AU619586B2

AU619586B2 - Pharmaceutical product which can be applied transdermally containing pharmaceutically usable glycosides

Info

Publication number: AU619586B2
Application number: AU41016/89A
Authority: AU
Inventors: Karl Heinrich Dr. Pegel; Hans Dr. Walker
Original assignee: Roecar Holdings NV; Roecar Holdings Netherlands Antilles NV
Current assignee: Roecar Holdings Netherlands Antilles NV
Priority date: 1988-09-01
Filing date: 1989-09-01
Publication date: 1992-01-30
Anticipated expiration: 2009-09-01
Also published as: NO893503D0; FI893776A; JPH02180831A; DK430889D0; GR890100519A; PT91572A; EP0356754A1; ATE72982T1; DE3829640C1; DK430889A; AU4101689A; NO893503L; PT91572B; EP0356754B1; GR1000353B; FI893776A0

Abstract

The invention relates to transdermally applicable pharmaceutical compositions which contain glycosides as active substances and which are characterised in that ethoxylated sterols and/or C12-C30 alcohols are employed as solubilisers in lipophilic phase.

Description

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I r 619 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION FOR OFFICE USE Form Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: 48 +~040 0 0 0o a 0 0 0 o TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: t ROECAR HOLDINGS (NETHERLANDS ANTILLES) N.V.

Kerkstraat 10a, Willemstad Curacao, Netherlands Antilles Dr. Hans WALKER and Dr. Karl Heinrich

PEGEL

GRIFFITH HACK CO.

71 YORK STREET SYDNEY NSW 2000

AUSTRALIA

Complete Specification for the invention entitled: PHARMACEUTICAL PRODUCT WHICH CAN BE APPLIED TRANSDERMALLY CONTAINING PHARMACEUTICALLY USABLE GLYCOSIDES The following statement is a full description of this invention, including the best method of performing it known to me/us:- -z 2 PHARMACEUTICAL PRODUCT WHICH CAN BE APPLIED TRANSDERMALLY CONTAINING PHARMACEUTICALLY USABLE

GLYCOSIDES

The invention relates to a new transdermal pharmaceutical product containing pharmaceutically usable glycosides.

There is a very large number of important medicines "0 in the form of glycosides which are generally only effective in this form, whereas their aglycons have 0 0 lesser or different effects. The medically effective S glycosides frequently used include, for example, the cardiac glycosides such as occur in the adonis, 0 15 digitalis, nymphaea, strophantus, convallaria, or urginaea species. It has been known for a long time that such glycoside active substances frequently exhibit better efficiency, or at least a more balanced o effectiveness, if they are dispensed in the form of °o0.o0 plant or animal extracts and not as pure substances. It ahas been concluded from this that accompanying 0 00 0 substances of natural material are probably effective as entrainer but it is very difficult, or has been impossible hitherto on an individual basis, to 25 determine exactly which substances act as entrainers A here. In the case of isolated or synthetically manufactured glycosides, it is in any case frequently evident that the resorption capacity is lower in comparison with plant extracts and therefore some of these glycosides can not be used for therapy, or are only usable on a small scale, For example, it is known that peroral application of digitoxin at 100%, lanatoside A at 70%, lanatoside C at only 40%, g- -4 E ,I all. Therefore, attempts have been made in certain cases to bypass resorption through the gastrointestinal tract and to have the active substances absorbed through the skin. In those cases where the active substances are glycosides, however, resorption is only very poor, whereas in the case of other active substances this is frequently very good.

°0a:,10 It has now, surprisingly, been discovered that the resorption capacity of glycoside active substances is o in fact increased on transdermal application if the 0400 o active substances are used together with ethylene 000000 0 0 oxide addition compounds with about 20-30 ethylene oo 15 oxide units to sterols or alcohols with about 12-30 C atoms.

a It could not be predicted that it is possible to 0 0 0 0" dissolve glycosides, which are not only poorly .o"o0O soluble in water but also generally in lipophil 046 solvents, in an oil phase with the aid of solubilisers and to render this transdermally reabsorbable, even when this is in the form of an emulsion, and indeed at Sa far higher resorption level than was previously 25 ever possible either orally or transcutaneously.

According to the invention the active substances are mixed with ethoxylised sterols or ethoxylised alcohols with about 12-30 C atoms and dissolved in polyhydric alcohols such as 1,2-propandiol or glycerine on being slightly warmed. All ethoxylised sterols can be used, either as mixture or as monocompound, as solubiliser or entrainer in the subsequent transaermal resorption.

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II- 0 00 0 00 0 0 o 00.0 e 0 000 a .0 0000 The most suitable sterols include, for example, the sitosterols, cholesterol, stigmasterol and the mixtures of various sterols which occur in nature, such as are found for instance in non-saponifiable portions of fatty oils. As alcohols with about 12-30 C atoms, fatty alcohols can be preferably used, but also naturally occurring cross-linked, alicyclic or aromatic alcohols, such as derivatives of squalene or phytol for example. These compounds, which are easily manufactured .0 by converting free alcohols with ethylene oxide, are in part already available as the products marketed by the Henkel KGaA company under the name "Generol These are mainly sitosterol mixtures with an ethoxylisation rate of 20-30. An ethoxylised sitosterol with a chain .5 length of 25 EO units is preferably used.

The solutions of the glycosides used as active substances in solubilisers and polyhydric alcohol, in 0 Q 6 00.

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6 0 f turn, dissolve to form clear solutions in oils or 20 molten fats. This involves above all the usual ointment bases such as medium-chain triglycerides, glycerol monostearate, lanolin, pork grease etc. It has also been established, most surprisingly, that after the active substances have been worked into 25 the fat bases, they can be further processed into ointment emulsions since the mixture can be emulsified with about an equal quantity of water without any difficulties. Irrespective of whether the active substances are present in a waterless or aqueous fat base, experiments with active substance marked '"1C show that penetration into the skin and permeation are about five-times greater. In this case, the active substances not only penetrate the skin but even permeate right through the skin so that when the preparation is applied to larger areas, plasma levels can be reached at a depth which could not be reached through the intestines.

The average composition for the transdermal application is about 0,01-0,1% active substance, 1% EO addition compounds and 10% polyhydric alcohol. After the active suostance has been dissolved in the mixture of addition 1 0 compounds and polyhydric alcohol, the clear solution is O. either mixed with the corresponding amount of waterless ointment base or mixed, in a way known per se, with about half the quantity of ointment base, while adding the usual amount of non-ionogenic emulsifying agents 15 compounded with water, and emulsified in the usual way on stirring in with the residual material.

The invention is explained in more detail below by Q o "0 0 means of examples: a o EXAMPLE 1 o a While warming, 100mg of acetyl digoxin is dissolved in 10.0g ethoxylised soyasterin (25 EO units) and 100.Og 1,2-propandiol. The solution is heated to about and then dissolved with a melt, which has also been heated to 70C'=, comprising 100,0g of cetyl palmitate, 350g of stearyl heptamoate, 100g of sorbitane monostearate and 60.Og of PE sorbitane monostearate.

While the mixture is being stirred vigorously, distilled water at the same temperature is added to make up a total weight of 1000.Og and the emulsion is then cold-stirred.

6 EXAMPLE 2 Into a melt maintained at 70'C comprising 300.Og hydrogenated coconut oil, 50.0g medium-chain triglycerides, 120g glycerine monostearate and ethoxylised palmityl-stearyl alcohol (25 EO units), a mixture of 10.Og ethoxylised soyasterin (25 EO units), 100,Og 1,2-propandiol and 20mg K-strophantin is stirred, and this mixture is then filled with water maintained at 70'C to make up a weight of S 1000.0g. The emulsion is then slowly cold-stirred.

0000 000° EXAMPLE 3 00"0 Penetration or permeation measurements.

Male rabbits, approximately 10 weeks old with a body weight of about 2 kg, were used as test animals. On a shaved area of 10 x 5 cm on the back of a rabbit, 1.Og of cream was applied with a radioactivity of 20i Ci of 2'?0 the glucoside, marked in each case, and then covered with aluminium foil attached with waterproof cc adhesive plaster. After 24 hours, the rabbit is then put down and the application area is washed several times with swabs moistened with ethanol. The radioactivity of the occlusive bandage material and A swabs is measured after extraction using ethanol. The skin of the area of application is treated for 24 hours with 2m caustic soda/methanol/triton (6:3:1 ratio) at 53'='C and then washed with ethanol warmed to 40'=C. The radioactivity measured with a liquid scintillation counter (Philips PW 4700), is a dimension for the percentage penetration of the amount of substance applied. The permeation during 24 hours is calculated as follows: 100% (activity of the washing liquid activity of the penetration amount) permeation.

In the case of digoxin, the values given in this test were: penetration of 2.1% of the applied dose and permeation of 10.2% of the applied dose.

EXAMPLE 4 Soo0 The penetration or permeation of 'H Ouabain was Ogoo:0 measured in accordance Example 3.

0 0 0000 o 0o For Ouabain this test gave average values for the 0 penetration to 1.1% of the applied dose and for the 0000 oooo 15 permeation of 55.4%. xn view of the fact that the strophantins are only very slightly reabsorbed perorally, the high percutaneous absorption rate is surprising and opens up completely new possibilities o0 o for the medical use of strophantins.

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Claims

1. A transdermally applicable pharmaceutical preparation comprising an admixture of a cardiac glycoside and an ethoxylised sterol having 20-30 ethylene oxide units or a 12-30C ethoxylised monohydric alcohol having 20-30 ethylene oxide units dissolved in a polyhydric alcohol; o said preparation being optionally admixed with 6660 a waterless ointment base or 0 :o 15 a combination of a waterless ointment base, water and 0000 00o a non-ionogenic emulsifying agent. on 2. A pharmaceutical preparation according to claim .ooo 1, wherein the ethoxylised sterol is sitosterol with o000 about 25 ethylene oxide units.

3. A pharmaceutical preparation according to claim 1 or claim 2, wherein the polyhydric alcohol is oa ',2-propandiol. o 4. A transdermally applicable pharmaceutical 0o o preparation, substantially as herein described, with o 25 reference to Example 1 or Example 2. 0 o 0 So DATED this 6th day of November 1991 0 o ROECAR HOLDINGS (NETHERLANDS ANTILLES) N.V. By their Patent Attorney GRIFFITH HACK CO S s:20947B:438/6.11.91

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