Fluorouracil-containing formulation

Details Fluorouracil-containing formulation Fluorouracil-containing formulation

2001-03-05

2003-12-30

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S256000

Reexamination Certificate

active

06670335

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of The Invention
This invention relates to a formulation containing fluorouracil, and to its uses.
2. Description of Related Art
Fluorouracil (USP, INN), also known as 5-fluorouracil or 5-FU, chemically 5-fluoro-2,4(1H,3H)-pyrimidinedione, is a fluorinated nucleoside known to be useful as an antineoplastic antimetabolite. It effectively inhibits RNA function and thymidylate synthesis by blocking the methylation reaction of deoxyuridylic acid.
Fluorouracil delivered by injection has been reported to have beneficial effects in carcinomas of the breast and GI tract, of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas. It appears to exhibit even greater efficacy when administered concomitantly with other agents, including cyclophosphamide, methotrexate, and cisplatin.
Fluorouracil delivered topically is widely used to treat actinic or solar keratoses and superficial basal cell carcinomas. Topical fluorouracil exists in solution formulations containing 1%, 2%, and 5% by weight fluorouracil, and cream formulations containing 1% and 5% by weight fluorouracil. See the
Physicians' Desk Reference.
54 ed., Medical Economics Co., Montvale N.J., 2000, at pages 497-498 (Fluoroplex) and 1394-1395 (Efudex). The disclosures of these and other documents referred to elsewhere in this application are incorporated herein by reference. However, these formulations, while beneficial, are irritating to the skin, causing side effects such as burning, allergic contact dermatitis, erythema, pain, pruritus, and ulceration.
It would be of value to have a formulation containing fluorouracil, where a part of the fluorouracil is present impregnated in porous microparticles.
SUMMARY OF THE INVENTION
In a first aspect, this invention provides a formulation containing fluorouracil, comprising:
(i) an oil-in-water emulsion; and
(ii) dispersed within the oil-in-water emulsion,
(a) fluorouracil; and
(b) fluorouracil-impregnated porous microparticles.
In a second aspect, this invention provides a method of topical application of fluorouracil, comprising the topical administration of the formulation of the first aspect of this invention.
In a third aspect, this invention provides a method of treating a disease state capable of treatment by topical administration of fluorouracil, comprising the topical administration of the formulation of the first aspect of this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
According to the this invention, there are obtained oil-in-water emulsion formulations containing fluorouracil, in which the fluorouracil is present both free and as fluorouracil-impregnated porous microparticles. Thus, the invention comprises formulations in which a part of the fluorouracil is present for immediate release upon topical application, and the remainder of the fluorouracil is present as a reservoir in porous microparticles. Formulations according to this invention are stable and topically acceptable, thereby providing attractive forms for the topical administration of fluorouracil; and are useful for disease states in which topical administration of fluorouracil is indicated, such as actinic or solar keratoses and superficial basal cell carcinomas. Furthermore, such formulations show equal efficacy to, but are less irritating than, other formulations currently on the market containing equivalent concentrations of fluorouracil.
A “therapeutically effective amount” means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
“Treating” or “treatment” of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
Number ranges given in the specification, such as size ranges and the like, should be considered approximate, unless specifically stated.
Ingredient names are taken from the
International Cosmetic Ingredient Dictionary and Handbook,
8th edition, 2000, Cosmetic, Toiletry, and Fragrance Association, Washington, DC.
The Porous Microparticles
Suitable porous microparticles for this invention are solid, water-insoluble, polymeric microparticles having a network of interconnected pores open to the particle surface, providing substantially full communication between the internal pore space and the particle exterior surface. Microparticles of this type, and methods for their preparation and impregnation, are disclosed in U.S. Pat. Nos. 4,690,825 (Won), 4,873,091 (Jankower et al.), 5,073,365 (Katz et al.), 5,135,740 (Katz et al.), and 5,145,675 (Won et al.).
The porous microparticles are generally spherical in shape and have a weight average diameter from less than 1 &mgr;m to about 500 &mgr;m or more, particularly from about 5 &mgr;m to about 100 &mgr;m, more particularly from about 10 &mgr;m to about 50 &mgr;m, especially about 20 &mgr;m. The pore dimensions within the microparticles may vary, with optimum dimensions depending on the polymers used to form the microparticles and the diffusive characteristics of the material to be impregnated. Typical pore volumes are from about 0.01 cm
3
/g to about 4 cm
3
/g, particularly from about 0.1 cm
3
/g to about 2 cm
3
/g; typical surface areas are from about 1 m
2
/g to about 500 m
2
/g, particularly from about 20m
2
/g to about 350 m
2
/g; and typical pore diameters are from about 0.0001 &mgr;m to about 3 &mgr;m, particularly from about 0.003 &mgr;m to about 1 &mgr;m. The average diameter of the microparticles may be determined by sedimentation or by a laser microsizer; the pore volume may be determined by mercury intrusion; and the surface area may be determined by nitrogen adsorption (the BET method).
The porous microparticles are composed of organic polymers and are formed by suspension polymerization of a mixture of monoethylenically unsaturated and polyethylenically unsaturated monomers in the presence of a porogen (a pore-forming agent), as described in the patents listed above. Monoethylenically unsaturated monomers suitable for forming microparticles for use in this invention include styrene, ethylvinylbenzene, vinyltoluene, acrylic acid and its esters, such as ethyl acrylate, methacrylic acid and its esters, such as methyl methacrylate and lauryl methacrylate, vinyl esters, such as vinyl acetate, vinyl propionate, vinyl stearate, and vinyl laurate, vinylic ketones, such as vinyl methyl ketone and methyl isopropenyl ketone, and vinyl ethers, such as vinyl methyl ether, and the like. Polyethylenically unsaturated monomers suitable for forming microparticles for use in this invention include divinylbenzene, divinyl ketone, divinyl sulfone, polyvinyl or polyallyl esters of dibasic or polybasic acids, such as divinyl sebacate, diallyl adipate, diallyl phthalate, diallyl sebacate, polyvinyl or polyallyl ethers of diols or polyols, such as ethylene glycol divinyl ether and diethylene glycol diallyl ether, polyacrylate or polymethacrylate esters of diols or polyols, such as ethylene glycol dimethacrylate, polyethylene glycol diacrylate, trimethylolpropane trimethacrylate, and the like. Typically the monoethylenically unsaturated monomer will be present at from 20% to 80% of the monomer mixture, with the polyethylenically unsaturated monomer forming the remainder of the mixture. Preferred monomer mixtures include styrene/divinylbenzene, vinyl stearate/divinylbenzene, methyl methacrylate/ethylene glycol dimethacrylate, and lauryl methacrylate/ethylene glycol dimethacrylate.
The mixture of monomers, together with the porogen, which is typically a moderately low-boiling hydrocarbon such as heptane or toluene, and a polymerization catalyst, such as a peroxide, are added to an aqueous phase, typically containing a dispersant, and stirred to form

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