U.S. patent application number 10/979958 was filed with the patent office on 2005-08-04 for process and formulation containing epothilones and analogs thereof.
Invention is credited to Gogate, Uday S., Haby, Thomas A., Naringrekar, Vijay H..
Application Number | 20050171167 10/979958 |
Document ID | / |
Family ID | 34572906 |
Filed Date | 2005-08-04 |
United States Patent
Application |
20050171167 |
Kind Code |
A1 |
Haby, Thomas A. ; et
al. |
August 4, 2005 |
Process and formulation containing epothilones and analogs
thereof
Abstract
A process for formulating certain epothilones and analogs
thereof for parenteral administration is provided wherein the pH of
the formulation for administration can be controlled to enhance the
stability and thus, potency of the epothilone, or analog
thereof.
Inventors: |
Haby, Thomas A.;
(Hillsborough, NJ) ; Gogate, Uday S.; (North
Brunswick, NJ) ; Naringrekar, Vijay H.; (Princeton,
NJ) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
34572906 |
Appl. No.: |
10/979958 |
Filed: |
November 3, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60517020 |
Nov 4, 2003 |
|
|
|
Current U.S.
Class: |
514/365 |
Current CPC
Class: |
A61K 31/425
20130101 |
Class at
Publication: |
514/365 |
International
Class: |
A61K 031/427 |
Claims
What is claimed is:
1. A pharmaceutical preparation for administering to a patient a
formulation for administration, the formulation for administration
including an infusion fluid having an infusion fluid pH and a
compound of formula I: 9wherein, Q is selected from the group
consisting of: 10W is selected from --O-- and --N(R.sup.16)--; M is
selected from the group consisting of oxygen, sulfur,
--N(R.sup.8)--, and --C(R.sup.9R.sup.10)--; each R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, and R.sup.7 is, independently, selected
from the group consisting of hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, and heterocyclo, and wherein when R.sup.1
and R.sup.2 are alkyl, they can be joined to form cycloalkyl;
R.sup.6 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo,
and substituted heterocyclo; R.sup.8 is selected from the group
consisting of hydrogen, alkyl, substituted alkyl,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.2, and --S(O.sub.2)R.sup.13;
R.sup.9 and R.sup.10 are each independently selected from the group
consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl,
heterocyclo, hydroxy, --C(.dbd.O)R.sup.14, and
--C(.dbd.O)OR.sup.15; and each R.sup.11, R.sup.12, R.sup.3,
R.sup.14, R.sup.15, and R.sup.16 is, independently, selected from
the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, and heterocyclo; or a pharmaceutically-acceptable
salt or solvate thereof, wherein, the compound of formula I has a
pH of maximum stability different from the infusion fluid pH to
define a pH differential; the pharmaceutical preparation comprising
a surfactant, a solvent, a buffer, and a pH-adjusting ingredient,
wherein the buffer and the pH-adjusting ingredient are selected so
that when the pharmaceutical preparation is added to the infusion
fluid to provide the formulation for administration, the pH
differential is reduced.
2. The pharmaceutical preparation of claim 1 wherein the compound
of formula I is a compound of formula II: 11
3. The pharmaceutical preparation of claim 1 wherein the
pH-adjusting ingredient is a base, the solvent is an alcohol, and
the pharmaceutical preparation consists essentially of the buffer,
the base, the alcohol, and a nonionic surfactant.
4. The pharmaceutical preparation of claim 3 wherein the alcohol is
Dehydrated Alcohol.
5. The pharmaceutical preparation of claim 3 wherein the nonionic
surfactant is a polyethoxylated castor oil.
6. The pharmaceutical preparation of claim 5 wherein the
polyethoxylated castor oil is Cremophor EL.RTM. surfactant.
7. The pharmaceutical preparation of claim 3 wherein the buffer is
sodium lactate.
8. The pharmaceutical preparation of claim 3 wherein the base is
sodium hydroxide.
9. The pharmaceutical preparation of claim 3 wherein the alcohol is
Dehydrated Alcohol, the nonionic surfactant is Cremophor EL.RTM.
surfactant, the buffer is sodium lactate, and the base is sodium
hydroxide.
10. The pharmaceutical preparation of claim 1 wherein the infusion
fluid is selected from saline and dextrose.
11. The pharmaceutical preparation of claim 1 wherein the infusion
fluid is saline, the pharmaceutical preparation has a pH in the
range of about 6 to about 9, and the pH of the formulation for
administration is in the range of about 6 to about 10.
12. The pharmaceutical preparation of claim 1 wherein the infusion
fluid of the formulation for administration is dextrose, the
pharmaceutical preparation has a pH in the range of about 6 to
about 9, and the formulation for administration has a pH in the
range of about 6 to about 10.
13. The pharmaceutical preparation of claim 1 wherein the buffer is
present in the pharmaceutical preparation in a concentration
between about 10 to about 20 mg/mL.
14. The pharmaceutical preparation of claim 1 wherein the compound
of formula I is present in the formulation for administration in a
concentration between about 0.1 mg/mL and about 0.9 mg/mL.
15. The pharmaceutical preparation of claim 1 wherein the
pH-adjusting ingredient is a base selected from one or more of
platinum oxide (PtO.sub.2), potassium hydroxide (KOH), sodium
hydroxide (NaOH), lithium hydroxide (LiOH), potassium carbonate
(K.sub.2CO.sub.3), magnesium hydroxide (Mg(OH).sub.2), calcium
hydroxide (Ca(OH).sub.2), and sodium bicarbonate (NaHCO.sub.3).
16. The pharmaceutical preparation of claim 15 wherein the base is
sodium hydroxide and is present at a concentration of from about
0.01 mg/mL to about 1 mg/mL.
17. The pharmaceutical preparation of claim 1 wherein the buffer is
selected from the group consisting of sodium phosphate, sodium
citrate, sodium lactate, L-lysine, L-histidine, L-alanine, and
tris-hydroxymethyl aminomethane.
18. The pharmaceutical preparation of claim 1 wherein the compound
of formula I is lyophilized, and the pharmaceutical preparation
comprises a reconstitution vehicle.
19. A process for administering to a patient a compound of formula
I, with an infusion fluid having an infusion fluid pH, the compound
of formula I having the formula, 12wherein, Q is selected from the
group consisting of: 13W is selected from --O-- and
--N(R.sup.16)--; M is selected from the group consisting of oxygen,
sulfur, --N(R.sup.8)--, and --C(R.sup.9R.sup.0)--; each R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.7 is, independently,
selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl, substituted aryl, and heterocyclo, and wherein when
R.sup.1 and R.sup.2 are alkyl, they can be joined to form
cycloalkyl; R.sup.6 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, heterocyclo, and substituted heterocyclo; R.sup.8 is
selected from the group consisting of hydrogen, alkyl, substituted
alkyl, --C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12, and
--S(O.sub.2)R.sup.13; R.sup.9 and R.sup.10 are each independently
selected from the group consisting of hydrogen, halogen, alkyl,
substituted alkyl, aryl, heterocyclo, hydroxy, --C(.dbd.O)R.sup.14,
and --C(.dbd.O)OR.sup.15; and each R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, and R.sup.16 is, independently, selected from
the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, and heterocyclo; wherein the compound of formula
I has a pH of maximum stability that is different from the infusion
fluid pH, to define a pH differential; the process comprising
dissolving the compound of formula I in a first, solution vehicle
to provide an epothilone solution, wherein the solution vehicle
includes at least one buffer and at least one pH-adjusting
ingredient, the buffer and pH-adjusting ingredient being selected
so that, when the epothilone solution is mixed with the infusion
fluid to provide the formulation for administration, the difference
between the pH of the formulation for administration and the pH of
maximum stability for the compound is less than the pH
differential.
20. The process of claim 19, wherein the pH-adjusting ingredient is
a base, and the solution vehicle comprises the base, the buffer,
Dehydrated Alcohol, and a nonionic surfactant.
21. The process of claim 19, wherein the pH-adjusting agent is a
base, and the solution vehicle is prepared by mixing the buffer
with an anhydrous alcohol, followed by the addition of the base and
the surfactant.
22. The process of claim 19, wherein the pH-adjusting agent is a
base, and the solution vehicle is prepared by mixing the base with
an anhydrous alcohol, followed by the addition of at least one
surfactant and then the buffer.
23. The process of claim 19, wherein the compound of formula I is a
compound of formula II: 14
24. The process of claim 19, wherein the solution vehicle is
prepared to achieve a pH in the range of about 6 to about 9 and the
pH of the formulation for administration is in the range of about 6
to about 10.
25. The process of claim 19, wherein the pH-adjusting ingredient is
selected from one or more of platinum oxide (PtO.sub.2), potassium
hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH),
potassium carbonate (K.sub.2CO.sub.3), magnesium hydroxide
(Mg(OH).sub.2), calcium hydroxide (Ca(OH).sub.2), and sodium
bicarbonate (NaHCO.sub.3).
26. The process of claim 19, wherein the pH-adjusting ingredient is
sodium hydroxide.
27. The process of claim 26, wherein the sodium hydroxide is
present in the solution vehicle at a concentration of from about
0.01 mg/mL to about 1 mg/mL.
28. The process of claim 19, wherein the buffer is selected from
the group comprising sodium phosphate, sodium citrate, sodium
lactate, L-lysine, L-histidine, L-alanine, and tris-hydroxymethyl
aminomethane.
29. The process of claim 19, wherein the buffer is sodium lactate
or sodium lactate solution.
30. The process of claim 29, wherein the sodium lactate is added to
the solution vehicle at a concentration of from about 10 mg/mL to
about 20 mg/mL.
31. The process of claim 29, wherein the sodium lactate solution,
about 60% is added to the solution vehicle at a concentration of
about 25 mg/mL.
32. The process of claim 19, wherein the infusion fluid is 0.9%
Sodium Chloride Injection or 5% Dextrose Injection.
33. The process of claim 19, further comprising lyophilizing the
compound before dissolving the compound in the first solution
vehicle.
34. The process of claim 33, wherein the lyophilization process is
carried out in a chamber having a chamber pressure and a shelf
fluid temperature, wherein the chamber pressure is maintained in
the range of about 225 to about 275 microns, and the shelf fluid
temperature is maintained in the range of about -32.degree. C. to
about -28.degree. C.
35. The process of claim 34, wherein the lyophilization process is
carried out in a chamber having a chamber pressure and a shelf
fluid temperature, wherein the chamber pressure is maintained at
about 250 microns, and the shelf fluid temperature is maintained at
about -30.degree. C.
36. A kit for preparing a formulation for administration, the
formulation for administration comprising: i) an infusion fluid
having an infusion fluid pH; and ii) a compound of formula I:
15wherein, Q is selected from the group consisting of: 16W is
selected from --O-- and --N(R.sup.16)--; M is selected from the
group consisting of oxygen, sulfur, --N(R.sup.8)--, and
--C(R.sup.9R.sup.10)--; each R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, and R.sup.7 is, independently, selected from the group
consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted
aryl, and heterocyclo, and wherein when R.sup.1 and R.sup.2 are
alkyl, they can be joined to form cycloalkyl; R.sup.6 is selected
from the group consisting of hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, heterocyclo, and substituted
heterocyclo; R.sup.8 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, and --S(O.sub.2)R.sup.13; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo,
hydroxy, --C(.dbd.O)R.sup.14, and --C(.dbd.O)OR.sup.15; and each
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, and R.sup.16 is,
independently, selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo;
or a pharmaceutically-acceptable salt or solvate thereof, wherein,
the compound of formula I has a pH of maximum stability different
from the infusion fluid pH to define a pH differential; the kit
comprising: in a first vial, the compound of formula I; and in a
second vial, a pharmaceutical preparation comprising a surfactant,
a solvent, a buffer, and a pH-adjusting ingredient, wherein the
buffer and pH-adjusting ingredient are selected so that when the
buffer and pH-adjusting ingredient are added to the infusion fluid
to provide the formulation for administration, the pH differential
is reduced.
37. The kit of claim 36, wherein the compound of formula I in the
first vial is lyophilized, and the pharmaceutical preparation in
the second vial is a reconstitution vehicle.
38. The kit of claim 36, wherein the compound of formula I is a
compound of formula II: 17
39. The kit of claim 36 further comprising: a third vial comprising
the infusion fluid.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the priority benefit of U.S.
Provisional Application No. 60/517,020, filed Nov. 4, 2003,
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a process and formulation
for preparing certain epothilones and analogs thereof for
administration to patients, in which there is achieved enhanced
control of infusion pH, leading to increased infusion
stability.
BACKGROUND OF THE INVENTION
[0003] Epothilones are macrolide compounds having utility in the
pharmaceutical field. For example, Epothilones A and B are
naturally-occurring compounds that can be isolated from certain
microorganisms, having the structures: 1
[0004] Known epothilones exert microtubule-stabilizing effects
similar to TAXOL.RTM. and therefore exhibit cytotoxic activity
against rapidly proliferating cells, such as occur in cancer and
other hyperproliferative cellular diseases (See Angew. Chem. Int.
Ed. Engl., Vol. 35, No. 13/14, 1996 and D. M. Bollag, Exp. Opin.
Invest. Drugs, 6(7): 867-873, 1997).
[0005] Since the introduction of epothilones into the art, many
groups have been designing, synthesizing and testing analogs of the
naturally occurring epothilones in an attempt to develop useful
pharmaceuticals. (See, e.g., D. Schinzer et al., Angew. Chem. Int.
Ed. Engl., 1997, 36, No. 3, 523-524; K. C. Nicolaou, et al., J.
Amer. Chem. Soc., 1997, 119, 7974-7991; K. C. Nicaloau et al.,
Angew. Chem. Int. Ed. Engl., 1996, 35, No. 20, 2399-2401; A. Balog
et al., Angew. Chem. Int. Ed. Engl., 1996, 35, No. 23/24,
2801-2803).
[0006] Before epothilones can be used to treat diseases in
patients, however, they must be formulated into a pharmaceutical
composition that can be administered to the patient; for example,
into a dosage form suitable for oral, mucosal (e.g., nasal,
sublingual, vaginal, buccal, or rectal), parenteral (e.g.,
subcutaneous, intravenous, bolus injection, intramuscular, or
intraarterial), or transdermal administration.
[0007] Certain epothilones and analogs thereof having advantageous
activity are represented by formula I: 2
[0008] wherein the various symbols are as defined below. These and
other epothilone analogs are further described, for example, in
U.S. Pat. Nos. 6,605,599, 6,262,094, 6,288,237 B1, 6,613,912, and
U.S. patent application Ser. Nos. 09/836,134 and 10/602,770, each
of which is assigned to the present assignee and incorporated
herein by reference in its entirety.
[0009] While these and other epothilone analogs possess significant
therapeutic properties, they also present challenges to those
skilled in the art of pharmaceutical compounding as a result of
certain chemical properties. For example, certain epothilones
and/or analogs thereof are susceptible to acid-catalyzed hydrolysis
and thus, can rapidly degrade at low pH. In accordance with the
present invention, a process and formulation have been found
whereby epothilones and analogs thereof can be administered to a
patient while achieving enhanced pH control of the formulation and
thus, enhanced stability of the epothilones and analogs thereof. In
one embodiment, the invention comprises a formulation for
intravenous injection using cost-effective and readily-available
infusion fluids such as saline and/or dextrose. Other formulations
for administration of epothilones and epothilone analogs are
described in U.S. patent application Ser. Nos. 10/051,727 filed
Jan. 17, 2002, Ser. No. 10/055,653, filed Jan. 23, 2002, and Ser.
No. 10/404,324, filed Apr. 1, 2003, each of which is assigned to
the present assignee, and each of which is incorporated herein by
reference in its entirety.
SUMMARY OF THE INVENTION
[0010] The present invention describes a pharmaceutical preparation
comprising epothilones and analogs thereof, of formula I: 3
[0011] wherein the various symbols are as defined below. According
to one aspect of the invention, there is provided a process of
formulating at least one epothilone or analog thereof for
administration to a patient, said process comprising dissolving the
epothilone, or analog thereof, with a solution vehicle which
includes at least one buffer and a pH-adjusting ingredient, to
define an epothilone solution. The epothilone solution is then
further diluted in an infusion fluid to provide a formulation for
administration, wherein the pH of the formulation for
administration is controlled by the buffer and pH-adjusting
ingredient in the first solution vehicle. According to one aspect
of the invention, an epothilone analog is lyophilized, and then the
lyophilized epothilone analog is dissolved in solution vehicle (in
this embodiment, the solution vehicle defines a vehicle for
reconstitution of the lyophilized epothilone analog) to provide an
epothilone solution, wherein the solution vehicle includes a
surfactant, dehydrated alcohol, a buffer, and a base, and then the
epothilone solution is diluted with an infusion fluid to a
concentration appropriate for a formulation for administration,
thereby achieving a formulation that can be administered without
appreciable loss of potency.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0012] 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.
[0013] When reference herein is made to epothilones and analogs
thereof represented by formula I: 4
[0014] it is meant that the groups designated as W, Q, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, and R.sup.5, shall unless otherwise
designated have the following meanings:
[0015] Q is selected from the group consisting of: 5
[0016] W is selected from --O-- and --N(R.sup.16)--;
[0017] M is selected from the group consisting of oxygen, sulfur,
--N(R.sup.8)--, and --C(R.sup.9R.sup.10)--;
[0018] each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and
R.sup.7 is, independently, selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and
heterocyclo, and wherein when R.sup.1 and R.sup.2 are alkyl, they
can be joined to form cycloalkyl;
[0019] R.sup.6 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,
heterocyclo, and substituted heterocyclo;
[0020] R.sup.8 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, and --S(O.sub.2)R.sup.13;
[0021] R.sup.9 and R.sup.10 are each independently selected from
the group consisting of hydrogen, halogen, alkyl, substituted
alkyl, aryl, heterocyclo, hydroxy, --C(.dbd.O)R.sup.14, and
--C(.dbd.O)OR.sup.15; and
[0022] each R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, and
R.sup.16 is, independently, selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and
heterocyclo.
[0023] 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 alkyl groups having from 1
to 4 carbon atoms. A "substituted lower alkyl" refers to an alkyl
group having from 1 to 4 carbon atoms and one, two, or three
(preferably one or two) substituents selected from those recited
for "substituted alkyl" groups.
[0024] The term "substituted alkyl" refers to an alkyl group
substituted by, for example, one to four substituents (preferably
one to two substituents), such as, halo, trifluoromethyl,
trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocyclooxy,
oxo (.dbd.O), 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,
and/or aralkyl), alkanoylamino, aroylamino, aralkanoylamino,
substituted alkanoylamino, substituted arylamino, substituted
aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio,
cycloalkylthio, heterocyclothio, alkylthiono, arylthiono,
aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,
sulfonamido (e.g., SO.sub.2NH.sub.2), substituted sulfonamido,
nitro, cyano, carboxy, carbamyl (e.g., CONH.sub.2), substituted
carbamyl (e.g., CONRR', wherein R and R' are selected from
hydrogen, alkyl, and/or aryl, provided at least one of R and R' is
other than hydrogen), alkoxycarbonyl, aryl, substituted aryl,
guanidino and heterocyclo, such as indolyl, imidazolyl, furyl,
thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like.
Wherein, as noted above, the substituents themselves are further
substituted, such further substituents are selected from the group
consisting of halogen, alkyl, alkoxy, aryl and aralkyl. The
definitions given herein for alkyl and substituted alkyl apply as
well to the alkyl portion of alkoxy groups.
[0025] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine, and iodine.
[0026] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having from about 6 to about 12 carbon atoms in
the ring portion, for example, phenyl, and naphthyl.
[0027] The term "aralkyl" refers to an aryl group bonded to a
larger entity through an alkyl group, for example, a benzyl
group.
[0028] The term "substituted aryl" refers to an aryl group
substituted by, for example, one to four substituents (preferably
one to two substituents) such as alkyl, substituted alkyl, halo,
trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy,
heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino,
dialkylamino, aralkylamino, cycloalkylamino, heterocycloamino,
alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio,
ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl,
alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido,
aryloxy, and the like. The substituent may be further substituted
by one or more members selected from the group consisting of halo,
hydroxy, alkyl, alkoxy, aryl, substituted alkyl, substituted aryl,
and aralkyl.
[0029] The term "cycloalkyl" refers to optionally substituted
saturated cyclic hydrocarbon ring systems, preferably containing 1
to 3 rings and 3 to 7 carbons per ring, which may be further fused
with an unsaturated C.sub.3-C.sub.7 carbocyclic ring. Exemplary
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl.
Exemplary substituents include one or more alkyl or substituted
alkyl groups as described above, or one or more of the groups
described above as substituents for alkyl groups. Additionally, a
cycloalkyl may contain a carbon-carbon bridge of one to two
bridgehead carbon atoms, and/or one or two (preferably one) of the
ring carbon atoms optionally may be replaced with a carbonyl group
(substituted with keto).
[0030] The terms "heterocycle", "heterocyclic" and "heterocyclo"
refer to an optionally substituted, unsaturated, partially
saturated, or fully saturated, aromatic or nonaromatic cyclic
group, for example, which is a 4 to 7 membered monocyclic, 7 to 11
membered bicyclic, or 10 to 15 membered tricyclic ring system,
which has at least one heteroatom in at least one carbon
atom-containing ring. Each ring of the heterocyclic group
containing a heteroatom may have 1, 2, or 3 heteroatoms selected
from nitrogen atoms, oxygen atoms and sulfur atoms, where the
nitrogen and sulfur heteroatoms may also optionally be oxidized and
the nitrogen heteroatoms may also optionally be quaternized. The
heterocyclic group may be attached at any heteroatom or carbon
atom.
[0031] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,
4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,
thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane,
and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl,
thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
[0032] Exemplary bicyclic heterocyclic groups include
benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl,
quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,
benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl,
indazolyl, pyrrolopyridyl, furopyridinyl (such as
furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isochromanyl, indolyl, isoindolinyl, naphthyridinyl, phthalazinyl,
piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
and the like.
[0033] Smaller heterocyclos, such as, epoxides, aziridines, and the
like, are also included.
[0034] Exemplary substituents for the groups "heterocycle,"
"heterocyclic," and "heterocyclo" include alkyl, substituted alkyl,
or one or more substituent groups as described above for
substituted alkyl or substituted aryl groups.
[0035] The term "alkanoyl" refers to --C(O)-alkyl.
[0036] The term "substituted alkanoyl" refers to --C(O)-substituted
alkyl.
[0037] The term "heteroatoms" shall include oxygen, sulfur, and
nitrogen.
[0038] The term "pH-adjusting ingredient" denotes an acid, base, or
mixtures thereof (preferably a base, such as sodium hydroxide,
potassium hydroxide, lithium hydroxide), which is selected to
adjust the pH of the infusion fluid that is used for delivery of
the epothilones and analogs thereof. According to one aspect of the
invention, the pH-adjusting ingredient is preferably selected in
amount and type sufficient to achieve, for the formulation for
administration, a pH that approximates the epothilone or epothilone
analog's pH of maximum stability.
[0039] The term "low pH" as used herein means a pH below 7, more
preferably a pH below 6.
[0040] The term "pH differential" as used herein refers to the
difference between (a) the pH of maximum stability for the
epothilone or analog thereof to be administered to a patient, and
(b) the pH of the infusion fluid selected to be used to administer
the epothilone, or analog thereof, to a patient.
[0041] The term, "pH of maximum stability," or "maximum stability
pH" means the pH at which a compound (or mixture of compounds) is
least likely to degrade, or at which the compound (or mixtures of
compounds) will degrade most slowly. Each compound or mixture of
compounds will have a pH of maximum stability. However, the pH of
maximum stability also may encompass a range of pH's. For example,
it may be determined that a compound is equally stable at the pH of
7 and 7.2, but less stable at pH 6.9. In this case, the pH of
maximum stability is 7.1.+-.0.1.
[0042] The terms "diluent" and "infusion fluid" are used
interchangeably herein to denote the fluid for administration to a
patient, such as via parenteral (e.g., subcutaneous, intravenous,
bolus injection, intramuscular, or intraarterial)
administration.
[0043] When it is stated herein that a formulation is provided
having enhanced stability, the term "enhanced stability" is
intended to mean that the epothilones, or analogs thereof, included
in the formulation will degrade less rapidly as compared with the
same epothilones, or analogs thereof, included in a formulation
having the same ingredients except without the buffer and
pH-adjusting ingredient included. Preferably, the formulation
according to the invention will have an enhanced stability of about
25% or greater determined over a period of up to 24 hours (in the
range of 0 to 24 hours).
[0044] The compounds represented by formula I form salts with a
variety of organic and inorganic acids. Such salts include those
formed with hydrogen chloride, hydrogen bromide, methanesulfonic
acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid,
trifluoroacetic acid, maleic acid, benzenesulfonic acid,
toluenesulfonic acid and various others as are recognized by those
of ordinary skill in the art of pharmaceutical compounding. Such
salts are formed by reacting a compound represented by formula I in
an equivalent amount of the acid in a medium in which the salt
precipitates or in an aqueous medium followed by evaporation.
[0045] In addition, zwitterions ("inner salts") can be formed and
are included within the term salts as used herein.
[0046] The present invention also provides a process for the
formulation of an epothilone analog of formula I. The present
invention further provides a process for preparing a pharmaceutical
preparation for parenteral administration.
Preferred Epothilone Analogs
[0047] Preferred epothilone analogs of formula I, advantageous for
use in the present invention include compounds of formula (I*),
6
[0048] and pharmaceutically acceptable salts and solvates thereof,
wherein,
[0049] Q is selected from the group consisting of: 7
[0050] W is --O-- or NH;
[0051] R.sup.7 is hydrogen or lower alkyl (more preferably methyl);
and
[0052] R.sup.11 is selected from lower alkyl (more preferably
methyl), optionally substituted with hydroxy, lower alkoxy, amino,
or C.sub.1-4alkylamino (more preferably hydroxy or amino, even more
preferably amino).
[0053] A particularly preferred example of an epothilone analog of
formula I is [I
S-[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-7
oxabicyclo[14.1.0]heptadecane-5,9-dione (represented by formula
II): 8
[0054] The compounds represented by formulae I and II and processes
for their preparation are described in U.S. Pat. No. 6,605,599, and
international patent application WO99/02514 published Jan. 21, 1999
(both assigned to the present assignee), as well as U.S. Pat. No.
6,518,421, U.S. Pat. No. 6,262,094, the disclosures of each of
which are incorporated herein by reference. The compounds
represented by formulae I and II may exist as multiple optical,
geometric, and stereoisomers. While the compounds shown herein are
depicted for one optical orientation, included within the present
invention are all isomers and mixtures thereof.
Utility
[0055] Compounds represented by formulae I and II are
microtubule-stabilizing agents. They are thus useful in the
treatment of a variety of cancers and other proliferative diseases
including, but not limited to, the following:
[0056] carcinoma, including that of the bladder, breast, colon,
kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, and
skin, including squamous cell carcinoma;
[0057] hematopoietic tumors of lymphoid lineage, including
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,
B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma, and Burketts lymphoma;
[0058] hematopoietic tumors of myeloid lineage, including acute and
chronic myelogenous leukemias and promyelocytic leukemia;
[0059] tumors of mesenchymal origin, including fibrosarcoma and
rhabdomyoscarcoma;
[0060] other tumors, including melanoma, seminoma, teratocarcinoma,
neuroblastoma, and glioma;
[0061] tumors of the central and peripheral nervous system,
including astrocytoma, neuroblastoma, glioma, and schwannomas;
[0062] tumors of mesenchymal origin, including fibrosarcoma,
rhabdomyoscaroma, and osteosarcoma; and
[0063] other tumors, including melanoma, xeroderma pigmentosum,
keratoacanthoma, seminoma, thyroid follicular cancer, and
teratocarcinoma.
[0064] Compounds represented by formulae I and II will also inhibit
angiogenesis, thereby affecting the growth of tumors and providing
treatment of tumors and tumor-related disorders. Such
anti-angiogenesis properties will also be useful in the treatment
of other conditions responsive to anti-angiogenic agents including,
but not limited to, certain forms of blindness related to retinal
vascularization, arthritis, especially inflammatory arthritis,
multiple sclerosis, restenosis, and psoriasis.
[0065] Compounds represented by formulae I and II will induce or
inhibit apoptosis, a physiological cell death process critical for
normal development and homeostasis. Alterations of apoptotic
pathways contribute to the pathogenesis of a variety of human
diseases. Compounds represented by formula I and II, as modulators
of apoptosis, will be useful in the treatment of a variety of human
diseases with aberrations in apoptosis including, but not limited
to, cancer and precancerous lesions, immune response related
diseases, viral infections, kidney disease, and degenerative
diseases of the musculoskeletal system.
[0066] Compounds represented by formulae I and II may also be
formulated or co-administered with other therapeutic agents that
are selected for their particular usefulness in administering
therapies associated with the aforementioned conditions. For
example, methods for administering compounds of formula I and II
are described in U.S. patent application Ser. No. 10/091,061, filed
Mar. 5, 2002, incorporated herein by reference in its entirety.
Compounds of formulae I and II may be formulated with agents to
prevent nausea, hypersensitivity, and gastric irritation, such as
anti-emetics, and H.sub.1 and H.sub.2 antihistamines. The above
therapeutic agents, when employed in combination with a compound of
formulae I or II, may be used in those amounts indicated in the
Physicians' Desk Reference (PDR) or as otherwise determined by one
of ordinary skill in the art.
[0067] Furthermore, compounds represented by formulae I and II may
be administered in combination with other anti-cancer and cytotoxic
agents and treatments useful in the treatment of cancer or other
proliferative diseases. Especially useful are anti-cancer and
cytotoxic drug combinations wherein the second drug chosen acts in
a different manner or different phase of the cell cycle, e.g., S
phase, than the present compounds of formulae I and II which exert
their effects at the G.sub.2-M phase. Examples of classes of
anti-cancer and cytotoxic agents include, but are not limited to,
alkylating agents, such as nitrogen mustards, alkyl sulfonates,
nitrosoureas, ethylenimines, and triazenes; antimetabolites, such
as folate antagonists, purine analogues, and pyrimidine analogues;
antibiotics, such as anthracyclines, bleomycins, mitomycin,
dactinomycin, and plicamycin; enzymes, such as L-asparaginase;
farnesyl-protein transferase inhibitors; hormonal agents, such as
glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens,
progestins, and luteinizing hormone-releasing hormone anatagonists,
octreotide acetate; microtubule-disruptor agents, such as
ecteinascidins or their analogs and derivatives;
microtubule-stabilizing agents such as paclitaxel (TAXOL.RTM.),
docetaxel (TAXOTERE.RTM.); plant-derived products, such as vinca
alkaloids, epipodophyllotoxins, and taxanes; topoisomerase
inhibitors; prenyl-protein transferase inhibitors; and
miscellaneous agents such as, hydroxyurea, procarbazine, mitotane,
hexamethylmelamine, platinum coordination complexes such as
cisplatin and carboplatin; and other agents used as anti-cancer and
cytotoxic agents such as biological response modifiers, growth
factors, immune modulators, and monoclonal antibodies. Compounds
represented by formulae I and II may also be used in conjunction
with radiation therapy.
[0068] Representative examples of these classes of anti-cancer and
cytotoxic agents include, but are not limited to, mechlorethamine
hydrochlordie, cyclophosphamide, chlorambucil, melphalan,
ifosfamide, busulfan, carmustin, lomustine, semustine,
streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine,
mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine,
fluorouracil, doxorubicin (including salts such as doxorubicin
hydrochloride), daunorubicin, idarubicin, bleomycin sulfate,
mitomycin C, actinomycin D, safracins, saframycins, quinocarcins,
discodermolides, vincristine, vinblastine, vinorelbine tartrate,
etoposide (including salts such as etoposide phosphate),
teniposide, paclitaxel, tamoxifen, estramustine, estramustine
phosphate sodium, flutamide, buserelin, leuprolide, pteridines,
diyneses, levamisole, aflacon, interferon, interleukins,
aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin,
irinotecan hydrochloride, betamethosone, capecitabine, gemcitabine
hydrochloride, altretamine, and topoteca and analogs or derivatives
thereof.
[0069] Other examples of these classes of anticancer and cytotoxic
agents include, but are not limited to, cisplatin, carboplatin,
carminomycin, aminopterin, methotrexate, methopterin, ecteinascidin
743, porfiromycin, 5-fluorouracil (5-FU), 6-mercaptopurine,
gemcitabine, cytosine arabinoside, podophyllotoxin or
podophyllotoxin derivatives, leurosidine, vindesine, and leurosine.
It is to be understood the compounds of formulae I and II may be
administered in combination with particular anticancer and
cytotoxic agents falling within these classes of agents, for
example, the compounds of formulae I and II may be administered in
combination with any 5-FU agents, and/or prodrugs thereof,
including without limitation capecitabine (XELODA.RTM.).
[0070] Further examples of anti-cancer and other cytotoxic agents
include the following: cyclin dependent kinase inhibitors as found
in WO 99/24416; and prenyl-protein transferase inhibitors as found
in WO 97/30992 and WO 98/54966.
[0071] Without being bound by any theory regarding mechanism or
morphology, the compounds represented by formulae I and II may also
be used to treat conditions other than cancer or other
proliferative diseases. Such conditions include, but are not
limited to viral infections such as herpesvirus, poxvirus,
Epstein-Barr virus, Sindbis virus and adenovirus; autoimmune
diseases such as systemic lupus erythematosus, immune mediated
glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory
bowel diseases, and autoimmune diabetes mellitus; neurodegenerative
disorders such as Alzheimer's disease, AIDS-related dementia,
Parkinson's disease, amyotrophic lateral sclerosis, retinitis
pigmentosa, spinal muscular atrophy, and cerebellar degeneration;
AIDS; myelodysplastic syndromes; aplastic anemia; ischemic injury
associated myocardial infarctions; stroke and reperfusion injury;
restenosis; arrhythmia; atherosclerosis; toxin-induced or alcohol
induced liver diseases; hematological diseases such as chronic
anemia and aplastic anemia; degenerative diseases of the
musculoskeletal system such as osteoporosis and arthritis;
aspirin-sensitive rhinosinusitis; cystic fibrosis; multiple
sclerosis; kidney diseases; and pain, particularly cancer pain.
[0072] The effective amount of a compound represented by formulae I
and II may be determined by one of ordinary skill in the art.
Exemplary dosage amounts may be found in U.S. patent application
Ser. No. 10/055,653, filed Jan. 23, 2002, incorporated herein by
reference. Alternatively, for a human of from about 0.05 mg/kg/day
to about 200 mg/kg/day, compounds of formula I and II may be
administered in a single dose or in the form of individual divided
doses, such as from 1 to about 4 times per day. For example, the
compounds used in the present invention may be administered in a
dosage of less than about 100 mg/kg/day, in a single dose or in
about 2 to about 4 divided doses. It will be understood that the
specific dose level and frequency of dosage for any particular
subject may be varied and will depend upon a variety of factors
including the activity of the specific compound employed, the
metabolic stability and length of action of that compound, the
species, age, body weight, general health, sex, and diet of the
subject, the mode and time of administration, rate of excretion,
drug combination, and severity of the particular condition.
Subjects for treatment include animals, including species such as
humans, and domestic animals such as dogs, cats and the like,
subject to the aforementioned disorders.
Description of Process and Formulation
[0073] The compounds represented by formulae I and II present
challenges from the viewpoint of pharmaceutical compounding for
administration to patients for a number of reasons. For example,
compounds of formula I and II present a number of solubility and
stability issues, e.g., they possess low solubility and can degrade
when in contact with aqueous media and/or when exposed to light. Of
particular concern with the present invention, compounds of
formulae I and II can degrade when exposed to low pH, e.g., certain
compounds of formula I presumably are susceptible to acid-catalyzed
hydrolysis. For example, the time for 5% drug loss (t.sub.95) at
25.degree. C. for an aqueous solution of compound II is
approximately 2 h at pH 7, but less than 0.2 h at pH 2.5.
[0074] This pH sensitivity presents drawbacks in that a number of
readily-available, commonly-used, and cost-effective infusion
fluids (such as saline and dextrose) exhibit low pH. In particular,
the infusion fluids (or diluents) comprising 0.9% Sodium Chloride
Injection (USP) have a relatively low pH ranging from a pH of 4.5
to 7.0, and diluents comprising 5% Dextrose Injection (USP) have a
pH of 3.5 to 6.5, and therefore, may lead to instability of the
epothilone formulations.
[0075] One alternative to address these drawbacks relating to the
pH sensitivity of the epothilones and analogs thereof, is to use an
alternative diluent, having a higher pH. For example, U.S. patent
application Ser. No. 10/055,653, filed Jan. 23, 2002, states that
because of its narrow pH range, Lactated Ringer's Injection (LRI)
is preferred as a diluent in that formulation. Per 100 mL, Lactated
Ringer's Injection contains Sodium Chloride USP 0.6 g, Sodium
Lactate 0.31 g, Potassium chloride USP 0.03 g and Calcium
Chloride.2H.sub.2O USP 0.02 g. The osmolarity is 275 mOsmol/L,
which is very close to isotonicity, and it has a pH of 6.0 to 7.5.
However, LRI may not be as widely-available as saline or dextrose
infusion fluids, and it is more expensive. If the pH drawbacks
associated with saline and dextrose could be overcome, these
infusion fluids would be advantageous, as they are readily
available world-wide, are commonly-used, and are less expensive
than some other infusion fluids, such as LRI.
[0076] Applicants have found a novel process and preparation that
enables use of such infusion fluids having low pH, wherein the
epothilones and analogs thereof have enhanced stability as compared
with previous formulations including the use of such infusion
fluids. According to one aspect of the invention, the epothilone,
or analog thereof, is dissolved in a first, solution vehicle to
provide an epothilone solution, wherein the solution vehicle
includes (in addition to solvent) at least one buffer and at least
one pH-adjusting ingredient, e.g., a base, and then the epothilone
solution is mixed with an infusion fluid to provide a formulation
for administration. The selection and concentration of the buffer
is determined as a function of the dose of epothilone, or analog
thereof. The solution vehicle is advantageously prepared to achieve
a pH for the epothilone solution whereby, when the epothilone
solution is mixed with the infusion fluid, the pH of the
formulation for administration is approximately equal to the pH of
maximum stability of the epothilone, or analog thereof.
[0077] For example, in the embodiment involving use of the
epothilone analog of formula II, the pH of maximum stability is
about 7.0. A preferred dose of this epothilone analog when diluted
in the infusion fluid is approximately in the range of about 0.05
to about 1.0 mg/mL, more preferably in the range of about 0.1 to
about 0.8 mg/mL, and most preferably in the range of about 0.2 to
about 0.6 mg/mL. The inventors herein have determined that for this
epothilone analog and preferred dose, an advantageous buffer is
sodium lactate, and a preferred concentration of this buffer in the
formulation for administration is in the range of about 3 to about
30 mg/mL, more preferably in the range of about 10 to about 20
mg/mL, even more preferably at a concentration of about 15 mg/mL.
To achieve this concentration of buffer in the formulation for
administration, an advantageous concentration of sodium lactate
solution (60% sodium lactate) buffer in the solution is about 20 to
30 mg/mL, more preferably about 25 mg/mL. Using this concentration
of buffer, the solution vehicle is then preferably prepared (e.g.,
using the type and amount of base selected for this objective) to
achieve a pH in the range of about 6 to about 9, more preferably in
the range 8.0 to 8.8, even more preferably in the range 8.2 to 8.6,
and most preferably at 8.4.+-.0.1. To achieve this pH, for example,
using 1N or 2N Sodium Hydroxide Solution, the final concentration
of sodium hydroxide in the solution vehicle advantageously ranges
from about 0.01 mg/mL to about 1 mg/mL. When the solution vehicle
containing dissolved epothilone, having the desired pH for said
solution vehicle, is then mixed with the infusion fluid, e.g.,
wherein the infusion fluid advantageously includes saline or
dextrose, the pH of the formulation for administration is
advantageously in the range of 6.0 to 10.0, more preferably in the
range 7.0 to 9.0.
[0078] According to the invention, the pH of the solution vehicle
can be adjusted (e.g., by choice and concentration of buffer and
base) to control the pH of the formulation for administration,
depending upon the selection and dose of the particular epothilone
or analog thereof, the choice and concentration of buffer, and the
composition or components of the infusion fluid. Applying these
concepts, the invention may be carried out in a number of ways. For
example, the solution vehicle may be prepared by mixing sodium
lactate with an anhydrous alcohol, such as Dehydrated Alcohol
followed by the addition of sodium hydroxide (1N or 2N solution)
and Cremophor EL.RTM. surfactant. Alternatively, the solution
vehicle can be prepared by mixing sodium lactate with an anhydrous
alcohol, such as Dehydrated Alcohol and Cremophor EL surfactant
followed by the addition of sufficient sodium hydroxide solution
(2N).
[0079] As may be appreciated from the foregoing, the inventors
herein have discovered a preparation including use of a buffer and
base, wherein when the preparation is added to the epothilone, or
analog thereof, dissolved in solution, the pH of the subsequent
formulation for administration, i.e., prepared upon addition of the
infusion fluid, can be controlled in the range of 6.0 to 10, for
example, 6.5 to 7.5. In other words, with the inventive
preparation, the pH differential between the infusion fluid pH, and
the pH of maximum stability for the compound being administered,
can be reduced. The ability to control the formulation pH thus
provides for a formulation for administration wherein the
epothilones or analogs thereof have enhanced stability and thus,
increased potency, as compared with the same formulation without
buffer and base included.
[0080] To illustrate the surprising advantages of the invention, a
formulation including the compound of formula II was diluted in a
0.9% Sodium Chloride Injection infusion fluid to a concentration of
0.2 mg/mL, without buffer and base. Over a six hour hold time, this
formulation demonstrated a loss of potency (degradation in active
compound) of about 6%. However, when the present invention was
applied with the same formulation but including the use of buffer
and base, the loss of potency (degradation of active compound) over
the six hour hold time was about 3.6%, representing an
approximately 40% enhancement in stability. As a further
illustration, a formulation including the compound of formula II
was diluted in a 5% dextrose injection fluid to a concentration of
0.2 mg/mL, without buffer and base. Over a six hour hold time, this
formulation demonstrated a loss of potency (degradation in active
compound) of about 13%. However, when the present invention was
applied with the same formulation but including the use of buffer
and base, the loss of potency (degradation of active compound) over
the six hour hold time was about 4%, representing an enhancement of
stability of greater than 65%.
[0081] In preparing the solution vehicle, the preferred buffer is
sodium lactate, more preferably 60% Sodium Lactate, USP, and a
preferred base is sodium hydroxide, more preferably added to the
solution as 1N or 2N sodium hydroxide solutions. However, other
buffers and bases may be used as determined by one skilled in the
field. Exemplary buffers that may be used include, but are not
limited to sodium phosphate, sodium citrate, L-lysine, L-histidine,
L-alanine, and tris-hydroxymethyl aminomethane. Exemplary bases
include, but are not limited to platinum oxide (PtO.sub.2),
potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium
hydroxide (LiOH), potassium carbonate (K.sub.2CO.sub.3), sodium
bicarbonate (NaHCO.sub.3), magnesium hydroxide (Mg(OH).sub.2), and
Calcium Hydroxide (Ca(OH).sub.2).
[0082] Additionally, the solution vehicle used to dissolve the
epothilones, or analogs thereof, in addition to buffer and base,
will naturally include one or more solvents and advantageously one
or more surfactants. One skilled in the field can select
appropriate solvents and surfactants for use with the invention.
For example, various solvents and surfactants are described in U.S.
patent application Ser. Nos. 10/051,727 filed Jan. 17, 2002, Ser.
No. 10/055,653, filed Jan. 23, 2002, and Ser. No. 10/404,324, filed
Apr. 1, 2003, each of which is assigned to the present assignee and
incorporated herein by reference in its entirety. A preferred
solvent for the solution vehicle is a Dehydrated Alcohol USP, and a
preferred surfactant is a nonionic surfactant, such as a
polyethoxylated castor oil surfactant. More preferably the
solvent/surfactant system includes Ethanol and Cremophor EL.RTM.
surfactant (available from GAF Corp., Mount Olive, N.J., under the
tradename Cremophor EL), more preferably in 1:1 amounts
thereof.
[0083] Advantageously, the epothilones or analogs thereof are
lyophilized prior to being dissolved in the solution vehicle. In
this embodiment, the solution vehicle may be considered a
reconstitution vehicle for reconstituting the lyophilized
epothilones into a liquid form. Techniques and processes for
lyophilization are set forth in U.S. patent application Ser. Nos.
10/051,727 and 10/055,653, incorporated herein and further
referenced above. More particularly, in one embodiment, the
epothilones or analogs thereof can be first placed into a solution
involving a mixture of tertiary-butanol and water for injection and
then lyophilized from this solution. This mixture is preferably
about 50% v/v, for example, from about 50% to about 80% v/v
tertiary butanol to reduce degradation of the subject epothilones
and analogs thereof. Due to poor wetting characteristics of the
subject epothilones and analogs thereof, the initial solution may
be prepared using, initially, a greater concentration of alcohol to
water, for example, a mixture of about 60% v/v, or from about 60%
to about 95% v/v, tertiary butanol and water. Once the solution is
made, the requisite amount of water or tertiary-butanol-water
mixture can be added to achieve the desired final concentration for
lyophilization as stated above.
[0084] Advantageously, as previously described in the above-cited
U.S. patent applications, the solution for lyophilization is
prepared at a temperature below ambient temperature, for example,
from about 5.degree. C. to about 15.degree. C., or at 5.degree. C.,
to minimize degradation of the subject epothilone analogs. Both the
process of forming the solution and subsequent lyophilization
advantageously can be carried out in vessels such that the
epothilones or analogs thereof are protected from exposure to
light. It is also beneficial to perform the lyophilization in
comparatively small batches so that the epothilones or analogs
thereof are exposed to an aqueous medium for a minimum amount of
time.
[0085] The lyophilization preferably is performed in two stages,
wherein the primary drying stage of lyophilization of the solution
formed as described above is carried out at temperatures from about
-10.degree. C. to about -40.degree. C., for example, about
-25.degree. C., under high vacuum, i.e., from about 50 millitorr to
about 300 millitorr, for example, about 200 millitorr, for an
extended period, i.e., from about 24 hours to about 100 hours, for
example, about 48 hours. Lyophilization in this temperature range
produces an amorphous product which is desirable for an intravenous
preparation. Those of ordinary skill in the art will appreciate
that conventional procedures, such as powder X-ray diffraction, can
be utilized to confirm the amorphous nature of the lyophilized
product.
[0086] A secondary drying stage preferably is carried out to remove
residual solvents. This secondary drying stage is preferably
carried out at temperatures of from about 10.degree. C. to about
30.degree. C., for example, about 25.degree. C., under high vacuum,
i.e., from about 50 millitorr to about 300 millitorr, for example,
about 150 millitorr for an extended period, i.e., from about 24
hours to about 96 hours, for example, about 48 hours.
[0087] In performing the lyophilization, in a preferred embodiment,
excipients commonly utilized for such purposes, such as lactose,
mannitol, dextran, and the like, are not included. Certain of these
excipients may have a negative effect on the stability of the
lyophilized product (lyophile). Hence, the epothilone analogs
formulated in accordance with the present invention preferably are
lyophilized neat, i.e., without any excipient. However, it is
contemplated that the invention herein may be carried out with use
of such excipients which will be known to one skilled in the
field.
[0088] During the lyophilization process, applicants discovered
that the successful drying of the product can be achieved by
carefully controlling shelf fluid temperature and chamber pressure.
Due to the high vapor pressure of tertiary butyl alcohol, the high
vacuum conditions that exist during lyophilization can cause
portions of the dry cake to break off and be carried out of the
vial. It was found that this loss of product from the vial can be
prevented by controlling the rate of sublimation. By carefully
controlling shelf fluid temperature and chamber pressure, the rate
of sublimation can be reduced so that loss of product is prevented.
During the primary drying phase of the lyophilization cycle,
chamber pressure is advantageously controlled in the range of about
200 to about 300 microns, more preferably in the range of about 225
to about 275 microns, and most preferably at about 250 microns, and
shelf fluid temperature is advantageously controlled in the range
of about -35.degree. C. to about -25.degree. C., more preferably in
the range of about -32.degree. C. to about -28.degree. C., and most
preferably at about -30.degree. C. Under these conditions, the rate
of sublimation is reduced and loss of product is reduced or does
not occur.
[0089] According to one embodiment of the invention, it is
contemplated that the epothilones or analogs thereof and the
solution vehicle (or reconstitution vehicle, in the case of
lyophilized compound) are each contained in separate vials and sold
as a two-vial kit. Advantageously, these vials are light-protected.
The infusion fluids or diluents are generally available in clinical
facilities and may or may not be sold in the kit. It is, however,
within the scope of the present invention to package the subject
epothilones or analogs with a third vial containing sufficient
infusion fluid or diluent to prepare the final concentration for
administration.
[0090] Varying potencies (such as 0.5 to 100 mg/vial) of the
lyophilized epothilones or analogs thereof, maybe packaged in
vials. For example, vials containing 15 mg/vial, 20 mg/vial, or 30
mg/vial of an epothilone analog of formula I or II may be produced.
When the solution or reconstitution vehicle is sold in a kit with
at least one vial of epothilone or analog thereof, sufficient
amount of the reconstitution vehicle may be provided to form a
solution having a concentration of about 1 mg/mL to about 10 mg/mL
of the epothilone or analog thereof, more preferably a
concentration of about 1 mg/mL to 4 mg/mL. For example, vials
containing the reconstitution vehicle may be provided with varying
amounts of reconstitution vehicle, such as 5.5 mL/vial, 8 mL/vial
or 16.5 mL/vial. The lyophilized compound is dissolved in the
reconstitution vehicle, and then the resulting solution is further
diluted in a suitable infusion fluid (or diluent) prior to
injection into a patient. Such infusion fluids or diluents are well
known to those of ordinary skill in the art. Upon addition of the
diluent, the final concentration for administration could, for
example, contain from about 0.1 mg/mL to about 0.9 mg/mL, such as
from about 0.2 mg/mL to about 0.6 mg/mL, of the epothilones or
analogs thereof, of formula I or II. This formulation has a pH of
from about 6 to about 10 and exhibits significantly diminished
acid-induced hydrolysis of the epoxide ring.
EXAMPLES
Example 1
[0091]
[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-oxabi-
cyclo[14.1.0]heptadecane-5,9-dione, 4.04 g, was wetted/partially
dissolved with 500 mL of a 4:1 mixture of tertiary butanol and
Water for Injection USP which had been pre-cooled to 5.degree. C.
Once the drug powder had become completely wetted, dissolution was
completed by the addition of 300 mL Water for Injection, thereby
making the final solution a 1:1 mixture. The dissolution was
carried out under protection from light.
[0092] The solution formed above was promptly lyophilized in a
Virtis GENESIS lyophilizer at -30.degree. C. under light protected
conditions over a period of about 100 hours. The resultant
lyophilized product (lyophile) was then further dried at 25.degree.
C. under high vacuum for about 35 hours. No detectable degradation
of the drug was observed during these procedures. The lyophile was
packaged under sterile conditions into 15 mL vials, each containing
20 mg of drug and standard excess to allow for vial/needle/syringe
loss.
[0093] The epothilone lyophile was reconstituted in reconstitution
vehicle. The reconstitution vehicle was prepared with Dehydrated
Alcohol USP, nonionic surfactant such as a polyethoxylated castor
oil surfactant (available from GAF Corp., Mount Olive, N.J., under
the tradename Cremophor EL), Sodium Lactate Solution, USP and
Sodium Hydroxide Solution (such as a 1N or 2N Sodium Hydroxide
solution). Sufficient amount of the reconstitution vehicle was
provided to form a solution having a concentration of about 1 mg/mL
to about 10 mg/mL of the epothilone analog. The reconstituted
epothilone was further diluted in 0.9% Sodium Chloride Injection or
5% Dextrose Injection to a final concentration of about 0.2 mg/mL
to about 0.6 mg/mL.
Example 2
[0094] The reconstitution vehicle was prepared as follows. The
total amount of Dehydrated Alcohol required for the batch was
calculated, and then 90% of the total required amount of Dehydrated
Alcohol was added to a batch tank. With constant stirring,
sufficient Sodium Lactate Solution (USP) was added so that the
concentration of sodium lactate in the final formulation would be
approximately 15 mg/mL. Next, cleaned Cremophor EL surfactant was
added and the batch was mixed for a minimum of 30 minutes. Sodium
Hydroxide Solution (2N) was then added to adjust batch pH to 8.2 to
8.6. Then the remaining amount of Dehydrated Alcohol was added and
mixed for a minimum of 30 minutes. The solution was then
aseptically filtered through a 0.22 .mu.m membrane filter into a
sterilized container. The solution was next filled into sterilized
vials. Finally, these vials containing the reconstitution vehicle
were fitted aseptically with stoppers and then sealed.
[0095] Example of the quantitative composition of the
reconstitution vehicle are shown in Table 1 below.
1TABLE 1 Quantitative Composition of the Reconstitution Vehicle
Ingredients Amount per 100 mL Cremophor E1 surfactant, Cleaned 49.0
mL Dehydrated Alcohol, USP 49.0 mL Sodium Lactate Solution, USP
1.91 mL 2N Sodium Hydroxide Solution Qs to pH 8.4
* * * * *