FI66533B - FOER HUDVAORD AVSEDD PHARMACEUTICAL COMPOSITION - Google Patents

Description

66533

This invention relates to a novel paraffin-based pharmaceutical composition for application to the skin. In particular, the invention relates to compositions using readily oxidizable drugs such as ditranol and its derivatives.

The disadvantages of ointment bases used in the treatment of dermatological diseases are the tendency to spread from diseased skin to the surrounding healthy skin and clothing. This is especially detrimental when using creams that contain poorly penetrating Vaseline, paraffin oil and soft waxes, which mainly affect the stratum corneum and epidermis. It is almost impossible to apply such creams only to diseased skin areas and their administration is difficult and too variable. This poses particular problems, especially if the cream contains skin irritants or substances that stain the skin and fabrics. One such inflammatory and coloring agent for healthy skin is ditranol 20, or anthranil, the drug still used in the topical treatment of psoriasis.

P. G. Unna was the first researcher to develop ointment suppositories containing dermatological drugs in an effort to reduce the above-mentioned disadvantages / Monatshefte fur Praktiselle Dermatologi 1886: 5 157-167 /. According to Unna, dry, limited, patchy rashes, such as psoriasis, dry eczema, and patchy fungal rashes, are best treated with ointments.

30 He suggests that the consistency of the ointment stick should be soft enough that not much force should be applied to pull the ointment into the skin, but on the other hand hard enough that the stick should not change shape when used and warm. These requirements, which also depend on the drug used, could be met

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according to him, satisfies with mixtures of olive oil and wax. In addition to wax, Unna used rosin as a hardener.

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Wax Unna used yellow beeswax (cera flava). Two of the ointment suppository recipes presented by Unna, almost all of which followed a similar suppository base composition, are: "Stilus acid, salicyl. Unguens 10%" 5 (Salicylic acid 10.0, rosin 5.0, yellow wax 45.0, olive oil 40.0) and " Stilus Chrysarobini unguens 30 (Chrysarobin 30.0, rosin 5.0, yellow wax 35.0, olive oil 30.0).

10 Unna had also designed a paraffin ointment (solid paraffin 50.0, liquid paraffin 50.0), but apparently had not mixed drugs with it because of the softness of the wand, but used the wand to lubricate dry, horny skin like lipstick.

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There have been very few publications on ointments in the treatment of skin diseases since Unna's groundbreaking publication.

F. Dietel 1941 mentions a chrysarobin-20 ointment for the treatment of psoriasis / Deutsche medizinische Woche ns ch ri f t 1941: 9 237-9 /. The composition of the stick was: Chrysarobin 30.0, yellow wax 20.0, wool grease 50.0.

Two publications from 1962 and 1966 in which 25 close relatives of chrysarobin (i.e., according to current practice, ditranol) were used as suppositories / Weber, G., Medizinische Welt 1962: 35 1839-40 and Schafö, MK, Zeitschrift fur Haut- und Ges ch le ch ts k rankhe i ten 1966 XL 347-51 /. The same commercial preparation "Psoriacid" was used in both. The exact composition of the ointment base was not reported, but it included: White petrolatum, sheep fat, solid paraffin and white wax.

In his study, F. Novotny 1970 used the following 35 ointment bases: Castor oil 1.0, liquid. paraffin 4.0, yellow wax 43.0, coconut oil 52.0, / Cs. Derm. 45 (19 70): 1 20-22 /.

3 66533 There is currently one ointment available in the Nordic countries as a commercial product. This is an AnthradernT stick (Pharma-Medica) containing 0,5, 1,0 or 2,0% ditranol. The percentage composition of the cream base is not indicated, 5 but the base contains wool alcohols, cocoa butter, white beeswax, whale wax (cetaceum ) and peanut oil (oleum arachidis) and 0.5% salicylic acid and 0.02% butylated hydroxytoluene as stabilizers.

10 Although rod-shaped preparations are a therapeutically advantageous dosage form for many dermatological drugs, they have not achieved a very significant role in practice. Apparently this is due to the fact that the ointment bases developed so far have been too soft and 15 above all because they have contained oxidizing vegetable oils and animal fats. In turn, rancid, peroxidizable oils and fats oxidize many drugs, such as ditranol and chrysarobin, to ineffective compounds, Jo Linna stated in his monoraphy on ditranol that compounds. It has also been found that the more unsaturated double bonds in fatty acids, the faster the oxidation of ditranol.

A further disadvantage of some needles is that they contain wool grease that causes contact allergies.

30 Those problems are also apparent from the abovementioned 'Anthraderm' stick. The unsaturated fatty acids contained in peanut oil and cocoa butter oxidize after opening the package and oxidize ditranol from the surface of the rod to a dark, ineffective dimer. Despite the antioxidants in the stick, it must be kept cool and used within 6 months of opening the outer package 4 66533. In addition, the unopened needle pack1 has been declared useful for one month.

□ E-application publication 2 335 549 discloses an ointment composition 5 consisting mainly of water-in-oil emulsions, which also contains polyols and gloss and the like additives. The composition is intended to be specifically cosmetically acceptable. Polyols are oxidizing compounds which, when used, do not add easily oxidizable drugs and the like to the mixture. substances.

It has now been found that a paraffin cream base containing about 40-60% liquid paraffin (white copper), about 40-60% solid paraffin and about 0.5-5% micro-crystalline paraffin wax is very well suited as a carrier for rod-shaped dermatological preparations. Most essential in the invention is the use of microwax as a hardener. The rod cannot be hardened by increasing the proportion of solid paraffin, since the rod then becomes easily breakable.

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In addition, it has been found that the carrier of the invention is particularly suitable for readily oxidizable drugs such as ditranol. However, it is to be expected that paraffin creams have a better shelf life of such substances than creams containing unsaturated fats because oxidation through peroxidation is prevented. Surprisingly, however, the addition of microwax to the mixture of liquid and hard paraffin provides even better antioxidant cream bases.

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Liquid paraffin (Paraffinum subliquidum) used in pharmacy is a mixture of liquid hydrocarbons boiling at high temperatures (above about 300 °) and is commonly used in various creams.

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Solid paraffin (Paraffinum solidum) is a mixture of solid hydrocarbons containing mainly straight-chain alkanes with a melting point of about 50 to 57 ° C. It is used as a curing agent in various creams.

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Microcrystalline waxes are mixtures of hydrocarbons with a melting point of about 60-90 ° and which contain mainly cyclic hydrocarbons, some branched acyclic alkanes and only small amounts of n-alkanes. Their crystal-5 coating is considerably finer than paraffin waxes. They have been used primarily as coatings for papers, textiles, metals and plastics. In addition, microwaxes have been used e.g. in wax coatings for cheeses, chewing gums and confectionery, in cosmetic products such as lipsticks, lotions 10 and hair sprays, rubber adhesives, car floor and other polishes, crayons and candles.

In the cream base according to the invention, microwaxes with a melting point of about 75 ... 90 °, in particular π, are particularly suitable. Θ5 ... ΒΘ0.

The composition of the ointment base may vary and depends on the materials used, the desired hardness and toughness, and the drug used and its concentration.

20 A composition containing about 45-55%, especially about 48-51%, liquid paraffin, about 45-55%, especially about 47-50%, solid paraffin is recommended. and about 1 ... 3%, especially about 1.5 ... 2.5%, microwax.

If desired, stabilizers and other additives can be added.

The mixture according to the invention can be made into sufficiently thin and hard, but unbreakable and well-adhering sticks, with which the dosing can be carried out precisely at the desired point. Dosing is more pleasant than with conventional ointment bases, because the stick according to the invention does not feel greasy. In addition, the drug stays well in the desired area of the skin and does not spread to healthy skin or stick to clothing to the same extent as when using conventional ointment bases. For example, until now, it has been possible to use ditranol mainly in hospital care. However, the needles according to the invention also enable treatment at home.

In addition, readily oxidizable drugs such as ditranol and chrysotropin have been shown to be very well preserved in the ointment bases of the invention.

Examples of drugs which can be used in the ointment bases according to the invention are ditranol, 10-acyl derivatives of ditranol, chrysarobine, podophyllin, local cytostats (e.g. 5-fluorouracil), idoxyuridine, benzoyl peroxide and tretinoin.

10 To investigate shelf life, experiments were performed with various ditranol preparations. Ditranol is known for its poor shelf life. Efforts have been made to stabilize ditranol preparations in various ways, e.g. by adding salicylic acid, but satisfactory results for the pleasant use of the preparations have not been obtained.

In the stability tests, the wand according to the invention was compared with two of the best ditranol paraffin-based creams and the wand on the market.

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Table 1 compares the ditranol preparation of the invention with two paraffin-based preparations of the same strength. The results show that in the ointment base according to the invention the shelf life is better than in ointments containing only copper * 25 line or paraffin.

Table 1: Change in ditranol content during storage in the invention and in two known ointment bases (3.0% preparation) 30

Storage - Ointment according to the invention Ointment II

time (months) bottom (eg 1) (Nestom.v. 99.0%, (Fixed parf. 25, B%,

Kiint.paraf. 1.0%) Nestem.paraf. 74.2%) 2 +1.9 -2.1 -3.4 5 +1.4 -1.7 -0.3 35 7 66533

Table 2 compares the formulation of the invention with the commercial "Anthraderm" formulation by determining the standards for comparing the concentrations of quinone and dimer formed during storage. It can be seen from the results 5 that the shelf life of the preparation according to the invention is substantially better despite the fact that it does not contain any stabilizers.

Table 2: Quinone and dimer contents (%) of ditranol during storage of the commercial "Anthra-10 Derm" preparation according to the invention Temperature Time "Anthraderm" preparation (kk) according to the invention 15 Quinone Dimer Quinone Oimer

Room 3 2-5 2-5 n. 10 10-20 lärrpät.

"5 2-5 2-5 n. 10 10-20 35 ° 2 2-5 2-5 20" 5 2-5 2-5

The following examples illustrate the invention. Example 1

Oitranolia 3.0 IMestem. paraffin 48.0 Solid paraffin 47.0 30 Microwax (Arcowax 9240 G) 2.0

The preparation is as follows: The actual base, paraffins and microwax are melted and mixed. The active ingredient is slurried in the mixture 35 and the mixture is poured into suitable molds or packages which at the same time act as casting molds.

66533

Example 2

Chrysarobin 15.0

A liquid. paraffin 42.0 5 Solid paraffin 40.0 "Arcowax 9240 G” 3.0

Example 3 10 Podophylline 1.0

A liquid. paraffin 49.0

Solid paraffin 48.0 "Arcowax 9240 G" 2.0 15 Example 4

Idoxyuridine 3.0

A liquid. paraffin 48.0

Solid paraffin 47.0 20 "Arcowax 9240 G" 2.0

Claims (6)

66533 A solid carrier composition for topical application to the skin, characterized in that it contains 40-60% liquid paraffin, about 40-60% solid paraffin and about 0.5-5% microcrystalline wax. A composition according to claim 1, characterized in that it contains about 45-55% liquid paraffin, about 45-55% solid paraffin and about 1-3% microcrystalline wax. Mixture according to Claim 1 or 2, characterized in that it contains about 48 to 51% of liquid paraffin. about 47-50% solid paraffin and about 1.5-2.5% microcrystalline wax. Mixture according to one of Claims 1 to 3, characterized in that the melting point of the microwax is 20 to about 75 to 90 °. Mixture according to one of Claims 1 to 4, characterized in that the melting point of the microwax is 85 to 88 ° C to 25 ° C. Use of a mixture according to any one of claims 1 to 5 as a carrier for easily oxidizable drugs.