Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1997-02-26
1999-02-09
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
424 121, 424489, 424490, 424498, 424502, A61K 5100, A61K 9127
Patent
active
058690913
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 U.S.C. 371 of PCT/GB95/01859 filed Aug. 7, 1995.
FIELD OF INVENTION
The present invention provides an aqueous formulation (especially an injectable formulation) comprising a pharmaceutically active agent present within vesicles suspended in an aqueous carrier. The formulation particularly though not exclusively contains a pentavalent antimony compound as active agent for the treatment of the parasite infection visceral leishmaniasis.
BACKGROUND
The first line drugs currently used for the treatment of visceral leishmaniasis are pentavalent antimony compounds such as sodium stibogluconate and meglumine antimoniate. These drugs due to their polar nature are inactive by the oral route and undergo rapid renal excretion following dosing by the parenteral route, which necessitates a multiple dosing regime. Compliance with such a regimen is difficult to achieve in remote areas such as the Sudan where visceral leishmaniasis is endemic and has reached epidemic proportions. Development of a vesicular formulation of such antimonial drugs could increase their efficacy, allowing both the number of doses and dose size to be lowered.
The constituents of a vesicular formulation can influence vesicle characteristics (e.g. stability, size, charge) and hence its suitability as a drug carrier system and depending on the intended usage the requirements of the formulation can be drug specific. In our previous studies using a murine model of visceral leishmaniasis we have shown that vesicle size is important since elimination of Leishmania parasites from deeper sites such as the spleen required the use of small, drug loaded vesicles. Incomplete removal of parasites from these sites results in relapse and probably underlies the 2-8% relapse rate reported after antimonial therapy.
Diverse non-ionic surfactants can be used to form vesicles with potential therapeutic applications such as drug delivery (Ozer et al., 1991) and immunological adjuvants (Brewer and Alexander, 1993). We have already demonstrated (Carter et al., 1989a,b) that stibogluconate loaded non-ionic surfactant vesicles are as effective as drug loaded liposomes for improving the treatment of experimental visceral leishmaniasis.
It is an object of the present invention to provide such a vesicle formulation of improved efficacy. This and other objects of the present invention will become apparent from the following description and examples.
STATEMENT OF INVENTION
Broadly stated, the present invention resides in the finding that improved therapeutic efficacy can be achieved by providing the active agent both in the vesicles themselves and also in the aqueous carrier vehicle.
Thus, the present invention provides a formulation which comprises: aqueous vehicle.
DETAILED DESCRIPTION
The presence of the pharmaceutically active agent in both the vesicle phase and the aqueous liquid phase improves the efficacy thereof. The concentration of active agent in the aqueous vehicle may be the same, greater or lower than the concentration thereof in the vesicles. For convenience, the aqueous vehicle containing the active agent will generally be that which is used to load the active agent into the vesicles, where such a method is used to introduce the active agent into the vesicles.
In principal, the vesicle may be formed in any manner known in the art and appropriate to the active-agent to be delivered. For example, vesicles can be formed using either a "homogenisation" method or a "freeze-dried" method, both methods being known in the art. In the homogenization method a required quantity of lipid material in a desired molar ratio can be processed in one of the following ways: Dry powders (i.e. lipid material) are hydrated with a solution of the active agent for entrapment at a desired temperature, in the range from 0.degree. up to 150.degree. C.) and homogenised at the required speed and for the required length of time to produce the desired vesicle characteristics. Alternatively the lipid material can be melted by the application of heat (e.g. te
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Baillie Alan James
Carter Katharine Christine
Williams Denise Margaret
Page Thurman K.
Shelborne Kathryne E.
University of Strathclyde
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