a 
very good vehicle for stick-shaped dermatological preparations. The 
essential aspect of the invention is the use of microwax as a hardening 
agent. The stick cannot be hardened by increasing the proportion of solid 
paraffin, because the stick then tends to be brittle. 
It has also been noticed that the carrier agent is particularly suitable 
for readily oxidizable pharmaceuticals such as dithranol. In paraffin 
ointments the storage stability of such agents is better than in ointments 
containing unsaturated fats, because oxidation via peroxidation is 
excluded. However, it is surprising that, when microwax is added to a 
mixture of liquid and hard paraffin, ointment bases are obtained that 
given even better protection against oxidation. 
The liquid paraffin used in pharmacy (Paraffinum subliquidum) is a mixture 
of liquid hydrocarbons with a high boiling point (above 300.degree.). It 
is commonly used for various ointments. 
The solid paraffin (Paraffinum solidum) is a mixture of solid hydrocarbons 
mainly containing straight-chain alkales; the melting point of the mixture 
is from 50.degree. to 57.degree.. It is used in various ointments as a 
hardening agent. 
Microcrystalline waxes are mixtures of hydrocarbons whose melting point is 
from 60.degree. to 90.degree. and which mainly contain cyclic 
hydrocarbons, some branched acyclic alkanes, but very few n-alkanes. Their 
crystal structure is considerably more delicate than that of paraffin 
waxes. They have been used as a coating agent for papers, textiles, metals 
and plastics. Microwaxes have also been used in wax coatings of cheese, in 
chewing gums and sweets, in cosmetic products such as lipsticks, skin 
ointments and hair sprays, rubber glues, car, floor polishes, in crayons, 
and in candles. 
In the ointment base presented here, microwaxes whose melting points are in 
the range 75.degree. to 90.degree., in particular about 85.degree.to 
88.degree., will be used. 
The composition of the ointment base varies depending on the materials 
used, the desired hardness and toughness, and on the pharmaceutical to be 
used and its concentration. A composition is recommended that contains 
about 45 to 55%, in particular about 48 to 51%, liquid paraffin, about 45 
to 55%, in particular about 47 to 50%, solid paraffin, and about 1 to 3%, 
in particular about 1.5 to 2.5%, microwax. 
If desired, stabilizers and other additives may be added. 
From the mixture presented here, it is possible to prepare sufficiently 
thin and hard, yet non-brittle sticks which adhere well to the skin and by 
means of which the preparation can be applied at precisely the desired 
point. The preparation is better than conventional ointment bases, because 
the stick does not feel greasy. Moreover, the pharmaceutical remains on 
the desired area on the skin and does not spread to the healthy skin or 
adhere to clothes to the same extent as from conventional ointment bases. 
So far, dithranol has mainly been used in hospital treatment. The sticks 
presented here also permit treatment at home. 
Readily oxidizable pharmaceuticals such as dithranol and chrysarobin keep 
well in the ointment bases presented here. 
Pharmaceuticals that can be used in the ointment bases presented here 
include dithranol, 10-acyl derivatives of dithranol, chrysarobin, 
podophyllin, topical cytostats (e.g. 5-fluorouracil), idoxuridine, 
benzoylperoxine, and tretinoin. 
In order to study storage stability, tests were performed on different 
dithranol preparations. Dithranol is well known for its poor stability. 
Attempts have been made to stabilize dithranol preparations in various 
ways, e.g. by adding salicylic acid, but the resulting preparations have 
not been pleasant to use. 
In the stability tests, the stick presented here was compared with two 
paraffin-based dithranol ointments as well as with the "Anthraderm"-stick. 
In Table 1, a dithranol preparation in accordance with the invention is 
compared with two paraffin-based preparations of the same concentration. 
The results indicate that in the ointment base presented here stability is 
better than in ointments containing vaseline or paraffin exclusively. 
TABLE 1 
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Change in dithranol content during storage in an 
ointment base prepared according to the invention and in 
two ointment bases (3.0% preparation) 
Storage 
Ointment base 
Ointment I Ointment II 
period as per inven- 
(Vas. fl. 99.0%, 
(Par. sol. 25.8% 
(months) 
tion (Ex. 1) Par. sol. 1.0%) 
Par. liq. 74.2%) 
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2 +1.9 -2.1 -3.4 
5 +1.4 -1.7 -0.3 
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In Table 2, the new preparation was compared with the commercial 
"Anthraderm" preparation by determining the concentrations of quinone and 
dimer formed in the preparations during storage. It can be seen that the 
storage stability of the preparation presented here is considerably better 
in spite of the fact that it does not contain any stabilizing agents. 
TABLE 2 
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Quinone and dimer concentrations (%) in dithra- 
nol preparation according to the invention and in the 
commercial "Anthraderm" preparation during storage 
Preparation as per 
Temperature 
Time the invention 
"Anthraderm" 
.degree.C. 
(months) Quinone Dimer Quinone 
Dimer 
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Room temp. 
3 2 to 5 2 to 5 
ca 10 10 to 20 
" 5 2 to 5 2 to 5 
ca 10 10 to 20 
35.degree. 
2 2 to 5 2 to 5 
" 5 2 to 5 2 to 5 
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