Flutamide compositions and preparations

Details Flutamide compositions and preparations Flutamide compositions and preparations

1998-04-14

2001-02-13

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S464000, C424S465000, C514S047000

Reexamination Certificate

active

06187345

ABSTRACT:

The present invention relates to the preparation of flutamide for incorporation into dosage forms for administration to male mammals, particularly humans, in need of treatment. The USAN name “flutamide” has been accepted for the compound having the chemical name 2-methyl-N-[4-nitro-3-(trifluomethyl)phenyl]propanamide of 4′-nitro-3′-trifluoromethylisobutyranilide. The preparation of flutamide is disclosed in U.S. Pat. No. 3,995,060, the disclosure of which is hereby incorporated herein by reference. Flutamide is a nonsteroidal compound devoid of androgenic, adrenocortical, anti-estrogenic, estrogenic, progestational, and antifertility actions.
Flutamide has been demonstrated to be a potent antiandrogen. More particularly, U.S. Pat. No. 4,329,364 discloses that flutamide is useful in treating, alleviating, and palliation of androgen-caused and/or androgen-dependent conditions such as prostatic hyperplasia including, for example, benign prostatic hypertrophy and prostatic carcinoma. In addition, U.S. Pat. No. 4,474,813 discloses conventional pharmaceutical preparations of flutamide adapted for systemic administration providing a therapeutic effect against prostatic carcinoma.
The United States Food and Drug Administration-approved therapeutic dose for flutamide is 750 mg/day in three divided doses of 250 mg/dose. The approved product, Eulexin® (Schering Corporation, Kenilworth, N.J.), is available in capsules containing 125 mg of flutamide.
However, flutamide is relatively insoluble and the approach taken to ensure adequate bioavailability and optimize the intended therapeutic benefit must be innovative. The aforementioned U.S. Pat. No. 3,995,060 mentions a standard formulation for flutamide in specific dosage units, including traditional blending, milling, and filling using traditional excipients. The '060 patent, in column 17, in a footnote, also mentions that the flutamide used in one formulation was, without more, milled post granulation so that the resulting particle size was from 5-240&mgr;. Of course, if milling of flutamide prior to formulating dosage units was known to be critical, the specifics of milling process, in addition to more specific range of critical particle sizes, including surface area, would likely have been described.
It has been discovered that the specific surface area of flutamide used in formulating final dosage forms is critical, and that the particle size range stated in the '060 patent will not provide adequate bioavailability of flutamide. In fact, it has been discovered that the particle size and specific surface area/volume (m
2
/cm
3
) of flutamide must meet specific criteria to ensure adequate bioavailability of formulated flutamide.
Accordingly, one of the objects of the present invention was to discover and define the impact particle size of flutamide active pharmaceutical ingredient has on the bioavailability of flutamide and, more particularly, flutamide's active metabolite 2-hydroxyflutamide. Through significant research, including three series of clinical trials in normal, healthy adult males, a particle size range and range of specific surface area which provide an optimal range of flutamide blood levels in such healthy subjects, in comparison to the innovator product, Eulexin®, has been discovered. As used herein, the term “flutamide active pharmaceutical ingredient” (or flutamide API) means flutamide, or a pharmaceutically-acceptable salt thereof, without any excipients; either preformulation of after all excipients have been fully dissolved leaving only flutamide as a drug substance.
Thus, one aspect of the present invention is flutamide, as an active pharmaceutical ingredient, having a specific surface area of at least about 0.35 m
2
/cm
3
(preferably at least 0.45 m
2
/cm
3
) and, preferably, in a range from about 0.40 m
2
/cm
3
to about 2.50 m
2
/cm
3
. An especially preferred range is from about 0.45 m
2
/cm
3
to about 1.50 m
2
/cm
3
, as calculated using a Sympatec laser light scattering device (Sympatec, Inc. Princeton, N.J.).
It has further been discovered that the range of particle sizes contained in any sample can also influence the bioavailability and, thus, the therapeutic benefit, from the administration of formulated flutamide API. As such, another aspect of the present invention is flutamide, as an active pharmaceutical ingredient, in which fifty percent (50%) of the particles of each sample (X
50
) is less than 26.0&mgr;, preferably in the range from about 5.0&mgr; to about 20.0&mgr;. Furthermore, the present invention also provides flutamide, as an active pharmaceutical ingredient, in which ninety percent (90%) of the particles in each sample (X
90
) is less than 130.0&mgr;, preferably from about 10.0&mgr; to about 130.0&mgr;, and especially from about 15.0&mgr; to about 60.0&mgr;.
Flutamide active pharmaceutical ingredient, having the specific surface area and/or the X
50
and/or X
90
values as set forth herein above, is prepared through milling techniques generally well known to one or ordinary skill in the art, without causing chemical and/or heat degradation of flutamide API. Typically, a jet mill, pin disc mill, ball mill, hammer mill, oscillating mill, roller mill, chaser mill, rotary cutters, collared mill, fluid energy mill, and the like may be used. Preferably, a jet mill is used to provide the desired specific surface area of at least about 0.35 m
2
/cm
3
, but each type of mill could give the desired results by varying the speed of the mill, the amount of flutamide API fed into the mill, and/or the grinding period. In all cases, it is also possible to obtain product with the desired specific surface area by mixing flutamide API of different specific surface areas.
Because unmilled flutamide has a consistency which readily agglomerates rendering milling difficult with inconsistent results, it was also discovered that flutamide API is best milled when combined with one or more pharmaceutically acceptable diluents including, for example, a starch such as corn starch, and the like, sugars such as lactose and mannitol, and the like, cellulose derivatives such as microcrystalline cellulose, and the like, inorganic salts such as dibasic calcium and phosphate dihydrate, and the like. Of these, lactose is especially preferred. The addition of such as diluent prevents agglomeration of flutamide API and improves the flow characteristics of flutamide API, thus aiding in accurately preparing the desired specific surface area and X
50
and X
90
particle size values. The addition of such diluents is accomplished using standard blending techniques which are well know in the art. It was further discovered that a ratio of diluent to flutamide API of about 4:1 to about 1:1 would facilitate the milling of flutamide API, while a ratio of about 2:1, particularly when the diluent was lactose, optimized the milling of flutamide API to the desired surface area and particle size parameters. When lactose was used at this ratio, the appropriate amounts of flutamide API and lactose are present for the next step in formulating flutamide to a final dosage form suitable for administration to a patient in need of treatment.
Accordingly, the present invention also provides a method of preparing flutamide API wherein the specific surface area of such flutamide API is at least 0.35 m
2
/cm
3
, preferably from about 0.40 m
2
/cm
3
to about 2.50 m
2
/cm
3
, and especially from about 0.45 m
2
/cm
3
to about 1.50 m
2
/cm
3
, and/or the particle X
50
size value is less than about 26.0&mgr;, preferably from about 5.0&mgr; to about 20.0&mgr;, and/or the X
90
particle size value is less than 130.0&mgr;, preferably from about 10.0&mgr; to about 130&mgr;, especially from about 15.0&mgr; to about 60.0&mgr;, comprising blending said flutamide API with a pharmaceutically acceptable diluent, preferably lactose, at a ratio of diluent to flutamide API from about 4:1 to about 1:1, preferably about 2:1, and milling the blended composition of diluent and flutamide API to the desired specific surface area and/or the

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