Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-28
2002-05-28
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S011400
Reexamination Certificate
active
06395770
ABSTRACT:
REFERENCE TO DISCLOSURE DOCUMENTS
This application incorporates material included in Disclosure Document No. 377063, filed Jun. 23, 1995, No. 386504, filed Dec. 11, 1995, No. 391109, filed Feb. 7, 1996, and No. 391228, filed Feb. 7, 1996.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to methods and compositions for orally administering to human patients pharmaceutical agents that are poorly absorbed from the gastrointestinal tract, and to methods of treatment of patients through the oral administration of such agents. One principal aspect of the invention relates to methods and compositions for orally administering paclitaxel and related taxanes to human patients.
2. Description of the Prior Art
Many valuable pharmacologically active compounds cannot be effectively administered by the oral route to human patients because of poor or inconsistent systemic absorption from the gastrointestinal tract. All these pharmaceutical agents are, therefore, generally administered via intravenous routes, requiring intervention by a physician or other health care professional, entailing considerable discomfort and potential local trauma to the patient and even requiring administration in a hospital setting with surgical access in the case of certain IV infusions.
One of the important classes of cytotoxic agents which are not normally bioavailable when administered orally to humans are the taxanes, which include paclitaxel, its derivatives and analogs. Paclitaxel (currently marketed as TAXOL® by BristolMyers Squibb Oncology Division) is a natural diterpene product isolated from the Pacific yew tree (
Taxus brevifolia
). It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. (
J. Am. Chem. Soc
., 93:2325, 1971), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al.,
Proc. Natl. Acad. Sci. USA
, 77:1561-1565 (1980); Schiff et al.,
Nature
, 277:665-67 (1979); Kumar,
J. Biol. Chem
., 256:10435-10441 (1981).
Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al.,
Yale Journal of Biology and Medicine
64:583, 1991; McGuire et al.,
Ann. Intern. Med
., 111:273, 1989). It is effective for chemotherapy for several types of neoplasms including breast (Holmes et al.,
J. Nat. Cancer Inst
., 83:1797, 1991) and has been approved for treatment of breast cancer as well. It is a potential candidate for treatment of neoplasms in the skin (Einzig et al.,
Proc. Am. Soc. Clin. Oncol
., 20:46), lung cancer and head and neckcarcinomas (Forastire et al.
Sem. Oncol
., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et al,
Nature
, 368:750, 1994) and malaria.
Paclitaxel is only slightly soluble in water and this has created significant problems in developing suitable injectable and infusion formulations useful for anticancer chemotherapy. Some formulations of paclitaxel for IV infusion have been developed utilizing CREMOPHOR EL™ (polyethoxylated castor oil) as the drug carrier because of paclitaxel's aqueous insolubility. For example, paclitaxel used in clinical testing under the aegis of the NCI has been formulated in 50% CREMOPHOR EL™ and 50% dehydrated alcohol. CREMOPHOR EL™ however, when administered intravenously, is itself toxic and produces vasodilation, labored breathing, lethargy, hypotension and death in dogs. It is also believed to be at least partially responsible for the allergic-type reactions observed during paclitaxel administration, although there is some evidence that paclitaxel may itself provoke acute reactions even in the absence of Cremophor.
In an attempt to increase paclitaxel's solubility and to develop more safe clinical formulations, studies have been directed to synthesizing paclitaxel analogs where the 2′ and/or 7-position is derivatized with groups that would enhance water solubility. These efforts have yielded prodrug compounds that are more water soluble than the parent compound and that display the cytotoxic properties upon activation. One important group of such prodrugs includes the 2′-onium salts of paclitaxel and docetaxel, particularly the 2′-methylpyridinium mesylate (2′-MPM) salts.
Paclitaxel is very poorly absorbed when administered orally (less than 1%); see Eiseman et al.,
Second NCI Workshop on Taxol and Taxus
(September 1992); Suffness et al. in
Taxol Science and Applications
(CRC Press 1995). Eiseman et al. indicate that paclitaxel has a bioavailability of 0% upon oral administration, and Suffness et al. report that oral dosing with paclitaxel did not seem possible since no evidence of antitumor activity was found on oral administration up to 160 mg/kg/day. Moreover, no effective method has been developed to enable the effective administration of oral paclitaxel (i.e., a method of increasing the oral bioavailability of paclitaxel) or of other oral taxanes or paclitaxel analogs such as docetaxel which exhibit antitumor activity. For this reason, paclitaxel has not until now been administered orally to human patients, and certainly not in the course of treating paclitaxel-responsive diseases.
Docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl paclitaxel) has become commercially available as TAXOTERE® (Rhone-Poulenc-Rorer S.A.) in parenteral form for the treatment of breast cancer. To date no reference has been made in the scientific literature to oral absorption of docetaxel in animals or patients.
It has been speculated that, in some cases, the poor or non-existent bioavailability of a drug such as paclitaxel after oral administration is a result of the activity of a multidrug transporter, a membrane-bound P-glycoprotein, which functions as an energyependent transport or efflux pump to decrease intracellular accumulation of drug by extruding xenobiotics from the cell. This P-glycoprotein has been identified in normal tissues of secretory endothelium, such as the biliary lining, brush border of the proximal tubule in the kidney and luminal surface of the intestine, and vascular endothelial cells lining the blood brain barrier, placenta and testis.
It is believed that the P-glycoprotein efflux pump prevents certain pharmaceutical compounds from transversing the mucosal cells of the small intestine and, therefore, from being absorbed into the systemic circulation. A number of known non-cytotoxic pharmacological agents have been shown to inhibit P-glycoprotein, including cyclosporin A (also known as cyclosporine), verapamil, tamoxifen, quinidine and phenothiazines, among others. Many of these studies were aimed at achieving greater accumulation of intravenously administered cytotoxic drugs inside tumor cells. In fact, clinical trials have been conducted to study the effects of cyclosporine on the pharmacokinetics and toxicities of paclitaxel (Fisher et al.,
Proc. Am. Soc. Clin. Oncol
., 13: 143, 1994); doxorubicin (Bartlett et al.,
J. Clin. Onc
. 12:835-842, 1994); and etoposide (Lum et al.,
J. Clin. Onc
. 10:1635-42, 1992), all of which are anti-cancer agents known to be subject to multidrug resistance (MDR). These trials showed that patients receiving intravenous cyclosporine prior to or together with the anti-cancer drugs had higher blood levels of those drugs, presumably through reduced body clearance, and exhibited the expected toxicity at substantially lower dosage levels. These findings tended to indicate that the concomitant administration of cyclosporine suppressed the MDR action of P-glycoprotein, enabling larger intracellular accumulations of the therapeutic agents. For a general discussion of the pharmacologic implications for the clinical use of P-glycoprotein inhibitors, see Lum et al.,
Drug Resist. Clin. Onc. Hemat
., 9: 319-336 (1995); Schinkel et al.,
Eur. J. Cancer
, 31A: 1295-1298 (1995).
In the aforedescribed studies relating to the use of cyclospor
Broder Samuel
Duchin Kenneth L.
Selim Sami
Baker Norton Pharmaceuticals, Inc.
Lerner David Littenberg Krumholz & Mentlik LLP
Raymond Richard L.
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