Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1994-10-07
1997-05-20
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514465, 514944, A61K 906
Patent
active
056312482
DESCRIPTION:
BRIEF SUMMARY
This application is the National phase of PCT/GB93/00692, filed on Apr. 2, 1993.
The present invention relates to the topical application of active substances to the human or animal body and in particular to two-component compositions intended for mixing together either in situ on application, or immediately prior to application.
The solubility of active substances in solvent systems is important in relation to the design of topical delivery systems. It has been shown that the degree of saturation of an active substance, for example a drug, in the solvent system or vehicle is a determining factor in controlling release of the active substance.
Coldman et al.; J. Pharm. Sci., 58, 1098-1102, 1969, demonstrated that percutaneous absorption could be enhanced by over-saturating a drug solution to a supersaturated level. A supersaturated state is generated when the concentration of a solute, for example a drug, in a given solvent system exceeds the saturated solubility of the solute in that system.
Coldman prepared a solution of a drug in a mixture of a volatile and a non-volatile solvent and applied it to the surface of a sample of human skin. The volatile solvent evaporated leaving the drug in solution in the non-volatile solvent at a concentration in excess of its saturated solubility in that solvent, thereby creating a supersaturated solution in situ on the skin surface.
European Patent Publication No. 0 151 953 describes a pharmaceutical composition for generating a drug solution in a supersaturated state which is not reliant on the prior evaporation of a volatile solvent.
The composition comprises two distinct but miscible liquid phases, at least one of which contains a drug dissolved therein. The composition of the phases is such that each has a different lipophilicity (or polarity) and thus each confers a different saturated solubility on the drug. The composition of the liquid phases and the concentration of drug in one or both phases is such that on admixture of the two phases, the total drug concentration in the mixture thus formed is greater than the concentration of drug which a mixture of the same composition can accommodate as a saturated solution.
On mixing the two liquid phases, the resulting mixture is therefore supersaturated with respect to the drug.
It is an inherent property of supersaturated solutions that they will seek to adopt a more thermodynamically stable saturated state. This will generally be achieved by precipitation of solute from the supersaturated solution. The tendency for precipitation and the time scale over which it will occur will be dependent on a number of internal and external factors, including for example the degree of saturation, the nature of solute and solvents, the presence of extraneous material and the ambient temperature.
European Patent Publication No. 0 272 045 describes a pharmaceutical composition for generating a supersaturated solution wherein the tendency for drug precipitation to occur is substantially reduced by incorporation of an antinucleating agent into at least one of the liquid phases of compositions described in EP-A 0 151 953.
EP-A-0 151 953 specifically describes two-phase compositions wherein one of the liquid phases comprises water. EP-A-0 151 953 discloses the generation of supersaturated drug solutions by mixing together a lipophilic liquid phase comprising organic solvents and a polar liquid phase comprising mainly water.
It has been found that duration of the supersaturated state, generated by certain two phase compositions in accordance with EP-A 0 151 953, is limited by solvent evaporation taking place after mixing together of the two liquid phases, for example after topical administration of the resulting supersaturated drug preparation in the form of a thin film intended for long contact time usage.
Evaporation of a volatile liquid component, after mixing of the two liquid phases has been found to have, for certain compositions, the effect of increasing the saturated solubility of the drug in the resultant mixture. An increase in dru
REFERENCES:
patent: 4767751 (1988-08-01), Davis
patent: 5110606 (1992-05-01), Geyer
Davis Adrian F.
Gordon Jennifer J.
Huang Evelyn
Ivy C. Warren
King William T.
Lentz Edward T.
SmithKline Beecham Plc
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