Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-23
2003-12-30
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000
Reexamination Certificate
active
06670384
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of administration for parenteral and oral compositions of certain epothilone analogs that are characterized by enhanced clinical efficacy.
BACKGROUND OF THE INVENTION
Epothilones are macrolide compounds having utility in the pharmaceutical field. For example, Epothilones A and B having the structures:
may be found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL®) and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Hofle et al.,
Angew. Chem. Int. Ed. Engl.
, Vol. 35, No.13/14, 1567-1569 (1996); WO 93/10121 published May 27, 1993; and WO 97/19086 published May 29, 1997.
Derivatives and analogs of Epothilones A and B have been synthesized and may be used to treat a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle et al., Id.; Nicolaou et al.,
Angew Chem. Int. Ed. Engl.
, Vol. 36, No. 19, 2097-2103 (1997); and Su et al.,
Angew Chem. Int. Ed. Engl.
, Vol. 36, No. 19, 2093-2097 (1997).
Analogs of the epothilones that have been found to have advantageous activity are represented by formula I:
wherein the various symbols are as defined below. While these compounds possess significant therapeutic properties, they also present difficulties to those skilled in the art of pharmaceutical compounding, as a result of certain properties, as will be detailed hereinbelow. In accordance with the present invention, a formulation has been found whereby the epothilone analogs described above can be safely dispensed and administered via injection, without appreciable loss of potency.
Furthermore, many anti-cancer drugs have toxicity concerns. Indeed, the therapeutic profile of many potent antitumor drugs is poor as a result of toxicity. Therefore, there is also a need for methods of administration and dosing schedules that reduce or avoid the toxicity associated with antitumor agents. The methods can allow exploitation of potent antitumor agents that would otherwise not be used clinically.
SUMMARY OF THE INVENTION
The invention encompasses a novel dosing schedule for epothilone compounds, which schedule is useful in treating patients having solid tumors, particularly advanced solid tumors. Further, the methods of the invention can be used to treat and/or prevent metastatic as well as primary tumors. In one embodiment, the invention encompasses the treatment of patients that have previously received either or both radiation therapy and chemotherapy for solid tumors. It has also been found that the epothilone compounds of the invention particularly the preferred compound, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, can be used to treat tumors refactory to radiation therapy or chemotherapy. The methods of the invention are useful against cancer cells, and thus, tumors, that are naturally or become insensitive to paclitaxel.
In one embodiment, the dosing schedule of the invention comprises the weekly administration of an epothilone compound of the invention preferably as a one (1) hour infusion weekly on a continuous basis. In another embodiment, the administration is made weekly for a three week cycle. The dose range for weekly infusion is from 1 mg/m
2
to 30 mg/m
2
and more preferably 1 mg/m
2
to 25 mg/m
2
. In another embodiment, the dosing schedule includes both oral and intravenous administration of the same epothilone compound. For example, the weekly infusion can be followed or preceded by an oral administration of 20 mg/m
2
or greater. In a specific embodiment, the administration regimen includes a three (3) week cycle of intravenous infusion once per week for about one (1) hour followed by or preceded by an oral dose administered one or more times in the week before the first intravenous administration of a cycle or the week after the last intravenous administration of a cycle. Other protocols are also encompassed within the present invention including but not limited to:
(a) a daily dosing for 5 to 10 days followed by at least 3 days of no dosing;
(b) weekly dosing for two to ten weeks followed by at least one week of no dosing; and
(c) dosing once every three weeks followed by at least one week of no dosing.
The invention also contemplates the use of H
1
and H
2
antihistamines before, after and/or before and after a cycle of epothilone administration. Similarly, the invention encompasses the use of other chemotherapeutics, particularly anti-tumor agents, with epothilone cycle alone, or with the H
1
and H
2
blockers and the epothilones.
In another embodiment, the epothilone dosing schedule is used after the standard regimen of paclitaxel.
As discussed herein a wide variety of cancers are encompassed by the methods of the present invention. In a preferred embodiment, the methods of the invention are for the treatment of solid tumors including but not limited to breast, head and neck, sarcoma, colorectal, UPT, melanoma, oesophagus, renal, cervix, thyroid, anal, ovarian, and colon.
The methods and compositions of the present invention describes a formulation and the preparation thereof for epothilone analogs represented by formula I:
wherein the various symbols are as defined below.
In one embodiment of the formulations of the present invention, the epothilone analog is initially solubilized with a mixture of tertiary-butanol and water and then lyophilized under optimized conditions. The lyophilized drug is reconstituted first with a mixture of a polyethoxylated castor oil surfactant and anhydrous ethanol, and thereafter diluted with Lactated Ringer's Injection to a concentration appropriate for administration.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides an advantageous formulation for the administration of epothilone analogs represented by formula I:
As used in formula I and throughout the specification, Q is selected from the group consisting of:
M is selected from the group consisting of oxygen, sulfur, NR
8
, and CR
9
R
10
;
each R
1
, R
2
, R
3
, R
4
, R
5
, R
7
, R
11
, R
12
, R
13
and R
14
is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R
1
and R
2
are alkyl, they can be joined to form cycloalkyl;
R
6
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;
R
8
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R
11
C═O, R
12
OC═O and R
13
SO
2
; and
each R
9
and R
10
is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R
14
C═O, and R
15
OC═O.
The following are definitions of various terms used herein to describe the present invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term “alkyl” refers to optionally substituted straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms, preferably from 1 to about 7 carbon atoms. The expression “lower alkyl” refers to optionally substituted alkyl groups having from 1 to about 4 carbon atoms.
The term “substituted alkyl” refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocylooxy, oxo, alkanoyl, aryl, aryloxy, aralkyl, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amino in which the two substituents on the amino group are selected from alkyl, aryl, aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, s
Bandyopadhyay Rebanta
Malloy Timothy M.
Panaggio Andrea
Raghavan Krishnaswamy Srinivas
Varia Sailesh Amilal
Bristol--Myers Squibb Company
Patel Rena
Reamer James H
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