U.S. patent application number 12/083771 was filed with the patent office on 2009-08-27 for reduction of side effects from aromatase inhibitors used for treating breast cancer.
This patent application is currently assigned to Chavah Pty Ltd.. Invention is credited to Stephen Nigel Birrell.
Application Number | 20090215731 12/083771 |
Document ID | / |
Family ID | 37962114 |
Filed Date | 2009-08-27 |
United States Patent
Application |
20090215731 |
Kind Code |
A1 |
Birrell; Stephen Nigel |
August 27, 2009 |
Reduction of Side Effects From Aromatase Inhibitors Used for
Treating Breast Cancer
Abstract
The present invention is directed generally to pharmaceutical
compositions, methods, and kits for improving side effects
associated with aromatase inhibitor treatment in a subject
diagnosed with breast cancer. More specifically, the present
invention provides compositions, methods, and kits comprising an
aromatase inhibitor and an androgenic agent.
Inventors: |
Birrell; Stephen Nigel;
(South Australia, AU) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Assignee: |
Chavah Pty Ltd.
Medindie, South Australia
AU
|
Family ID: |
37962114 |
Appl. No.: |
12/083771 |
Filed: |
October 18, 2006 |
PCT Filed: |
October 18, 2006 |
PCT NO: |
PCT/AU2006/001539 |
371 Date: |
May 6, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60732662 |
Nov 3, 2005 |
|
|
|
60798308 |
May 8, 2006 |
|
|
|
Current U.S.
Class: |
514/170 ;
514/171 |
Current CPC
Class: |
A61P 1/08 20180101; A61P
9/00 20180101; A61P 15/00 20180101; A61K 9/0019 20130101; A61P 3/00
20180101; A61P 25/20 20180101; A61K 31/568 20130101; A61P 11/04
20180101; A61P 31/00 20180101; A61P 3/04 20180101; A61P 19/02
20180101; A61P 1/00 20180101; A61P 9/12 20180101; A61P 1/12
20180101; A61P 15/10 20180101; A61P 25/22 20180101; A61P 19/10
20180101; A61K 31/4196 20130101; A61P 25/04 20180101; A61P 35/00
20180101; A61P 43/00 20180101; A61K 9/0053 20130101; A61P 9/08
20180101; A61K 45/06 20130101; A61P 11/14 20180101; A61P 19/08
20180101; A61P 3/06 20180101; A61P 29/00 20180101; A61P 1/14
20180101; A61P 25/24 20180101; A61K 9/20 20130101; A61K 31/4196
20130101; A61K 2300/00 20130101; A61K 31/568 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/170 ;
514/171 |
International
Class: |
A61K 31/56 20060101
A61K031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 19, 2005 |
AU |
2005905768 |
Claims
1. A pharmaceutical composition for improving one or more side
effects associated with aromatase inhibitor treatment in a subject
diagnosed with breast cancer, said pharmaceutical composition
comprising (a) an effective amount of an androgenic agent and (b)
an effective amount of an aromatase inhibitor, and optionally a
pharmaceutically acceptable excipient and/or carrier.
2. A pharmaceutical composition according to claim 1, wherein the
androgenic agent is selected from the group consisting of:
testosterone, methyitestosterone, androstenediol,
androstenediol-3-acetate, androstenediol-17-acetate,
androstenediol-3,17-diacetate, androstenediol-17-benzoate,
androstenediol-3-acetate-17-benzoate, androstenedione,
adrenosterone, androsterone acetate, androsterone propionate,
androsterone benzoate, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, oxymetholone, fluoxymesterone,
methandrostenolone, testolactone, pregnenolone,
17.alpha.-methylnortestosterone, norethandrolone,
dihydrotestosterone, 5.alpha.-dihydrotestosterone, dromostanolone,
dromostanolone propionate, nandrolone, nandrolone phenpropionate,
nandrolone decanoate, nandrolone furylpropionate, nandrolone
cyclohexanepropionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, danazol, oxymetholone, androsterone,
stanozolol, ethylestrenol, oxandrolone, bolasterone, mesterolone,
testosterone propionate, testosterone cypionate, testosterone
phenylacetate, testosterone enanthate, testosterone acetate,
testosterone buciclate, testosterone heptanoate, testosterone
decanoate, testosterone undecanoate, testosterone caprate,
testosterone isocaprate, and isomers, metabolites, derivatives, and
precursors of any of the aforementioned compounds, and combinations
thereof.
3. A pharmaceutical composition according to claim 2, wherein the
androgenic agent is testosterone.
4. A pharmaceutical composition according to claim 2, wherein the
androgenic agent is testosterone undecanoate.
5. A pharmaceutical composition according to claim 4, wherein the
effective amount is about 40 mg per day.
6. A pharmaceutical composition according to claim 2 wherein the
androgenic agent is methyltestosterone.
7. A pharmaceutical composition according to claim 2, wherein the
androgenic agent is DHT.
8. A pharmaceutical composition according to claim 1, wherein the
aromatase inhibitor is a steroidal aromatase inhibitor, or an
isomer thereof.
9. A pharmaceutical composition according to claim 1, wherein the
steroidal aromatase inhibitor is selected from a group consisting
of exemestane or formestane.
10. A pharmaceutical composition according to claim 1, wherein the
aromatase inhibitor is a nonsteroidal aromatase inhibitor, or an
isomer thereof.
11. A pharmaceutical composition according to claim 1, wherein the
nonsteroidal aromatase inhibitor is selected from a group
consisting of anastrozole, letrozole, vorozole or fadrozole.
12. A pharmaceutical composition according to claim 11, wherein the
nonsteroidal aromatase inhibitor is anastrozole.
13. A pharmaceutical composition according to claim 12, wherein the
effective amount is about 1 mg per day.
14. A pharmaceutical composition according to claim 1, comprising
(a) testosterone undecanoate, wherein the effective amount is about
40 mg, and (b) anastrozole, wherein the effective amount is about 1
mg.
15. A pharmaceutical composition according to claim 1, wherein the
side effects. Comprise: vasodilatation, osteoporosis, osteopenia,
loss of libido, weight gain, vaginal dryness, sleeping
difficulties, night sweats, asthenia, painful intercourse, pain,
arthritis, arthralgia, breast pain, pharyngitis, depression,
bloating, nausea, rash, mood swings, headache, hypertension,
insomnia, lymphoedema, back pain, peripheral edema, cold sweats,
abdominal pain, injury, constipation, coughing, diarrhea, fracture,
hypercholesteremia, infection, arthrosis, dizziness, dyspnea,
paresthesia, urinary tract infection, vulvovaginitis, anxiety, bone
pain, chest pain, dyspepsia, flu syndrome, gastrointestinal
disorder, sweating and leukorrhea.
16. A pharmaceutical composition for improving one or more side
effects associated with aromatase inhibitor treatment in a subject
diagnosed with breast cancer, said pharmaceutical composition
comprising an effective amount of an androgenic agent, and
optionally a pharmaceutically acceptable excipient and/or
carrier.
17. A pharmaceutical composition according to claim 16, wherein the
androgenic agent is selected from the group consisting of:
testosterone, methyltestosterone, androstenediol,
androstenediol-3-acetate, androstenediol-17-acetate,
androstenediol-3,17-diacetate, androstenediol-17-benzoate,
androstenediol-3-acetate-17-benzoate, androstenedione,
adrenosterone, androsterone acetate, androsterone propionate,
androsterone benzoate, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, oxymetholone, fluoxymesterone,
methandrostenolone, testolactone, pregnenolone,
17.alpha.-methylnortestosterone, norethandrolone,
dihydrotestosterone, 5.alpha.-dihydrotestosterone, dromostanolone,
dromostanolone propionate, nandrolone, nandrolone phenpropionate,
nandrolone decanoate, nandrolone furylpropionate, nandrolone
cyclohexanepropionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, danazol, oxymetholone, androsterone,
stanozolol, ethylestrenol, oxandrolone, bolasterone, mesterolone,
testosterone propionate, testosterone cypionate, testosterone
phenylacetate, testosterone enanthate, testosterone acetate,
testosterone buciclate, testosterone heptanoate, testosterone
decanoate, testosterone undecanoate, testosterone caprate,
testosterone isocaprate, and isomers, metabolites, derivatives, and
precursors of any of the aforementioned compounds, and combinations
thereof.
18. A pharmaceutical composition according to claim 17, wherein the
androgenic agent is testosterone.
19. A pharmaceutical composition according to claim 18, wherein the
androgenic agent is testosterone undecanoate.
20. A pharmaceutical composition according to claim 19, wherein the
effective amount is about 40 mg per day.
21. A pharmaceutical composition according to claim 17 wherein the
androgenic agent is methyltestosterone.
22. A pharmaceutical composition according to claim 17, wherein the
androgenic agent is DHT.
23. A pharmaceutical composition according to claim 16, wherein the
side effects comprise: vasodilatation, osteoporosis, osteopenia,
loss of libido, weight gain, vaginal dryness, sleeping
difficulties, night sweats, asthenia, painful intercourse, pain,
arthritis, arthralgia, breast pain, pharyngitis, depression,
bloating, nausea, rash, mood swings, headache, hypertension,
insomnia, lymphoedema, back pain, peripheral edema, cold sweats,
abdominal pain, injury, constipation, coughing, diarrhea, fracture,
hypercholesteremia, infection, arthrosis, dizziness, dyspnea,
paraesthesia, urinary tract infection, vulvovaginitis, anxiety,
bone pain, chest pain, dyspepsia, flu syndrome, gastrointestinal
disorder, sweating and leukorrhea.
24. A method for improving one or more side effects associated with
aromatase inhibitor treatment in a subject diagnosed with breast
cancer, said method comprising administering to said subject a
pharmaceutical composition according to claim 1.
25. A method according to claim 24, wherein either or both the
androgenic agent and the aromatase inhibitor are administered
orally, intraperitoneally, intradermally, transdermally,
transmucosally, subcutaneously, sublingually, intravenously,
intraarterially, intracavity, intracranially, intramuscularly,
parenterally, or topically, or a combination thereof.
26. A method according to claim 25, wherein said pharmaceutical
composition is administered orally.
27. A method according to claim 26, wherein said pharmaceutical
composition is administered as a tablet.
28. A method according to claim 27, wherein said tablet is
administered once a day.
29. A method according to claim 24, wherein the side effects
comprise: vasodilatation, osteoporosis, osteopenia, loss of libido,
weight gain, vaginal dryness, sleeping difficulties, night sweats,
asthenia, painful intercourse, pain, arthritis, arthralgia, breast
pain, pharyngitis, depression, bloating, nausea, rash, mood swings,
headache, hypertension, insomnia, lymphoedema, back pain,
peripheral edema, cold sweats, abdominal pain, injury,
constipation, coughing, diarrhea, fracture, hypercholesteremia,
infection, arthrosis, dizziness, dyspnea, paraesthesia, urinary
tract infection, vulvovaginitis, anxiety, bone pain, chest pain,
dyspepsia, flu syndrome, gastrointestinal disorder, sweating and
leukorrhea.
30. A method according to claim 24, wherein said subject is a
postmenopausal woman.
31. A method for improving the health of a subject with breast
cancer wherein said subject has side effects associated with
aromatase inhibitor treatment, comprising administering a
pharmaceutical composition according to claim 1.
32. A method according to claim 31, wherein either or both the
androgenic agent and the aromatase inhibitor are administered
orally, intraperitoneally, intradermally, transdermally,
transmucosally, subcutaneously, sublingually, intravenously,
intraarterially, intracavity, intracranially, intramuscularly,
parenterally, or topically, or a combination thereof.
33. A method according to claim 32, wherein said pharmaceutical
composition is administered orally.
34. A method according to claim 33, wherein said pharmaceutical
composition is administered as a tablet.
35. A method according to claim 34, wherein said tablet is
administered once a day.
36. A method according to claim 31, wherein the side effects
comprise: vasodilatation, osteoporosis, osteopenia, loss of libido,
weight gain, vaginal dryness, sleeping difficulties, night sweats,
asthenia, painful intercourse, pain, arthritis, arthralgia, breast
pain, pharyngitis, depression, bloating, nausea, rash, mood swings,
headache, hypertension, insomnia, lymphoedema, back pain,
peripheral edema, cold sweats, abdominal pain, injury,
constipation, coughing, diarrhea, fracture, hypercholesteremia,
infection, arthrosis, dizziness, dyspnea, paraesthesia, urinary
tract infection, vulvovaginitis, anxiety, bone pain, chest pain,
dyspepsia, flu syndrome, gastrointestinal disorder, sweating and
leukorrhea.
37. A method according to claim 31, wherein said subject is a
postmenopausal woman.
38. A method for manufacturing a pharmaceutical composition
according to claim 1, comprising selecting an androgenic agent.
39. A method according to claim 38, further comprising adding an
aromatase inhibitor.
40. A kit for improving one or more side effects associated with
aromatase inhibitor treatment in a subject diagnosed with breast
cancer, comprising (a) an androgenic agent and (b) an aromatase
inhibitor, and, optionally, instructions for administration of
compounds (a) and (b).
41. A kit according to claim 40, wherein the androgenic agent is
selected from the group consisting of testosterone,
methyltestosterone, androstenediol, androstenediol-3-acetate,
androstenediol-17-acetate, androstenediol-3,17-diacetate,
androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,
androstenedione, adrenosterone, androsterone acetate, androsterone
propionate, androsterone benzoate, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, oxymetholone, fluoxymesterone,
methandrostenolone, testolactone, pregnenolone,
17.alpha.-methylnortestosterone, norethandrolone,
dihydrotestosterone, 5.alpha.-dihydrotestosterone, dromostanolone,
dromostanolone propionate, nandrolone, nandrolone phenpropionate,
nandrolone decanoate, nandrolone furylpropionate, nandrolone
cyclohexanepropionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, danazol, oxymetholone, androsterone,
stanozolol, ethylestrenol, oxandrolone, bolasterone, mesterolone,
testosterone propionate, testosterone cypionate, testosterone
phenylacetate, testosterone enanthate, testosterone acetate,
testosterone buciclate, testosterone heptanoate, testosterone
decanoate, testosterone undecanoate, testosterone caprate,
testosterone isocaprate, and isomers, metabolites, derivatives, and
precursors of any of the aforementioned compounds, and combinations
thereof.
42. A kit according to claim 41, wherein the androgenic agent is
testosterone.
43. A kit according to claim 42, wherein the androgenic agent is
testosterone undecanoate.
44. A kit according to claim 42, wherein the androgenic agent is
methyltestosterone.
45. A kit according to claim 42, wherein the androgenic agent is
DHT.
46. A kit according to claim 40, wherein the aromatase inhibitor is
a steroidal aromatase inhibitor, or an isomer thereof.
47. A kit according to claim 46, wherein the steroidal aromatase
inhibitor is selected from a group consisting of exemestane or
formestane.
48. A kit according to claim 40, wherein the aromatase inhibitor is
a nonsteroidal aromatase inhibitor, or an isomer thereof.
49. A kit according to claim 48, wherein the nonsteroidal aromatase
inhibitor is selected from a group consisting of anastrozole,
letrozole, vorozole or fadrozole.
50. A kit according to claim 49, wherein the nonsteroidal aromatase
inhibitor is anastrozole.
51. A kit according to claim 40, wherein the side effects comprise:
vasodilatation, osteoporosis, osteopenia, loss of libido, weight
gain, vaginal dryness, sleeping difficulties, night sweats,
asthenia, painful intercourse, pain, arthritis, arthralgia, breast
pain, pharyngitis, depression, bloating, nausea, rash, mood swings,
headache, hypertension, insomnia, lymphoedema, back pain,
peripheral edema, cold sweats, abdominal pain, injury,
constipation, coughing, diarrhea, fracture, hypercholesteremia,
infection, arthrosis, dizziness, dyspnea, paraesthesia, urinary
tract infection, vulvovaginitis, anxiety, bone pain, chest pain,
dyspepsia, flu syndrome, gastrointestinal disorder, sweating and/or
leukorrhea.
52. A pharmaceutical composition according to claim 1, wherein said
aromatase inhibitor treatment is an adjuvant therapy treatment to
said subject already having received chemotherapy.
53. A method according to claim 24, wherein said aromatase
inhibitor treatment is an adjuvant therapy treatment to said
subject already having received chemotherapy.
54. A method according to claim 31, wherein said aromatase
inhibitor treatment is an adjuvant therapy treatment to said
subject already having received chemotherapy.
55. A method for enhancing the efficacy of aromatase inhibitors
comprising administering a pharmaceutical composition according to
claim 1.
56. A pharmaceutical composition for improving one or more side
effects associated with aromatase inhibitor treatment in a subject
diagnosed with breast cancer comprising (a) an effective amount of
an androgenic agent, and (b) an effective amount of an agent that
blocks conversion of testosterone to estradiol.
57. A method for improving one or more side effects associated with
aromatase inhibitor treatment in a subject diagnosed with breast
cancer, said method comprising administering a pharmaceutical
composition according to claim 56.
58. A method for increasing the bioavailability of an androgenic
agent comprising administering a pharmaceutical composition
according claim 1.
59. A method according to claim 52, wherein said androgenic agent
is testosterone.
60. A method according to claim 53, wherein said aromatase
inhibitor is anastrozole.
61. A method according to claim 53, wherein said aromatase
inhibitor blocks conversion of said testosterone to estrogen.
62. A method according to claim 55, wherein said conversion is
blocked in small bowel lymphatics and liver.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the priority benefit of the
following applications: 1) Australian Provisional Serial No.
2005905768, filed on Oct. 19, 2005, 2) U.S. Provisional Ser. No.
60/732,662, filed Nov. 3, 2005, and 3) U.S. Provisional Ser. No.
60/798,308, filed May 8, 2006. These applications, in their
entirety, are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to the reduction of side
effects caused by aromatase inhibitors which are used to treat
subjects with breast cancer. In particular, the present invention
provides compositions, methods, and kits for reducing side effects
in post-menopausal women with breast cancer already being treated
with aromatase inhibitor comprising administering an effective
amount of an androgenic agent. Furthermore, the present invention
provides compositions, methods, and kits for reducing side effects
associated with aromatase inhibitor treatment in post-menopausal
women with breast cancer comprising administering a pharmaceutical
composition comprising an aromatase inhibitor and an androgenic
agent.
BACKGROUND OF THE INVENTION
[0003] Breast cancer is the most common non-cutaneous malignancy in
women. It is estimated that there were 212,600 new cases in 2003 in
the USA. It is estimated that at least 13% of women will develop
breast cancer at some time in their life, and this incidence is
increasing. As more than 80% of breast tumors grow in response to
sex hormone stimulation caused by estrogen, part of adjuvant
therapy (i.e. therapy in addition to surgical removal of the tumor)
is to administer an agent to block this growth stimulation,
including by means of blocking estrogen receptor activation or
blocking estrogen production.
[0004] One such agent has been tamoxifen. Notwithstanding its
success in adjuvant breast cancer therapy, tamoxifen has unwanted
side-effects, which can be categorized into estrogen receptor
stimulating (uterine cancer, deep venous thrombosis) and estrogen
receptor antagonizing (vaginal dryness, hot flushes, mood swings)
and has led to the search for a better alternative. A more
selective estrogen receptor regulator has so far not been
successful in taking the place of tamoxifen and the current trend
in hormonal therapy is to reduce the level of bio-available
estrogen.
[0005] Another such agent has been aminoglutethimide (Cash, Brough
et al 1967). This drug was poorly tolerated and resulted in a
marked adrenal suppression that limited the use of the drug.
[0006] Over the past 15 years, however, more specific enzyme
inhibitors have been developed, which specifically inhibit the
aromatase enzyme that converts testosterone to estradiol. These
compounds are known as aromatase inhibitors. They are used to block
the conversion of testosterone to estradiol, resulting in
non-tissue-specific enzymatic inhibition and almost complete
ablation of testosterone conversion to estradiol. The relevant
conversion pathways are shown in FIG. 1.
[0007] The development of these aromatase inhibitors, such as
exemestane (Aromasin.RTM.), anastrozole (Arimidex.RTM.) and
letrozole (Femara.RTM.) has brought about a major change in the
therapeutic approach to patients with hormone-sensitive breast
cancer. In randomized clinical trials, each of these aromatase
inhibitors has demonstrated efficacy in the adjuvant treatment of
post-menopausal women with receptor-positive tumors. Although
long-term follow up for safety and overall survival continues in
each of these trials, currently available data suggest that an
aromatase inhibitor should now be included as part of adjuvant
endocrine therapy for the great majority of receptor-positive
post-menopausal patients. The current strategy comprises at least
five years of global estrogen deprivation with a tissue
non-specific aromatase inhibitor. These aromatase inhibitors
overcome the significant adrenal toxicity of the previous
anti-estrogen medications, and this has allowed them to now become
the most widely prescribed hormonal therapy for breast cancer.
[0008] A significant problem with these aromatase inhibitors,
however, is that they cause unwanted and substantial short and
long-term side effects. Examples of these side effects include, but
are not limited to, vasodilatation, osteoporosis, osteopenia, loss
of libido, weight gain, vaginal dryness, sleeping difficulties,
night sweats, asthenia, painful intercourse, pain, arthritis,
arthralgia, breast pain, pharyngitis, depression, bloating, nausea,
rash, mood swings, headache, diminished cognitive function,
hypertension, insomnia, lymphoedema, back pain, peripheral edema,
cold sweats, abdominal pain, injury, constipation, coughing,
diarrhea, fracture, hypercholesteremia, infection, arthrosis,
dizziness, dyspnea, paraesthesia, urinary tract infection,
vulvovaginitis, anxiety, bone pain, chest pain, dyspepsia, flu
syndrome, gastrointestinal disorder, sweating and/or
leukorrhea.
[0009] The present invention described herein differs from other
hormonal therapy methods for the treatment of breast cancer. It
provides the advantages of androgen replacement therapy in
combination with an aromatase inhibitor.
[0010] Current therapeutic circumstances in which an aromatase
inhibitor (e.g., Arimidex.RTM.) and an androgenic agent (e.g.,
testosterone) have been used in combination previously are to
reduce the estrogenic effect of testosterone abuse in body
building, in particular gynaecomastia (Hoffmann J Raatamess N
Journal of Sports Science and Medicine 5, 182-183 (2006), to reduce
estrogenic side-effects in hypogonadal men on T therapy (Leder et
al. 2004, and Leder et al. 2005), and to explore the safety issues
(risk of cardiovascular disease) of androgen replacement therapy,
specifically in female to male transexuals undergoing testosterone
therapy. (Bunck et al. 2006). None of these circumstances of
androgen replacement therapy, however, were for the treatment of a
woman diagnosed with breast cancer. In fact, there has been a great
reluctance by the medical profession to prescribe hormone
substrates to women who have hormonally active breast cancers. The
use of androgen replacement is controversial in post-menopausal
women generally, and its use in women who have had breast cancer is
almost universally contra-indicated. For example, a Proctor &
Gamble application to the FDA for the Intrinsa product cited breast
cancer as an absolute contra-indication to using the Intrinsa patch
because of the concern about the testosterone being converted to
estradiol and being used as a growth substrate by the malignancy
(Shifren J L et al Testosterone patch for the treatment of
hypoactive sexual desire disorder in naturally menopausal women:
results from the INTIMATE NM1 study Menopause (in press).
[0011] Regardless of such medication, the conventional
understanding remains that androgen (e.g., testosterone)
replacement should be avoided in breast cancer subjects for fear of
spurring tumor regrowth.
[0012] The present invention, however, goes against this
conventional wisdom of not prescribing androgenic agents to women
diagnosed with breast cancer. The present invention provides a
novel therapy to alleviate side-effects of and/or to enhance the
efficacy of aromatase inhibitor therapy in breast cancer treatment
by supplementing and/or combining an aromatase inhibitor with an
androgenic agent.
SUMMARY OF THE INVENTION
[0013] The present invention is directed generally to
pharmaceutical compositions, methods, and kits for improving side
effects associated with aromatase inhibitor treatment in a subject
diagnosed with breast cancer.
[0014] One aspect of the present invention provides a
pharmaceutical composition for improving a side effect associated
with aromatase inhibitor treatment in a subject diagnosed with
breast cancer comprising (a) an effective amount of an androgenic
agent and (b) an effective amount of an aromatase inhibitor.
Optionally, the pharmaceutical composition may comprise a
pharmaceutically acceptable excipient and/or carrier.
[0015] Another aspect of the present invention provides a
pharmaceutical composition for improving one or more side effects
associated with aromatase inhibitor treatment in a subject
diagnosed with breast cancer comprising an effective amount of an
androgenic agent, and optionally a pharmaceutically acceptable
excipient and/or carrier.
[0016] A further aspect of the present invention is a method for
improving one or more side effects associated with aromatase
inhibitor treatment in a subject diagnosed with breast cancer
comprising administering to a subject a pharmaceutical composition
comprising (a) an effective amount of an androgenic agent and (b)
an effective amount of an aromatase inhibitor, and, optionally, a
pharmaceutically acceptable excipient and/or carrier.
[0017] Another aspect of the present invention is a method for
improving one or more side effects associated with aromatase
inhibitor treatment in a subject diagnosed with breast cancer
comprising administering to a subject a pharmaceutical composition
comprising an effective amount of an androgenic agent and,
optionally, a pharmaceutically acceptable excipient and/or
carrier.
[0018] An additional aspect of the present invention is a method
for improving the health of a subject with breast cancer having one
or more side effects associated with aromatase inhibitor therapy
comprising administering a pharmaceutical comprising an effective
amount of an androgenic agent, and, optionally, a pharmaceutically
acceptable excipient and/or carrier; or an effective amount of an
androgenic agent, an effective amount of an aromatase inhibitor,
and, optionally, a pharmaceutically acceptable excipient and/or
carrier.
[0019] Another aspect of the present invention provides methods of
manufacturing pharmaceutical compositions for improving one or more
side effects associated with aromatase inhibitor treatment in a
subject diagnosed with breast cancer comprising selecting an
androgenic agent.
[0020] Furthermore, an aspect of the present invention is a kit for
improving one or more side effects associated with aromatase
inhibitor treatment in a subject diagnosed with breast cancer
comprising an androgenic agent, an aromatase inhibitor, and
instructions.
[0021] Another aspect of the present invention is a method for
enhancing the efficacy of aromatase inhibitors comprising
administering a pharmaceutical composition of the present
invention
[0022] Another aspect of the present invention is a method for
increasing the bioavailability of an androgenic agent comprising
administering a pharmaceutical composition of the present
invention.
[0023] One aspect of the present invention provides a
pharmaceutical composition for improving a side effect associated
with an aromatase inhibitor such as third generation aromatase
inhibitor treatment in a subject diagnosed with breast cancer
comprising (a) an effective amount of an androgenic agent and (b)
an effective amount of a such third generation aromatase inhibitor.
Optionally, the pharmaceutical composition may comprise a
pharmaceutically acceptable excipient and/or carrier.
[0024] A further aspect of the present invention is a method for
improving one or more side effects associated with an aromatase
inhibitor such as third generation aromatase inhibitor treatment in
a subject diagnosed with breast cancer comprising administering to
a subject a pharmaceutical composition comprising (a) an effective
amount of an androgenic agent and (b) an effective amount of a
third generation aromatase inhibitor, and, optionally, a
pharmaceutically acceptable excipient and/or carrier.
[0025] An additional aspect of the present invention is a method
for improving the health of a subject with breast cancer having one
or more side effects associated with an aromatase inhibitor such as
third generation aromatase inhibitor therapy comprising
administering a pharmaceutical comprising an effective amount of an
androgenic agent, and, optionally, a pharmaceutically acceptable
excipient and/or carrier; or an effective amount of an androgenic
agent, an effective amount of a third generation aromatase
inhibitor, and, optionally, a pharmaceutically acceptable excipient
and/or carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The foregoing aspects and advantages of the present
invention will be readily apparent to one skilled in the art upon
reference to the figures and the detailed description which
follows.
[0027] FIG. 1 is a schematic diagram depicting various biological
steroid reaction pathways.
[0028] FIG. 2 is a chart demonstrating the effects of a combination
of an aromatase inhibitor (Arimidex.RTM.) and an androgenic agent
(testosterone undecanoate) upon serum hormone levels in
post-menopausal patients referred to in the example described
herein.
[0029] FIG. 3 is a chart demonstrating the effects of a combination
of an aromatase inhibitor (Arimidex.RTM.) and an androgenic agent
(testosterone undecanoate) upon serum markers for bone resorption
in post-menopausal patients referred to in the example described
herein.
[0030] FIG. 4 is a chart demonstrating the effects of a combination
of an aromatase inhibitor (Arimidex.RTM.) and an androgenic agent
(testosterone undecanoate) as measured by arthralgia evaluations in
post-menopausal patients referred to in the example described
herein.
[0031] FIG. 5 is a chart demonstrating the effects of a combination
of an aromatase inhibitor (Arimidex.RTM.) and an androgenic agent
(testosterone undecanoate) as measured by FACT-ES side-effect
profile evaluations in post-menopausal patients referred to in the
example described herein.
[0032] FIG. 6 is a chart demonstrating the effects of a combination
of an aromatase inhibitor (Arimidex.RTM.) and androgenic agent
(testosterone undecanoate) as measured by cognitive function
evaluations in post-menopausal patients referred to in the example
described herein.
[0033] FIG. 7 is a chart demonstrating the effects of a combination
of an aromatase inhibitor (Arimidex.RTM.) and an androgenic agent
(testosterone undecanoate) upon serum lipid levels in
post-menopausal patients referred to in the example described
herein.
[0034] FIG. 8 is a questionnaire of the endocrine subscale for the
FACT-B.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
[0035] Terms are used herein as generally used in the art, unless
otherwise defined in the following:
[0036] The term "a" or "an" refers to one or more of the described
entity; for example, "an aromatase inhibitor" is understood to
represent one or more aromatase inhibitors. Another example is "an
androgenic agent" is understood to represent one or more androgenic
agents. Another example is "for improving a side effect" is
understood to include improving one or more side effects. As such,
the terms "a" (or "an"), "one or more," and "at least one" can be
used interchangeably herein.
[0037] The term "about" as used herein may be applied to modify any
quantitative representation that could permissively vary without
resulting in a change in the basic function to which it is
related.
[0038] "Adjuvant therapy" may include adjuvant, neo-adjuvant and/or
palliative therapy.
[0039] "Androgenic agent" refers to a chemical that increases
androgenic activity or synthesis. Typically, an androgenic agent is
a steroid hormone that binds with high affinity (in the pM or nM
range) and specificity to its intracellular mediator, the androgen
receptor, to stimulate transactivation activity and thus regulate
the expression of target genes. Examples are provided herein.
[0040] "Aromatase inhibitor" refers to a chemical compound or
polypeptide that blocks or inhibits the activity of aromatase which
is an enzyme that converts androgens to estrogens. Examples are
provided herein.
[0041] "Breast cancer" refers to a malignant proliferation of
epithelial cells lining the ducts or lobules of the breast.
[0042] "Collagen crosslink" refers to a pyridinoline and
deoxy-pyridinoline crosslink.
[0043] "Diagnosed" is meant to include a subject suspected or
predicted to have breast cancer.
[0044] "Effective amount" or "pharmaceutically effective amount" of
an agent or compound as provided herein refers to a nontoxic but
sufficient amount of the agent or compound to provide the desired
therapeutic effect. As will be pointed out below, the exact amount
required will vary from subject to subject, depending on age,
general condition of the subject, the severity of the condition
being treated, and the particular agent or compound administered,
and the like. An appropriate "effective amount" in any individual
case may be determined by one of ordinary skill in the art by
reference to the pertinent texts and literature and/or using
routine experimentation.
[0045] "Improving one or more side effects" includes, but is not
limited to, the prevention, treatment, reversal, part-reversal,
reduction, diminution, or amelioration of a side effect.
[0046] "Improving the health of a subject" includes, but is not
limited to, improving one or more side effects and/or improving the
therapeutic effect of the aromatase inhibitor.
[0047] "Pharmaceutically acceptable" refers to those compounds,
agents, materials, compositions, excipients, and/or dosage forms
that are, within the scope of sound medical judgment, suitable for
contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other
problems or complications commensurate with a reasonable
benefit/risk ratio.
[0048] "Post-menopausal woman" is defined to include not only a
woman of advanced age who has passed through menopause, but also a
woman who has been hysterectomized or for some other reason has
suppressed estrogen production, such as one who has undergone
long-term administration of corticosteroids, suffer from Cushions'
syndrome or have gonadal dysgenesis.
[0049] "Side effect" refers to a consequence other than the one(s)
for which an agent or measure is used, as the adverse effects
produced by a drug, especially on a tissue or organ system other
then the one sought to be benefited by its administration. Examples
are providing herein.
[0050] "Subject" is an animal including the human species that is
treatable with the compositions, methods and kits of the present
invention. The term "subject" or "subjects" is intended to refer to
both the male and female gender unless one gender is specifically
indicated.
[0051] The term "treatment" or "therapy" as used herein includes
preventative (e.g., prophylactic) and palliative treatment and
"treating" as used herein refers to the act of providing
preventative and/or palliative treatment.
[0052] It will be apparent to one skilled in the art, in view of
the following detailed description and the claims appended hereto,
that various substitutions and/or modifications may be made to the
present invention without departing from the scope of the invention
as claimed.
Pharmaceutical Compositions
[0053] A pharmaceutical composition for improving one or more side
effects associated with aromatase inhibitor treatment in a subject
with breast cancer, comprising (a) an effective amount of
androgenic agent, and optionally (b) a pharmaceutically acceptable
excipient and/or carrier is within the scope of the present
invention. Furthermore, a pharmaceutical composition for improving
one or more side effects associated with aromatase inhibitor
treatment in a subject with breast cancer comprising (a) an
effective amount of androgenic agent, (b) an effective amount of an
aromatase inhibitor, and optionally (c) a pharmaceutically
acceptable excipient and/or carrier is within the scope of the
present invention.
[0054] An androgenic agent of the present invention can, for
example, be selected from the group consisting of: testosterone,
methyl testosterone, testosterone undecanoate, testosterone
propionatedihydrotestosterone, 5.alpha.-dihydrotestosterone, or
alternatively androstenediol androstenediol-3-acetate,
androstenediol-17-acetate, androstenediol-3,17-diacetate,
androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,
androstenedione, adrenosterone, androsterone acetate, androsterone
propionate, androsterone benzoate, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, oxymetholone, fluoxymesterone,
methandrostenolone, testolactone, pregnenolone,
17.alpha.-methylnortestosterone, norethandrolone, dromostanolone,
dromostanolone propionate, nandrolone, nandrolone phenpropionate,
nandrolone decanoate, nandrolone furylpropionate, nandrolone
cyclohexanepropionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, danazol, oxymetholone, androsterone,
stanozolol, ethylestrenol, oxandrolone, bolasterone, mesterolone,
testosterone cypionate, testosterone phenylacetate, testosterone
enanthate, testosterone acetate, testosterone buciclate,
testosterone heptanoate, testosterone decanoate, testosterone
caprate, testosterone isocaprate, and isomers, metabolites,
derivatives, and precursors of any of the aforementioned compounds,
and combinations thereof. In addition to the pharmaceutically
acceptable esters of testosterone, esters of dihydrotestosterone,
include, but are not limited to, the enanthate, propionate,
cypionate, phenylacetate, acetate, isobutyrate, buciclate,
heptanoate, decanoate, undecanoate, caprate and isocaprate esters.
The aforementioned esters are commercially available or may be
readily prepared using techniques known to those skilled in the art
or described in the pertinent literature.
[0055] The aforementioned androgenic agents are selected from the
group consisting of naturally occurring androgens, synthetic
androgens, metabolites, precursors, and derivatives thereof. The
agents may be incorporated into the present dosage units and thus
administered in the form of a pharmaceutically acceptable
derivative, metabolite, precursor, analog, ester, salt, or amide,
or the agents may be modified by appending one or more appropriate
functionalities to enhance selected biological properties such as
penetration through mucosal tissue. In general, with regard to
androgenic agents, esters are preferred relative to salts or other
derivatives.
[0056] Preparation of esters, as noted in the preceding section,
involves functionalization of hydroxyl and/or carboxyl groups that
may be present, as will be appreciated by those skilled in the arts
of pharmaceutical chemistry and drug delivery. For example, to
prepare testosterone esters, the 17-hydroxyl group of the
testosterone molecule is generally caused to react with a suitable
organic acid under esterifying conditions, such conditions
typically involving the use of a strong acid such as sulfuric acid,
hydrochloric acid, or the like, and a temperature sufficient to
allow the reaction to proceed at reflux. Esters can be reconverted
to the free acids, if desired, by using conventional hydrogenolysis
or hydrolysis procedures.
[0057] Preferably, the androgenic agent of the present invention is
testosterone, methyltestosterone, testosterone undecanoate,
testosterone propionate, dehydroepiandrosterone, or sodium
dehydroepiandrosterone sulfate, or a metabolic precursor,
metabolite, or derivative thereof. More preferably, the androgenic
agent of the present invention is testosterone, methyltestosterone,
testosterone undecanoate, or testosterone propionate, or a
metabolic precursor, metabolite, or derivative thereof. Most
preferably, the androgenic agent is provided in the form of
testosterone undecanoate, an orally active testosterone preparation
that is a fatty acid ester of the natural androgen testosterone.
Unlike other oral testosterone preparations, testosterone
undecanoate is able to by-pass the liver via the lymphatic system
and is therefore orally bioavailable.
[0058] Additionally, testosterone is difficult to deliver orally,
as 80-90% is broken down in the liver as it is absorbed from the
gut. As such, alternate delivery mechanisms have been explored,
e.g. the aforementioned testosterone patch (Intrinsa.RTM.) by
Proctor & Gamble used to improve sexual libido in
post-menopausal women because of the progressive decline in
testosterone levels with age and in women who have their ovaries
removed.
[0059] An effective amount of an androgenic agent may vary among
each androgenic agent. For example, an effective amount per day of
testosterone may vary. In one embodiment, an effective amount of
testosterone may be between about 2 to about 80 mg, between about 5
to about 75 mg, between about 10 to about 70 mg, between about 20
to about 60 mg, between about 30 to about 50 mg, and between about
35 to about 45 mg. In another embodiment, a preferred amount is
about 20 mg. In one embodiment, a preferred amount is about 40 mg.
In one embodiment, a preferred amount is about 50 mg.
[0060] An effective amount per day of methyltestosterone may vary.
In one embodiment, an effective amount of methyltestosterone may be
between about 0.1 mg to about 10 mg, between about 0.5 mg to about
9 mg, between about 1 mg to about 9 mg, between about 2 mg to about
8 mg, between about 3 mg to about 7 mg, and between about 4 mg to 5
mg. In one embodiment, a preferred. amount is about 0.5 mg. In
another embodiment, a preferred amount is about 1.25 mg. In one
embodiment, a preferred amount is about 2.5 mg.
[0061] An effective amount per day of testosterone undecanoate may
vary. In some embodiments, an effective amount of testosterone
undecanoate may be between about 10 to about 120 mg, between about
20 to about 110 mg, between about 30 to about 100 mg, between about
40 to about 90 mg, between about 50 to about 80 mg, and between
about 60 to about 70 mg. In one embodiment, a preferred amount is
about 20 mg. In another embodiment, a preferred amount is about 40
mg. In one embodiment, a preferred amount is about 80 mg.
[0062] An effective amount per day of testosterone propionate may
vary. In some embodiments, an effective amount of testosterone
propionate may be between about 10 to about 120 mg, between about
20 to about 110 mg, between about 30 to about 100 mg, between about
40 to about 90 mg, between about 50 to about 80 mg, and between
about 60 to about 70 mg. In one embodiment, a preferred amount is
about 20 mg. In another embodiment, a preferred amount is about 40
mg. In one embodiment, a preferred amount is about 80 mg.
[0063] The effective amount of androgenic agent used in conjunction
with an aromatase inhibitor is relatively lower than a standard
dose because of low levels of sex hormone binding globulin which
may be caused by the aromatase inhibitor.
[0064] Sex hormone binding globulin binds an androgenic agent
(e.g., testosterone) and transports it around the body. Its
production is regulated by several mechanisms, but one of the most
profound effectors of its level is the amount of estrogen in the
serum: the higher the estrogen, the higher the sex hormone binding
globulin and the lower the free androgenic agent. Conversely, the
lower the estrogen, the lower the sex hormone binding globulin, and
the higher the free androgenic agent, which means the androgenic
agent is has higher bioavailability. Thus after menopause, as the
estrogen level falls, the sex hormone binding globulin level falls
and the free androgenic agent such as testosterone rises. This free
androgenic agent has multiple functions, as the androgen receptor
is expressed in all cells of the body.
[0065] In some instances, dosage levels below the lower limit of
the aforesaid range may be more than adequate, while in other cases
still larger doses above the upper limit of the aforesaid range may
be employed without causing any harmful side effects.
[0066] An aromatase inhibitor of the present invention, for
example, can be selected from the group consisting of either
steroidal or nonsteroidal aromatase inhibitors, and/or isomers
thereof. Steroidal aromatase inhibitors developed to date build
upon the basic androstenedione nucleus and incorporate chemical
substituents at varying positions on the steroid. Examples of
steroidal aromatase inhibitors include, but are not limited to,
exemestane (Aromasin.RTM.) and formestane. Additional examples
include mechanism-based steroidal aromatase inhibitors that mimic
the substrate, are converted by the enzyme to a reactive
intermediate, and result in the inactivation of aromatase.
Preferably, an aromatase inhibitor of the present invention is
exemestane.
[0067] Nonsteroidal aromatase inhibitors can be divided into three
classes: aminoglutethimide-like molecules, imidazole/triazole
derivatives, and flavonoid analogs. Examples of non-steroidal
aromatase inhibitors include, but are not limited to, anastrozole
(Arimidex.RTM.), letrozole (Femara.RTM.), vorozole and fadrozole.
Preferably, an aromatase inhibitor of the present invention is
either anastrozole or letrozole.
[0068] Aromatase inhibitors often include third-generation
aromatase inhibitors, such as anastrozole (Arimidex.RTM.),
exemestane (Aromasin.RTM.), and letrozole (Femara.RTM.). These
third generation aromatase inhibitors have brought about a major
change in the therapeutic approach to patients with
hormone-sensitive breast cancer. Such aromatase inhibitors are very
specific in their action in that they virtually ablate estrogen in
the serum and thus lower sex hormone binding globulin, which
enables the achievement of a synergistic effect in embodiments of
the invention.
[0069] An effective amount of an aromatase inhibitor may vary among
each aromatase inhibitor. For example, an effective amount per day
for Aromasin.RTM. may vary. In some embodiments, an effective
amount may be between about 5 to about 100 mg, between about 10 to
about 80 mg, between about 20 to about 70 mg, between about 30 to
about 60 mg, and between about 40 to about 50 mg. Also, in some
embodiments, an effective amount may be between about 25 to about
100 mg and between about 35 to about 100 mg. Furthermore, in some
embodiments, an effective amount may be between about 25 to about
150 mg, about 50 to about 150 mg, and about 80 to about 150 mg. In
one embodiment, a preferred amount is about 25 mg.
[0070] An effective amount per day of Arimidex.RTM. may vary. In
some embodiments, an effective amount for Arimidex.RTM. may be
between about 0.1 mg to about 5 mg, between about 0.5 mg to about 4
mg, between about 1 mg to about 3 mg, and between about 1.5 mg to
about 2.5 mg. Also, in some embodiments, an effective amount may be
between about 1 mg to about 5 mg and between about 1.5 mg to about
5 mg. Furthermore, in some embodiments, an effective amount may be
between about 1 mg to about 7.5 mg, between about 1 mg to about 10
mg, and between about 1 mg to about 20 mg. In one embodiment, a
preferred amount is about 1 mg.
[0071] An effective amount per day of Femara.RTM. may vary. In some
embodiments, an effective amount may be between about 1 to about 5
mg, between about 1.5 to 4 mg, between about 2 to about 3.5 mg, and
between about 2.5 to about 3 mg. Also, in some embodiments, an
effective amount may be between about 2.5 mg to about 5 mg and
between about 3.5 mg to about 5 mg. Furthermore, in some
embodiments, an effective amount may be between about 2.5 mg to
about 7.5 mg, between about 2.5 mg to about 10 mg, and between
about 2.5 mg to about 20 mg. In one embodiment, a preferred amount
is about 2.5 mg.
[0072] In some instances, dosage levels below the lower limit of
the aforesaid range may be more than adequate, while in other cases
still larger doses above the upper limit of the aforesaid range may
be employed without causing any harmful side effects. For example,
dosages of an aromatase inhibitor above the upper limit may be used
to improve the bioavailability of an androgenic agent such as
testosterone or dihydrotestosterone, as described below.
[0073] Testosterone naturally is not highly absorbed because it is
broken down approximately 85% in the intestines by aromatase and
other metabolic pathways into by-products such as inactive
testosterone and dihydrotestosterone. The administration of an
aromatase inhibitor in combination with testosterone, however,
results in an increased absorption, and subsequently greater
bioavailability.
[0074] In one embodiment of the invention, the administration of an
aromatase inhibitor in combination with testosterone results in an
improvement in the bioavailability of testosterone between about
10% to about 50%, between about 20% to about 40%, and between about
25% to about 35%. A preferred amount of increase in bioavailability
is greater than about 15%, greater than about 25%, greater than
about 30%, or greater than about 35%.
[0075] In another embodiment of the invention, the administration
of aromatase inhibitor in combination with testosterone results in
an improvement in the bioavailability of dihydrotestosterone
between about 25% to about 75%, between 35% to about 65%, and
between 45% to 55%. A preferred amount of increase in
dihydrotestosterone bioavailability is greater than about 25%,
greater than about 35%, greater than about 45, or greater than
about 55%.
[0076] An embodiment of the invention includes a pharmaceutical
composition comprising an androgenic agent and an aromatase
inhibitor. A preferred embodiment is a pharmaceutical composition
comprising a testosterone. A specific embodiment consists of
testosterone undecanoate. An additional embodiment consists of
about 40 mg of testosterone undecanoate.
[0077] Another embodiment of the invention includes a
pharmaceutical composition comprising an androgenic agent and an
aromatase inhibitor selected from the group consisting of
exemestane, formestane, anastrozole, letrozole, vorozole, or
fadrozole. A preferred embodiment consists of anastrozole. A
specific embodiment consists of about 1 mg of anastrozole.
[0078] A specific embodiment taught by the invention consists of a
pharmaceutical composition comprising testosterone undecanoate and
anastrozole. More specifically, this embodiment comprises about 40
mg of testosterone undecanoate and about 1 mg of anastrozole.
[0079] An alternative embodiment of the invention includes a
pharmaceutical composition comprising an androgenic agent.
[0080] An alternative embodiment of the invention includes a
pharmaceutical composition comprising an androgenic agent linked to
an aromatase inhibitor, e.g., via an ester linkage.
[0081] Another alternative embodiment of the invention includes a
pharmaceutical composition comprising an androgenic agent/aromatase
inhibitor complex, wherein the complex is created by known methods
in the art.
Methods of Administering the Pharmaceutical Compositions of the
Present Invention
[0082] A method of administering a pharmaceutical composition of
the present invention to improve one or more side effects
associated with aromatase inhibitor treatment in a subject with
breast cancer is within the scope of the present invention.
[0083] Pharmaceutical compositions of this invention can be
administered by any route compatible with a desired outcome. Thus,
routes of administration include orally (e.g., ingestion or
inhalation), intraperitoneally, intradermally, transdermally,
transmucosally, subcutaneously, sublingually, intravenously,
intraarterially, intracavity, intracranially, intramuscularly,
parenterally, or topically. Preferably, the aromatase inhibitor and
the androgenic agent are administered orally or transdermally.
[0084] The pharmaceutically acceptable agents are administered
alone or in combination with pharmaceutically acceptable carriers,
excipients, or diluents, and such administration may be carried out
in single or multiple doses. More particularly, the therapeutic
agents of this invention can be administered in a wide variety of
different dosage forms, i.e., they may be combined with various
pharmaceutically acceptable inert carriers or excipients in the
form of tablets, capsules, emulsions, lozenges, troches, hard
candies, lollipops, powders, sprays, creams, salves, suppositories,
jellies, gels, pastes, lotions, ointments, aqueous suspensions,
injectable solutions, elixirs, syrups, injectable depots, implants,
microencapsulated delivery systems, oil-based suspensions, and the
like.
[0085] For example, androgenic agents may be administered by the
aforementioned routes and dosage forms. In one embodiment,
testosterone esters may be injected. These may include testosterone
enanthate (Delatestryl) which is suspended in sesame oil,
testosterone cypionate (Depo-Testosterone) which is suspended in
cottonseed oil, testosterone propionate (Testovis; Virormone),
testosterone phenylpropionate (Testolent), and a blend of four
testosterone esters (Sustanon; Omnadren) which include testosterone
propionate, testosterone phenylpropionate, testosterone
isocaproate, and testosterone decanoate.
[0086] In another embodiment, testosterone may be injected as an
aqueous suspension (Aquaviron).
[0087] In another embodiment, testosterone may be administered via
a transdermal patch (Androderm; Testoderm TTS).
[0088] In another embodiment, testosterone may be administered by a
gel (Androgel; Testim).
[0089] In another embodiment, methyltestosterone may be
administered orally, e.g., tablet. (Metesto, Methitest, Testred,
Oreton Methyl, and Android).
[0090] In another embodiment, testosterone undecanoate may be
administered orally, e.g., tablet (Androxon, Understor, Restandol,
and Restinsol).
[0091] In one embodiment, testosterone may be administered buccally
(Striant).
[0092] In another embodiment, testosterone may be administered
subcutaneously, e.g., pellet (Testopel).
[0093] The instant pharmaceutical combinations comprising an
aromatase inhibitor of the invention in combination with an
androgenic agent include administration of a single pharmaceutical
dosage formulation which contains both substances, as well as
administration of each agent in its own separate pharmaceutical
dosage formulation.
[0094] It is well known that patient compliance is a factor in
receiving a good result in medical treatment. Causes for poor
compliance may include, but are not limited to, complicated
regimen, unattractive and/or painful formulation such as needles,
and physical difficulty in complying. Therefore, administration of
two or even more different dosage forms to the patient may not be
convenient or satisfactory to achieve the most optimal results. A
pharmaceutical composition of the present invention comprising an
androgenic agent and aromatase inhibitor combined into a single
dosage form may provide improved patient compliance.
[0095] Where separate dosage formulations are used, the aromatase
inhibitor and the androgenic agent can be administered at
essentially the same time, i.e., concurrently, or at separately
staggered times, i.e., sequentially. The pharmaceutical
compositions of the present invention is understood to include all
these regimens. Administration of the pharmaceutical composition by
any routes mentioned above using any of these regimens is suitable
for the present invention as long as the beneficial pharmaceutical
effect of the aromatase inhibitor and androgenic agent are realized
by the patient. It is preferred that the aromatase inhibitor and
androgenic agent be administered concurrently on a once-a-day
dosing schedule; however, varying dosing schedules, such as the
aromatase inhibitor once per day and the androgenic agent once,
twice or more times per day, or the androgenic agent once per day
and the aromatase inhibitor once, twice or more times per day, is
also encompassed herein. A single oral daily dosage formulation
comprised of both the aromatase inhibitor and androgenic agent is
preferred. A single dosage formulation will provide convenience for
the subject.
[0096] The appropriate dosing regimen utilizing the pharmaceutical
compositions, the amount of each dose administered, and the
intervals between doses of the compounds according to the present
invention will depend on various factors such as the particular
aromatase inhibitor and androgenic agent being used in combination,
the type of pharmaceutical formulation being used, the type of
physiological condition being treated, the characteristics of the
subject being treated (e.g., species, age, weight, sex, medical
condition, fed/fasted), the route of administration, and the
severity of the disorder being treated. A physician or veterinarian
of ordinary skill can readily determine and prescribed the
effective amount of the pharmaceutical composition to prevent or to
treat the specific physiological condition.
[0097] Such compositions may be administered in a single daily
dose, or the total daily dosage may be administered in divided
doses several times daily. Furthermore, the pharmaceutical
compositions may be administered as a single dose or over a period
of time. Additionally, the pharmaceutical composition can be
administered continuously or intermittently. The daily dosage may
be varied over wide range and can be such that the amount of the
active compound selected from the androgenic agent and/or aromatase
inhibitor is sufficient to cause its desired effects.
[0098] The pharmaceutical compositions of the present invention are
administered to a subject diagnosed with breast cancer, preferably
a perimenopausal or a postmenopausal woman.
[0099] The duration of treatment for administration of the
pharmaceutical compositions of the present invention may vary
between about three months to about ten years, between about four
months to about five years, and between about six months to about
four years. A preferred duration of treatment is about six months.
Another preferred duration of treatment is about five years.
[0100] The composition or formulation to be administered will
contain a quantity of the compounds or pharmaceutically acceptable
salts thereof of the invention in an amount effective to treat the
disease/condition of the subject being treated. Because two
different compounds are being used together in a combination
therapy, the potency of each of the compounds and the interactive
effects achieved by combining them together must also be taken into
account. A consideration of these factors is well within the
purview of the ordinarily skilled clinician for the purpose of
determining the therapeutically effective or prophylactically
effective dosage amounts needed to improve side effects.
[0101] Administration, of the pharmaceutical composition to the
subject includes both self-administration and administration to the
subject by another person (e.g., physician, health care worker,
friend).
[0102] An embodiment of the present invention includes a method for
improving one or more side effects associated with aromatase
inhibitor treatment in a subject diagnosed with breast cancer
comprising administering a pharmaceutical composition, as described
previously, to a subject orally or transdermally. A specific
embodiment includes a method of administering a solid oral dosage
form (e.g., tablet) once a day.
[0103] Another embodiment of the present invention involves a
method of administering pharmaceutical compositions, described
above, as adjuvant, neo-adjuvant or palliative therapy to a subject
with breast cancer who has already received chemotherapy.
[0104] An additional embodiment of the present invention involves a
method of increasing the absorption rate of an androgenic agent in
a subject diagnosed with breast cancer comprising administering
pharmaceutical compositions described within the specification. A
specific embodiment of the present invention includes increasing
the absorption rate of testosterone orally if conversion of
estrogen is blocked in small bowel mucosa, submucosa, microvessels,
lymphatics and liver by an aromatase inhibitor. As aromatase is a
major enzyme in the small bowel and liver, specific high efficiency
aromatase inhibitors will reduce testosterone metabolism on oral
intake.
Measuring Side Effects Associated with Aromatase Inhibitor
Treatment
[0105] A method for measuring side effects associated with
aromatase inhibitor treatment is within the scope of the present
invention.
[0106] Both steroidal and non-steroidal aromatase inhibitors have
shown clinical efficacy in the treatment of breast cancer.
Recently, the American Society of Oncology has recommended that
aromatase inhibitor be used as adjuvant therapy in all
post-menopausal women with hormonally sensitive early breast
cancer. This raises significant problems with the management of
side-effects caused by total estrogen deprivation for periods of
between five and ten years. Currently, the duration of hormonal
adjuvant therapy is five years. However, this concept is being
challenged, which may result in a longer duration of estrogen
deprivation (Baum 2005). Most of the side-effects of aromatase
inhibitors can be attributed to estrogen deprivation in specific
tissues, but some are difficult to categorize. An example is loss
of libido, which may have several synergistic etiologies, but
appears to be significantly higher in Al than in TAM usage
(Fallowfield, Cella et al 2004). However, there is little doubt
that the musculoskeletal side-effects, such as arthralgia and
osteoporosis, are a direct result of estrogen deprivation in these
tissues and are a frequent occurrence in aromatase inhibitor users
(Ingle 2005). Bone fractures during aromatase inhibitor therapy may
be increased by as much as 60%, and this is probably a result of
increased bone turnover (up by 20%), as well as accelerated bone
loss (Eastell and Hannon 2005). The long-term side-effects of
aromatase inhibitors are not known but are of concern, especially
in the area of cognition (Jenkins, Shilling et al 2004), where
estrogen is known to be especially important (reviewed in Sherwin
2003). There appears to be a critical window in the peri-menopausal
period in which hormone levels may be critical to cognitive
function (Sherwin 2003).
[0107] Administration of an androgenic agent simultaneously in
combination with an aromatase inhibitor or following the
administration of an aromatase inhibitor serves to improve one or
more side effects associated with aromatase inhibitor
administration, such as hot flush, hot flash, vasodilatation,
osteoporosis, osteopenia, loss of libido, weight gain, vaginal
dryness, sleeping difficulties, night sweats, asthenia, painful
intercourse, pain, whole body pain, arthritis, arthralgia, breast
pain, pharyngitis, depression, bloating, nausea, rash, mood swings,
headache, diminished cognitive function, hypertension, insomnia,
lymphoedema, back pain, peripheral edema, cold sweats, abdominal
pain, injury, constipation, coughing, diarrhea, fracture,
hypercholesteremia, dyslipidemia, infection, arthrosis, dizziness,
dyspnea, paraesthesia, urinary tract infection, vulvovaginitis,
anxiety, bone pain, chest pain, dyspepsia, flu syndrome,
gastrointestinal disorder, sweating and/or leukorrhea. Preferably,
administration of an androgenic agent simultaneously in combination
with an aromatase inhibitor or following the administration of an
aromatase inhibitor serves to improve one or more side effects
associated with aromatase inhibitor administration, such as hot
flush, hot flash, vasodilatation, osteoporosis, osteopenia, night
sweats, whole body pain, arthritis, arthralgia, pain, diminished
cognitive function, and arthrosis.
[0108] One embodiment of the present invention involves measuring
serum, urine, and/or fecal levels of markers for bone resorption.
Such markers of bone resorption include, but are not limited to,
carboxy-terminal collagen crosslinks (pyridinoline,
deoxypryridinoline) N-telopeptide, hydroxyproline,
tartrate-resistant acid phosphatases, and galactosyl hydroxylysine.
Also, markers for bone formation such as osteocalcin may be
measured. Another measurement of bone resorption/bone formation are
changes in calcium and phosphorus balances (positive or negative)
which are determined by measuring the difference between the total
excretion (feces and urine) and the dietary intake of calcium or
phosphorus ion. (These balances are positive when the total
excretion is less than the dietary intake.) Preferably, serum
levels of-carboxy-terminal crosslinks are measured.
[0109] Another embodiment of the present invention involves
measuring the quality of life caused by estrogen deprivation. There
are endocrine therapies for use with women who have breast cancer.
Several clinical trials of adjuvant therapy comparing different
drugs with the aim of determining efficacy, toxicity and overall
general health and well-being are in progress or have recently
reported. Publications containing the systematic collection of
comprehensive subjective data to date are few thus little is known
about the impact that hormone therapy exert on the quality of
women's lives. The side-effects of some endocrine therapies may be
underestimated by healthcare professionals when their views are
compared with those of patients. However the side-effects of
different treatments and the impact that these may have on quality
of life (QOL) must be determined if informed choices about disease
management are to be made. For example, menopausal symptoms may be
considered too high a price for some women to pay in adjuvant
therapy, especially if such treatment is still of unknown benefit
in terms of preventing recurrence of the disease. Furthermore,
without an assessment of quality of life, it is difficult to know
what supportive and ameliorative interventions may be needed to
accompany the treatment found to be most efficacious in terms of
treating breast cancer and preventing its recurrence. The magnitude
of difference between treatment groups that may be expected in
terms of QOL and the incidence of symptoms is likely to be larger
than the differences in survival.
[0110] There are several quality of life instruments or assessments
that can used to assess the impact that hormone treatment (and the
inventions disclosed herein) have on different aspects of a
person's functioning and well being. Other ways of measuring or
assessing the side effects associated with the inventions disclosed
herein are available and will be known to those of skilled in the
art and, if appropriate, may be used.
[0111] An endocrine subscale (FACT-ES) to accompany a
well-validated QOL measure called the FACT-B (Brady, M J., et al.,
Journal of Clinical. Oncology., Vol. 15, No. 3 (March 1997) pp.
974-986, which is incorporated in its entirety) was developed
specifically for use in trials using drugs likely to cause
endocrine related symptoms. See Fallowfield, L J, et al., Breast
Cancer Research and Treatment, Vol. 55, No. 2, 1999, pp. 189-199,
which is incorporated herein by reference in its entirety. Also,
FACT-ES is a validated questionnaire designed to measure quality of
life of women with breast cancer who are being treated with
endocrine therapies. It consists of the FACT-B questionnaire plus
an additional endocrine subscale. FACT-B (breast) consists of the
FACT-G (general) QOL tool for cancer patients plus the Breast
Cancer subscale. FACT-ES has been developed to measure QOL in
patients receiving endocrine therapy for breast cancer. This
instrument (FACT-ES) should, therefore, be sensitive to QOL changes
in patients in this trial. The FACT-B (version 4)is a
multi-dimensional self-report questionnaire measuring five domains:
physical well-being, social well-being, emotional well-being,
functional well-being, and breast cancer concerns. It has good
psychometric properties, discriminates well between groups and is
responsive to change. It is relatively simple and quick to
complete, has been translated into many different languages and is
being used in a large number of breast trials in the US and Europe.
This sub-protocol will assess the QOL in all consenting patients
over this period and at recurrence, should this occur within the
study period.
[0112] Another preferred embodiment of the present invention
involves measuring joint pain using the visual numeric scoring
(VNS) on the American College of Rheumatology scoring system. The
Western Ontario and McMaster Universities (WOMAC) Osteoarthritis
Index.TM. consists of three VAS, one each pertaining to pain, joint
stiffness and physical function. This then gives the WOMAC.TM.
osteoarthritis index composite score. (See Bellamy N. J Rheum
15:1833-1840, 1988, incorporated herein by reference in its
entirety).
[0113] Another embodiment of this invention involves measuring
cognitive function, including processing speed, working memory,
visual memory, and verbal memory. The improvement of one or more
side effects associated with aromatase inhibitor treatment in a
subject diagnosed with breast cancer may be measured by the
following (Fallowfied Assessment. (See Jenkins V. Psychooncology
13:61-66, 2004, incorporated herein by reference in its
entirety).
[0114] A further embodiment of this invention involves measuring
serum lipids, including, but not limited to, cholesterol, HDL, and
LDL.
Manufacturing the Pharmaceutical Compositions of the Present
Invention
[0115] A method for manufacturing a pharmaceutical composition of
the present invention and any articles of manufacture produced
thereof are within the scope of the present invention.
[0116] Tablets are prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations usually
incorporate diluents, binders, lubricants and disintegrators as
well as the compound. Typical diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium
phosphate or sulfate, inorganic salts such as sodium chloride and
powdered sugar. Powdered cellulose derivatives are also useful.
Typical tablet binders are substances such as starch, gelatin and
sugars such as lactose, fructose, glucose and the like. Natural and
synthetic gums are also convenient, including acacia, alginates,
methylcellulose, polyvinylpyrrolidine and the like. Polyethylene
glycol, ethylcellulose and waxes can also serve as binders. A
lubricant may be necessary in a tablet formulation to prevent the
tablet and punches from sticking in the die. The lubricant is
chosen from such slippery solids as talc, magnesium and calcium
stearate, stearic acid and hydrogenated vegetable oils. Tablet
disintegrators are substances which swell when wetted to break up
the tablet and release the compound. They include starches, clays,
celluloses, algins and gums. More particularly, corn and potato
starches, methylcellulose, agar, bentonite, wood cellulose,
powdered natural sponge, cation-exchange resins, alginic acid, guar
gum, citrus pulp and carboxymethylcellulose, for example, may be
used, as well as sodium lauryl sulfate. Also, super disintegrants
including, but not limited to, Ac-Di-Sol.RTM. (sodium
croscarmellose cellulose), Explotab.RTM. (sodium starch glycolate),
VivaStar.RTM. (sodium starch glycolate), and Polyplasdone
disintegrants may be used.
[0117] Tablets are often coated with sugar as a flavor and sealant.
The compounds may also be formulated as chewable tablets, by using
large amounts of pleasant-tasting substances such as mannitol in
the formulation, as is now well-established practice. Instantly
dissolving tablet-like formulations are also now frequently used to
assure that the patient consumes the dosage form, and to avoid the
difficulty in swallowing solid objects that bothers some patients.
The size and shape of the tablet may vary according to standard
dimensions and shapes known in the art.
[0118] Capsules are prepared by mixing the compound with a suitable
diluent and filling the proper amount of the mixture in capsules.
The usual diluents include inert powdered substances such as starch
of many different kinds, powdered cellulose, especially crystalline
and microcrystalline cellulose, sugars such as fructose, mannitol
and sucrose, grain flours and similar edible powders. The size and
shape of the capsule may vary according to standard dimensions and
shapes known in the art.
[0119] Furthermore, the capsule may be liquid-filled or
non-liquid-filled. The capsule may be a hard or soft capsule.
Furthermore, it may be a gelatin capsule, a starch capsule, a
hydroxypropylmethylcellulose (HPMC) capsule, or a cellulosic
capsule. Although not limited to capsules, such dosage forms can
further be coated with, for example, a seal coating, an enteric
coating, an extended release coating, or a targeted delayed release
coating. Additionally, liquid-filled capsules of the present
invention may be emulsions and/or may contain tocopherol as a
carrier for poorly soluble compounds such as testosterone.
[0120] In one embodiment, the invention is directed to the use of
tocopherol as the hydrophobic dispersed phase of emulsions
containing water insoluble, poorly water soluble therapeutic
agents, water soluble ones which have been modified to be less
water soluble, or mixtures thereof. In a preferred embodiment
alpha-tocopherol is employed. Alpha-tocopherol is secreted by the
enterocytes into the lymphatics and is processed in a similar
manner to other forms of vitamin E. Also called vitamin E,
alpha-tocopherol is not a typical lipid oil. It has a higher
polarity than most lipid oils, particularly triglycerides, and is
not saponifiable. It has practically no solubility in water.
[0121] In an alternative embodiment, the invention is an
alpha-tocopherol emulsion in the form of a self-emulsifying system
where the system is to be used for the oral administration of
water-insoluble (or poorly water-soluble or water-soluble agents
modified to be less water soluble or mixtures thereof) drugs where
that is desired. In this embodiment, an oil phase with surfactant
and drug or drug mixture is encapsulated into a soft or hard
gelatin capsule. Suitable solidification agents with melting points
in the range of 40 to 60.degree. C., such as high molecular weight
polyethylene glycols (MW>1000), and glycerides, such as those
available under the trade name Gelucire (Gattefose Corp., Saint
Priest, France), can be added to allow filling of the formulation
into a hard gelatin capsule at a high temperature. Semi-solid
formulations are formed upon room temperature equilibration. Upon
dissolution of the gelatin in the stomach and duodenum, the oil is
released and forms a fine emulsion with a mean droplet diameter of
between about 1 to about 15 microns, between about 2 to about 10
microns, or between about 2 to about 5 microns spontaneously. The
emulsion is then taken up by the microvilli of the intestine and
released into the bloodstream.
[0122] In an alternative embodiment, the invention comprises
microemulsions containing tocopherol, preferably alpha-tocopherol.
Microemulsions refer to a sub-class of emulsions where the emulsion
suspension is essentially clear and indefinitely stable by virtue
of the extremely small size of the oil/drug microaggregates
dispersed therein.
[0123] In another embodiment of the invention, PEGylated vitamin E
(alpha-tocopheryl polyethylene glycol succinate, abbreviated TPGS)
is used as a primary surfactant in emulsions of vitamin E. TPGS is
utilized as a primary surfactant, a stabilizer and also as a
supplementary solvent in emulsions of vitamin E. TPGS is a
water-soluble derivative of d-alpha-tocopheryl succinate. It is
also used as an absorption and bioavailability enhancer for certain
water-insoluble drugs (e.g. the HIV protease inhibitor amprenavir)
and fat-soluble vitamins such as vitamin D. TPGS, because of its
amphipathic nature (has both hydrophilic and lipophilic ends),
forms its own micelles and thus does not require bile salts to do
so. This makes it an excellent alpha-tocopherol substance for those
who have problems secreting bile salts into the intestine (e.g.,
those with chronic childhood cholestasis).
[0124] TPGS may enhance the absorption of lipophilic drugs if
formulated together with them. For this reason, the HIV protease
inhibitor amprenavir is formulated with TPGS. Further, the
enhancement of the oral bioavailability of some drugs when
co-administered with TPGS may, in part, be due to inhibition of
P-glycoprotein in the intestine. P-glycoprotein is the multidrug
resistance transporter and is involved in the mediation of
multidrug resistance.
[0125] In addition, polyethylene glycol (PEG) is also useful as a
co-solvent in the emulsions of this invention. Of particular use is
polyethylene glycol 200, 300, 400 or mixtures thereof.
[0126] The alpha-tocopherol concentration of the emulsions of this
invention can be between about 1 to about 10% w/v, between about 2
to about 5% w/v, or between about 3 to about 4% w/v. The ratio of
alpha-tocopherol to TPGS is optimally between about 1:1 to about
10:1 (w/w), between about 1:1 to about 5:1 (w/w), or between about
1:1 to about 15:1 (w/w).
[0127] The emulsions of the invention may further include
surfactants such as ascorbyl-6 palmitate, stearylamine, PEGylated
phospholipids, sucrose fatty acid esters and various vitamin E
derivatives comprising Q-tocopherol nicotinate, tocopherol
phosphate, and nonionic, synthetic surfactant mixtures, such as
polyoxypropylene-polyoxyethylene glycol nonionic block
copolymer.
[0128] The emulsions of the invention can comprise an aqueous
medium. The aqueous phase generally has an osmolality of
approximately 300 mOsm and may include sodium chloride, sorbitol,
mannitol, polyethylene glycol, propylene glycol albumin, polypep
and mixtures thereof. Osmolality may also range between about 100
to about 500 mOsm and between about 200 to about 400 mOsm. This
medium can also contain various additives to assist in stabilizing
the emulsion or in rendering the formulation biocompatible.
Acceptable additives include acidifying agents, alkalizing agents,
antimicrobial preservatives, antioxidants, buffering agents,
chelating agents, suspending and/or viscosity-increasing agents,
and tonicity agents. Preferably, agents to control the pH,
tonicity, and increase viscosity are included. Optimally, a
tonicity of at least 250 mOsm is achieved with an agent which also
increases viscosity, such as sorbitol or sucrose. Tonicity may also
be of at least 300 mOsm, at least 400 mOsm, or at least 500
mOsm.
[0129] The emulsions of the invention for intravenous injection
have a particle size (mean droplet diameter) of about 10 to about
500 nm, preferably about 10 to about 200 nm and most preferably
about 10 to about 100 nm. For intravenous emulsions, the spleen and
liver will eliminate particles greater than 500 nm in size through
the RES.
[0130] An embodiment of the invention includes testosterone within
a liquid-capsule emulsion system.
[0131] Aqueous suspensions and/or elixirs are prepared by combining
the active ingredient with various sweetening or flavoring agents,
coloring matter or dyes, and, if so desired, emulsifying and/or
suspending agents as well, together with such diluents as water,
ethanol, propylene glycol, glycerin and various like combinations
thereof. The amount of suspension may vary according to standard
volumes known in the art.
[0132] Enteric formulations are often used to protect an active
ingredient from the strongly acid contents of the stomach. Such
formulations are created by coating a solid dosage form with a film
of a polymer which is insoluble in acid environments, and soluble
in basic environments. Exemplary films are cellulose acetate
phthalate, polyvinyl acetate phthalate, hydroxypropyl
methylcellulose phthalate and hydroxypropyl methylcellulose acetate
succinate. It is preferred to formulate duloxetine and
duloxetine-containing combinations as enteric compositions, and
even more preferred to formulate them as enteric pellets. The size
and shape of such formulations may vary according to standard
dimensions and shapes known in the art.
[0133] Transdermal patches may also be used. Transdermal
administration significantly enhances patient compliance by
alleviating the discomfort of needles and other dosage forms by
providing a convenient dosage form for once or twice weekly
application. Such administration also provides the benefit of
having sustained blood levels of the drug being administered.
Typically patches comprise a resinous composition in which the
drugs will dissolve, or partially dissolve, which is held in
contact with the skin by a film which protects the composition.
Other, more complicated patch compositions are also in use,
particularly those having a membrane pierced with innumerable pores
through which the drugs are pumped by osmotic action. The size of
the patch may vary according to sizes known in the art.
[0134] When it is desired to administer the combination as a
suppository, the usual bases may be used. Cocoa butter is a
traditional suppository base, which may be modified by addition of
waxes to raise its melting point slightly. Water-miscible
suppository bases comprising, particularly, polyethylene glycols of
various molecular weights are also in wide use.
[0135] For parenteral, intradermal, intramuscular, or subcutaneous
administration pharmaceutical compositions may include one of the
following, or any combination thereof: a sterile diluent, such as
water, saline solution, fixed oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
surfactants such as polysorbate 80, sodium lauryl sulfate, sorbitan
monopalmitate; alcohols; suspending agent such as agar, bentonite,
microcrystalline cellulose, sodium carboxymethylcellulose,
hydroxypropyl methylcellulose, tragacanth, veegum; antibacterial
agents such as benzyl alcohol or methyl parabens; antioxidants such
as ascorbic acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; and buffers such as acetates,
citrates or phosphates and agents for the adjustment of tonicity
such as sodium chloride or dextrose.
[0136] Pharmaceutical compositions can also include carriers to
protect the composition against rapid degradation or elimination
from the body, such as a controlled release or sustained release or
extended release formulation, including implants and
microencapsulated delivery systems. For example, a time delay
material such as glyceryl monostearate or glyceryl stearate alone,
or in combination with a wax, may be employed. Also, pharmaceutical
compositions can include excipients that modify gut metabolism.
[0137] Additional methods of preparing various pharmaceutical
compositions with a certain amount of each active ingredient are
known, or will be apparent in light of this disclosure, to those
skilled in this art.
[0138] The present invention is also directed to articles of
manufacture such as kits which include the active ingredients of
the invention in suitable pharmaceutical compositions packaged for
distribution. Kits of the invention can additionally include
instructions for using the kit components in a method of the
invention. Instructions can include instructions for practicing any
of the methods of the invention described herein. Thus, for
example, a kit can include an androgenic agent or an aromatase
inhibitor in a pharmaceutical formulation in a container, pack, or
dispenser together with instructions for administration to a human
subject. Instructions may additionally include indications of a
satisfactory clinical endpoint or any adverse symptoms that may
occur, or any additional information required by the Food and Drug
Administration for use in humans.
[0139] The instructions may be on "printed matter," e.g., on paper
or cardboard within the kit, or on a label affixed to the kit or
packaging material, or attached to a vial or tube containing a
component of the kit. Instructions may additionally be included on
a computer readable medium, such as a disk (floppy diskette or hard
disk), optical CD such as CD- or DVD-ROM/RAM, magnetic tape,
electrical storage media such as RAM and ROM, and hybrids of these
such as magnetic/optical storage media.
[0140] Kits can additionally include a buffering agent, a
preservative, or a stabilizing agent. Each component of the kit can
be enclosed within an individual container and all of the various
containers can be within a single package.
[0141] Since the present invention relates to treatment with a
combination of the two active ingredients which may be administered
separately, the invention also relates to combining separate
pharmaceutical compositions in kit form. The kit includes two
separate pharmaceutical compositions: an androgenic agent and an
aromatase inhibitor. The kit includes a container for containing
the separate compositions such as a divided bottle or a divided
foil packet, however, the separate compositions may also be
contained within a single, undivided container. Typically the kit
includes directions for the administration of the separate
components. The kit form is particularly advantageous when the
separate components are preferably administered in different dosage
forms (e.g., oral and parenteral), are administered at different
dosage intervals, or when titration of the individual components of
the combination is desired by the prescribing physician.
[0142] An example of a kit is a so-called blister pack. Blister
packs are well known in the packaging industry and are being widely
used for the packaging of pharmaceutical unit dosage forms (e.g.,
tablets, capsules, and the like). Blister packs generally consist
of a sheet of relatively stiff material covered with a foil of a
preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0143] It is desirable to provide a memory aid on a card insert,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be administered.
Another example of such a memory aid is a calendar printed on the
card. Other variations of memory aids will be readily apparent.
[0144] Packaging can be accomplished by any of a number of means
utilized in the pharmaceutical industry. Examples of such packaging
are: unit dose containers for dispensing liquid compositions
enclosed in a box or container along with package inserts; plastic
and/or foil wrappers holding solid ocular inserts which contain the
active ingredients of the invention and which are enclosed in a box
or container along with package inserts. Other modes of packaging
would be readily apparent to one skilled in the pharmaceutical
packaging arts.
[0145] The following example is included for purposes of
illustration only and is not intended to limit the scope of the
present invention, which is defined by the appended claims. All
references cited in the Example are incorporated herein by
reference in their entireties.
EXAMPLE 1
Working
[0146] The following example demonstrates the advantages of
administering to a subject diagnosed with breast cancer a
pharmaceutical composition comprising an androgenic agent and an
aromatase inhibitor.
[0147] Five post-menopausal women having similar patient
socio-demographic characteristics and ranging in age from 49 years
to 56 years (median age 54) were selected for study. Each woman had
been diagnosed with node-negative estrogen receptor and PR
(Progesterone Receptor) positive BCa (Breast cancer), with tumor
sizes ranging from 1.9 cm to 2.3 cm (median tumor size of 2.1 cm)
and selected post-surgery (e.g., mastectomy, lumpectomy, or
quadrantectomy for primary breast cancer) and post-chemotherapy.
None had been subjected to previous attempts at hormone replacement
therapy.
[0148] Each woman selected was subjected to four weeks of aromatase
inhibitor therapy (anastrozole 1 mg (ARIMIDEX.RTM.) orally as a
tablet once a day), and thereafter to an additional eight weeks of
the same aromatase inhibitor therapy in combination with the oral
administration of 40 mg of testosterone undecanoate as a tablet
once a day. During this study, side effects associated with
aromatase inhibitor treatment were measured at three separate
times: prior to the first week of aromatase inhibitor therapy,
following the fourth week of aromatase inhibitor therapy but before
administration of testosterone undecanoate was begun, and following
the eighth week of combined aromatase inhibitor and androgen
replacement therapy. Measures of side effects were as follows:
serum hormone levels, serum markers for bone resorption, serum
lipid levels (see Haper-Wynne, et. al., Cancer Epidemiology,
Biomakers & Prevention, Vol. 11, pp 614-621, July 2002, which
is incorporated in its entirety herein), FACT-ES side-effect
profile evaluations, arthralgia (joint pain) evaluations, and
cognitive function evaluations. Charts depicting the results for
these six measures as recorded at each of the three times are
presented as FIG. 2 through FIG. 7. All result are the mean of
individual scores with the bars representing standard error. As
described hereafter, the novel therapies according to the present
invention from this study demonstrate that androgen replacement
therapy alleviates many of the side-effects of and/or enhances the
efficacy of aromatase inhibitor therapy in breast cancer
treatment.
[0149] First, the chart in FIG. 2 demonstrates that testosterone
aromatization to estradiol is almost completely ablated during
aromatase inhibitor therapy, thus validating that the methods
according to the present invention do not elevate levels of
estrogen appreciably in a manner that could result in increased
risk of relapse of breast cancer. The y axis is picomoles/L of
serum. As depicted in FIG. 2, following the fourth week of
aromatase inhibitor therapy (denoted by the "Al only" bars ) the
average estradiol (denoted by "E2" in the figure legend) serum
level drops significantly from the average level prior to the
beginning of aromatase inhibitor therapy (denoted "Pre-therapy"),
while the remainder of the serum hormone levels appear relatively
unchanged. After the subsequent eight weeks of combination
aromatase inhibitor and androgen (testosterone undecanoate)
replacement therapy (denoted "Al+TU"), there was only an
insignificantly small increase in serum hormone levels of estradiol
while levels of testosterone (denoted by "T" in the figure legend),
free-testosterone (denoted by "FreeT" in the figure legend) and, in
particular, dihydrotestosterone (denoted by "DHT" in the figure
legend) have shown notable increases;
[0150] Applicants believe that this increase in DHT is the cause of
improved patient well being and health as described hereafter with
reference to FIG. 3 through FIG. 6, as increases in tissue-specific
DHT levels will result in a reduction in the side-effects
associated with aromatase inhibitors.
[0151] The chart depicted in FIG. 3 depicts the effects of
combination aromatase inhibitor (ARIMIDEX.RTM.) and androgenic
agent (testosterone undecanoate) upon the serum markers for bone
resorption during the course of this study of post-menopausal
patients. The y axis is picomoles/L of serum. In particular, it is
noted that measurements of carboxy-terminal collagen crosslinks
("CTx") in serum in pmol/l for the patients in the study showed
that following eight weeks of combination aromatase inhibitor and
androgen replacement therapy, bone resorption returned to levels
experienced prior to the beginning of aromatase inhibitor therapy.
In fact, while not significantly large, there even appeared to have
been a small decrease in bone resorption relative to the levels
measured for the post-menopausal patients prior to the beginning of
any drug therapy. Measurements of carboxy-terminal collagen
crosslinks were approximately 25% less in the Al+TU therapy than in
the pre-therapy. Thus, the study supports the conclusion that
androgen replacement therapy according to the present invention
could counterbalance the undesirable bone loss side-effects
associated with extended therapy with aromatase inhibitors.
[0152] FIG. 4 is a chart demonstrating the effects of combination
aromatase inhibitor (ARIMIDEX.RTM.) and androgenic agent
(testosterone undecanoate) as measured by arthralgia evaluations in
the post-menopausal patients in this study. The y axis is a visual
analogue pain scale. Specifically, the y axis indicates a
percentage score of a subjective quantification of pain measured
out of 100.Again, the data regarding reported arthralgia symptoms
by the patients in the study showed that arthralgia returned to
pre-therapy levels after administration of testosterone undecanoate
was added to aromatase inhibitor therapy, as opposed to elevated
levels of arthralgia that were reported during administration of
anastrozole only. Measurements of arthralgia were approximately 45%
less in Al+TU therapy than in the pre-therapy.
[0153] At the three assessment times during the study, the quality
of life for each patient was assessed using standard Functional
Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES)
questionnaire (See FIG. 8), which questionnaire is a standard
method for determining the occurrence and prominence of
treatment-related symptoms and side-effects in breast cancer
patients. The y axis is a FACT-ES score. The total points from the
FACT-ES questionnaire for each subject was subtracted from 200 to
yield a FACT-ES score. A lower FACT-ES score, therefore, means the
worse the symptoms. Thus, a chart provided in FIG. 5 depicts the
effect of combination aromatase inhibitor (ARIMIDEX.RTM.) and
androgenic agent (testosterone undecanoate) as measured by FACT-ES
side-effect profile evaluations at the three assessment times in
this study, with a higher FACT-ES score being associated with an
overall better quality of life. The data reported in FIG. 5 shows
that quality of life as measured by FACT-ES questionnaires
decreased upon the patients undergoing aromatase inhibitor-only
therapy, but later improved to approximate pre-therapy levels upon
the introduction of testosterone undecanoate administration.
[0154] With regard to the effect upon the cognitive function of the
study patients, the chart in FIG. 6 depicts the results measured by
cognitive function evaluations in the patients at each of the three
different assessment times. The y axis is a mean Z score. The
cognitive function scores for the study patients in the pre-therapy
evaluations, as expected, varied slightly around scores for control
populations in the four different types of cognitive abilities that
were tested, namely processing speed, working memory, visual
memory, and verbal memory. As shown in FIG. 6, the cognitive
function scores for the study patients decreased across all four
ability types following the four weeks of anastrozole-only therapy.
Following the eight weeks of combined aromatase inhibitor and
testosterone undecanoate, however, the cognitive function scores
improved across all four ability types enough to restore, or even
possibly slightly improve, cognitive function in the study
patients. Control was five age match healthy subjects.
[0155] Finally, the chart in FIG. 7 reports the data for the study
patients collected to monitor the effects of the combination
aromatase inhibitor and testosterone undecanoate therapy upon serum
lipid levels. The Y axis is mmol/L of serum. The results reported
in the chart demonstrate that the combination therapy according to
the present invention appears to raise no concerns regarding
cholesterol.
EXAMPLES 2-13
Prophetic
[0156] The following examples demonstrate the advantages of
administering to a subject diagnosed with breast cancer a
pharmaceutical composition comprising an androgenic agent and/or an
aromatase inhibitor, in combination or sequentially. It is to be
understood that treatment of the patient with the disclosed
products (both in these examples and in the rest of the
specification) can be start from the first day and continued for
the appropriate time period to effectively treat the patient
without first administering the aromatase inhibitor by itself for a
period of time. It is contemplated that the treatment period would
continued for about 3 months, for about 6 months, for about 1 year,
for about 2 years, for about 4 years or any longer or shorter time
period that is deemed appropriate.
EXAMPLE 2
Prophetic
[0157] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 1 mg anastrozole (ARIMIDEX.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone undecanoate: 20 mg, 40 mg, or
80 mg once a day. The combination of anastrozole and testosterone
undecanoate is administered in a single dose capsule that has
crystallized anastrozole and encapsulated testosterone undecanoate
in an oil suspension. The side effects associated with anastrozole
treatment are measured as described in Example 1. Data are expected
to show improvement of at least one or more side effects. It is to
be understood that the above treatment could also be start with the
combination product from the first day and continued for the
appropriate time period to effectively treat the patient. It is
contemplated that the treatment would be continued for about 6
months to about four years or as long as is deemed appropriate.
EXAMPLE 3
Prophetic
[0158] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 25 mg exemestane (AROMASIN.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone undecanoate: 20 mg, 40 mg, or
80 mg once a day. The combination of exemestane and testosterone
undecanoate is administered in a single dose capsule that has
crystallized exemestane and encapsulated testosterone undecanoate
in an oil suspension. The side effects associated with exemestane
treatment are measured as described in Example 1. Data are expected
to show improvement of at least one or more side effects.
EXAMPLE 4
Prophetic
[0159] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 2.5 mg letrozole (FEMARA.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone undecanoate: 20 mg, 40 mg, or
80 mg once a day. The combination of letrozole and testosterone
undecanoate is administered in a single dose capsule that has
crystallized we need AZ comment here letrozole and encapsulated
testosterone undecanoate in an oil suspension. The side effects
associated with letrozole treatment are measured as described in
Example 1. Data are expected to show improvement of at least one or
more side effects.
EXAMPLE 5
Prophetic
[0160] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 1 mg anastrozole (ARIMIDEX.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone: 20 mg, 40 mg, or 50 mg once
a day. The combination of anastrozole and testosterone is
administered as a tablet and an injection, a tablet and an a
transdermal patch, a tablet and subcutaneously, or a tablet and a
capsule, respectively. The side effects associated with anastrozole
treatment are measured as described in Example 1. Data are expected
to show improvement of at least one or more side effects.
EXAMPLE 6
Prophetic
[0161] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 25 mg exemestane (AROMASIN.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone: 20 mg, 40 mg, or 50 mg once
a day. The combination of exemestane and testosterone is
administered as a tablet and an injection, a tablet and an a
transdermal patch, a tablet and subcutaneously, or a tablet and a
capsule, respectively. The side effects associated with exemestane
treatment are measured as described in Example 1. Data are expected
to show improvement of at least one or more side effects.
EXAMPLE 7
Prophetic
[0162] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 2.5 mg letrozole (FEMARA.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone: 20 mg, 40 mg, or 50 mg once
a day. The combination of letrozole and testosterone is
administered as a tablet and an injection, a tablet and an a
transdermal patch, a tablet and subcutaneously, or a tablet and a
capsule, respectively. The side effects associated with letrozole
treatment are measured as described in Example 1. Data are expected
to show improvement of at least one or more side effects.
EXAMPLE 8
Prophetic
[0163] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 1 mg anastrozole (ARIMIDEX.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of methyltestosterone: 0.5 mg, 1.25 mg, or
2.5 mg once a day. The combination of anastrozole and
methyltestosterone is administered in a single dose tablet. The
side effects associated with anastrozole treatment are measured as
described in Example 1. Data are expected to show improvement of at
least one or more side effects.
EXAMPLE 9
Prophetic
[0164] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 25 mg exemestane (AROMASIN.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of methlytestosterone: 0.5 mg, 1.25 mg, or
2.5 mg once a day. The combination of exemestane and
methyltestosterone is administered in a single dose tablet. The
side effects associated with exemestane treatment are measured as
described in Example 1. Data are expected to show improvement of at
least one or more side effects.
EXAMPLE 10
Prophetic
[0165] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 2.5 mg letrozole (FEMARA.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of methyltestosterone: 0.5 mg, 1.25 mg, or
2.5 mg once a day. The combination of letrozole and
methyltestosterone is administered in a single dose tablet. The
side effects associated with letrzole treatment are measured as
described in Example 1. Data are expected to show improvement of at
least one or more side effects.
EXAMPLE 11
Prophetic
[0166] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 1 mg anastrozole (ARIMIDEX.RTM.)) orally as
a tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone propionate: 20 mg, 40 mg, or
80 mg once a day. oral The combination of anastrozola and
testosterone undecanoate is administered in a single dose capsule
that has crystallized anastrozole and encapsulated testosterone
undecanoate in an oil suspension. The side effects associated with
anastrozole treatment are measured as described in Example 1. Data
are expected to show improvement of at least one or more side
effects.
EXAMPLE 12
Prophetic
[0167] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 25 mg exemestane (AROMASIN.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone propionate: 20 mg, 40 mg, or
80 mg once a day oral. The combination of exemestane and
testosterone undecanoate is administered in a single dose capsule
that has crystallized exemestane and encapsulated testosterone
undecanoate in an oil suspension. The side effects associated with
exemestane treatment are measured as described in Example 1. Data
are expected to show improvement of at least one or more side
effects.
EXAMPLE 13
Prophetic
[0168] Each woman selected is subjected to four weeks of aromatase
inhibitor therapy with 2.5 mg letrozole (FEMARA.RTM.) orally as a
tablet once a day, and thereafter to an additional eight weeks of
the same aromatase inhibitor in combination with at least one of
the following amounts of testosterone propionate: 20 mg, 40 mg, or
80 mg once a day. The combination of letrozole and testosterone
undecanoate is administered in a single dose capsule that has
crystallized letrozole and encapsulated testosterone undecanoate in
an oil suspension. The side effects associated with
letrozole-treatment are measured as described in Example 1. Data
are expected to show improvement of at least one or more side
effects.
[0169] Pharmaceutical compositions according to this invention
generally will be administered in a convenient formulation. The
following formulation examples only are illustrative and are not
intended to limit the scope of the present invention.
[0170] While the present invention has been described in terms of
preferred embodiments in order to facilitate better understanding
of the invention, it should be appreciated that various
modifications can be made without departing from the principles of
the invention. Therefore, the invention should be understood to
include all such modifications within its scope. Numerous
insubstantial variations, changes, and substitutions will now be
apparent to those skilled in the art without departing from the
scope of the invention disclosed herein. Accordingly, it is
intended that the invention be limited only by the spirit and scope
of the claims as will be allowed.
* * * * *