Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-12-11
2001-08-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C514S564000
Reexamination Certificate
active
06277411
ABSTRACT:
This application is related to PCT No. US97/20424, filed Oct. 31, 1997, designating the United States, the EP Application No. 97946915.2, filed Oct. 31, 1997, the Canadian Application No. 2/241,896, filed Oct. 31, 1997, the Japanese Application No. 10-520855, filed Oct. 31, 1997, and the Mexican Application No. 985376, filed Jul. 1, 1998.
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical formulation and its use for the treatment of cancer. More specifically, the present invention relates to alphadifluoromethylornithine (DFMO) containing oral pharmaceutical formulations having a varied release profile for the treatment of cancer. These formulations may be modified for treating specific cancers.
BACKGROUND OF THE INVENTION
Both in vivo and in vitro, DFMO is an enzyme activated irreversible inhibitor of ornithine decarboxylase (ODC) which is responsible for the conversion of L-ornithine to putrescine, which in turn is converted to longer chain polyamines such as spermidine and spermine. These longer chain polyamines are required for cellular proliferation. Therefore, by inhibiting ODC, DFMO suppresses polyamine formation and consequently cellular proliferation. Aberrant and accelerated cellular proliferation occurs in carcinogenic tissues. Since DFMO is able to suppress polyamine formation, it is able to suppress cellular proliferation and ultimately to ameliorate or prevent cancer. A number of animal studies and/or human clinical trials relate to use of racemic DFMO and specific neoplastic disorders. In addition, a clinical study to determine the pharmacokinetics of racemic DFMO in healthy men has been reported. (Haegele, 1981). Racemic DFMO was reported to have a short elimination half-life, i.e., t
½
is about 3.5 hours, as it undergoes rapid renal elimination. Peak plasma concentrations occur within about 6 hours after oral administration of racemic DFMO containing solutions. Mean total body clearance is about 1.20 mL/min/LcKg, where mean renal clearance is about 0.99 mL/min/LcKg accounting for 83% of drug elimination. The mean apparent volume distribution is about 0.337 L/LcKg, corresponding to 24 L for a 70 LcKg man. The amount of unchanged drug in 24-hour urine samples is about 44% after oral administration and about 80% after L.c. administration.
At a dose of about 3 g/m
2
V, a steady state level of DFMO, 386-622, &mgr;M may be achieved. A DFMO dose of 2.25 g/m
2
every six hours has been recommended for Phase II studies in patients previously treated with cytotoxic drugs (Abeloff et al., 1984).
The maximally tolerated dose (MTD) of oral DFMO has also been examined (Abeloff et al., 1984). The MTD of a 4-day DFMO course given orally, by CI, or by pulse IV infusions (Griffin et al., 1987) to patients with advanced solid tumors or lymphomas has also been studied. Some patients receiving twenty-four courses of oral DFMO on a 28-day schedule developed thrombocytopenia (the DLT). Gastrointestinal side effects have also been observed in treated patients (Abeloff et al., 1984). Audiometric abnormalities is a further side effect associated with DFMO treatment (Griffin et al., 1987). No therapeutic responses were noted in these patient populations.
A study by Griffin et al. (1987) compared routes (PO, CI and IV) and schedules (bolus and continuous infusions) of DFMO administration. Nausea and vomiting were the most frequent and severe toxicities noted, but this occurred mainly in patients receiving oral DFMO. Diarrhea was also observed in patients receiving oral DFMO. Mild leukopenia was further observed with all routes of administration. Mild thrombocytopenia also occurred in some patients. No therapeutic responses were reported with any route of drug administration.
The known minimum effective dose (MED) for racemic DFMO in significantly reducing polyamine pools in vivo is about 0.43 g/day. The maximum tolerated dose of these preparations reported is about 12 g/m
2
/day (oral administration). The reported minimum toxic dose for these racemic preparations of DFMO, in terms of ototoxicity, is about 150 g/m
2
cumulative dose based upon 0.25-6.0 g/m
2
/day chronic oral administration. GI toxicity occurs predominantly during P.O. rather than I.V. administration of racemic DFMO preparations. (−)-DFMO has been reported by some to be the enantiomer primarily responsible for ODC inhibition (Danzin, 1987). However, the side effects associated with DFMO have been traced to a particular enantiomeric form.
Tricalcium phosphate (TCP) and aluminum calcium phosphate (AlCAP) capsule formulations have been tested as implants in rats and proposed for the treatment of trypanosomiasis. (Benghuzzi et al., 1988) A layered tablet formulation comprising racemic DFMO and a slow release layer compressed to a rapid release layer has been tested for controlling fertility and gestation in rat and mouse models. (Bey et al., U.S. Pat. No. 4,309,442). Conventional release hard gelatin capsule and tablet formulations comprising racemic DFMO are also known and have been tested in rat, dog and/or mouse models for controlling gestation, treating non-malignant proliferative skin diseases and/or cancer chemoprevention. (Bey et al., U.S. Pat. No. 4,496,588).
A need continues to exist in the medical arts for formulations capable of maintaining high plasma levels of DFMO during therapy in spite of its rapid clearance rate, without the toxic andlor non-pleasant side effects associated with available DFMO therapies.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an oral solid DFMO-containing pharmaceutical formulation for the treatment or prophylaxis of cancer. The formulations of the invention in some aspects maintain DFMO plasma levels in a patient below the minimum toxic concentration or maximum tolerated concentration and above the minimum effective concentration or minimum therapeutic concentration.
It is yet another object of the invention to provide a method of treating or reducing the risk of cancer by administering to a patient a formulation as described above so as to provide to the gastrointestinal (GI) tract for an extended period of time a therapeutic amount of DFMO.
It is another object of the invention to provide a DFMO-containing dosage form having improved pharmacological activity relative to racemic DFMO. The dosage form will comprise optically pure (−)-DFMO or (+)-DFMO or a defined ratio of (−)-DFMO:(+)-DFMO with reduced side effects or toxicity, enhanced therapeutic efficacy and/or improved pharmacokinetics relative to racemic DFMO.
In one aspect, the invention provides an oral sustained release pharmaceutical formulation for the treatment or prophylaxis of colorectal cancer comprising an oral dosage form. In some embodiments, this dosage form comprises a core and an outer layer surrounding the core, where:
1) the core comprises a rapid release granule and a slow release granule, and each granule comprises a therapeutic amount of (+)-DFMO, (−)-DFMO or a defined ratio of (+)-DFMO:(−)-DFMO or pharmaceutically acceptable salts thereof; and
2) the outer layer comprises a pH-responsive coating for colorectal release of the core.
It is contemplated and within the scope of the invention that a formulation as described above will be useful for the inhibition of cancer or tumor cell proliferation and the amelioration of colorectal cancer.
It is also contemplated and within the scope of the present invention that the pharmaceutical formulation may comprise racemic, optically pure or a defined ratio of the (+):(−) enantiomers of DFMO in combination with other therapeutic compounds for the treatment or prophylaxis of cancer.
It is also contemplated and within the scope of the present invention that the granules which comprise the dosage form core may individually or cooperatively exhibit zero-order, first-order or second-order DFMO release profiles in vivo or in vitro. The rapid release and slow release granules can also act cooperatively to provide a patient being administered the oral sustain
McGinity James
Shaked Ze'ev
Fulbright & Jaworski
ILEX Oncology, Inc.
Page Thurman K.
Seidleck Brian K.
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