Self-emulsifying systems containing anticancer medicament

Details Self-emulsifying systems containing anticancer medicament Self-emulsifying systems containing anticancer medicament

2001-06-05

2001-11-13

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S937000, C514S938000, C514S941000, C514S943000

Reexamination Certificate

active

06316497

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a stabilized self-emulsifying system comprising anticancer medicament. The claimed invention is suitable for formulation of angiogenesis inhibitor o-(chloroacetylcarbamoyl)fumagillol.
BACKGROUND OF THE INVENTION
Fumagillins are a class of compounds naturally secreted from
aspergillus fumigatus
fungus. Synthetic analogues of fumagillins provide a class of angiogenesis inhibitors that exhibit potent anti-angiogenic activity and low systemic toxicity. A synthetic derivative of fumagillin having a formula (I):
has been described in European Patent No. 0 359 036 and European Patent No. 0 357 061 as having inhibitory effect of suppressing the proliferation of endothelial cells and inhibiting neovascularization. The compounds having angiogenesis inhibiting activity have use in treating tumors in cancerous conditions. (
Cancer Medicine
, 3d. edition, Lea & Febiger, Philadelphia (1993)).
Developing stable formulations for delivering effective amounts of medicament to target organs presents unique challenges in obtaining a suitable formulation for the medicament. Characterized by their lipophilic properties and low water solubility, these drugs typically result in formulations producing low oral bioavailability. European Patent No. 0 602 586 discloses a pharmaceutical composition comprising a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin. Typical formulations are less effective for delivery of the medicament to the angiogenic tumors due to low oral bioavailability of the medicament in the formulation.
Recent developments in drug formulation have resulted in self-emulsifying drug systems (SES) being used as vehicles for orally administering lipophilic medicaments. (Charman,
Pharmaceutical Research
, 39(1): 87-93 (1992)). Self-emulsifying systems are generally recognized to be mixtures of oil and surfactant which, upon exposure to aqueous media, form isotropic dispersions stabilized by an interfacial film of surfactant molecules.
Several self-emulsifying systems containing active drug in mixtures of oil and surfactant, which emulsify and form dispersions under gentle agitation, have been described using various components and for numerous uses.
European Patent No. 0 517 412 describes an oil-based self-emulsifying formulation containing benzodiazepine compounds useful for treating pain, panic, or anxiety.
The self-emulsifying systems described in Shah,
Intl. J. of Pharm
., 106:15-23 (1994) contain polyglycolized glyceride oils with varying fatty acid and polyethylene glycol.
Pouton, et al.,
Intl. J. of Pharm
., 27:335-348 (1985), discloses self-emulsifying systems containing Miglyol 812 or Miglyol 840 oils in combination with Tween 85 surfactant.
Pharmaceutical formulations wherein the composition is in the form of a self-emulsifying system have particularly advantageous properties with respect to the above fumagillol derivative. Formulations of fumagillin anticancer agents in typical self-emulsifying systems rapidly degrade if formulated without a suitable stabilizing component. Therefore, there continues to be a need to provide effective methods of formulating fumagillin anticancer agents to ensure more effective bioavailability and wider availability of the desired medicaments.
SUMMARY OF THE INVENTION
The present invention relates to a stabilized self-emulsifying system, comprising a therapeutically effective amount of o-(chloroacetylcarbamoyl)fumigillol, a pharmaceutically acceptable carrier, and a stabilizing component, wherein the pharmaceutically acceptable carrier comprises an oily constituent and at least one surfactant. In one aspect of the invention, the stabilizing component of the self-emulsifying system comprises from about 1% to about 15% water relative to the weight of the formulation. Another aspect of the invention relates to a self-emulsifying system comprising a therapeutically effective amount of o-(chloroacetylcarbamoyl)fumigillol and a pharmaceutically acceptable carrier stabilized by an acid. Yet another aspect of the present invention relates to a stable system for active medicament, comprising a self-emulsifying system comprising medicament, a pharmaceutically acceptable carrier, and a stabilizing component, wherein the stabilizing component is an adsorbent or complex-forming agent.


REFERENCES:
patent: 5422363 (1995-06-01), Yanai et al.
patent: 5846562 (1998-12-01), Yanai et al.

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