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.

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, 17α-methylnortestosterone, norethandrolone, dihydrotestosterone, 5α-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, 17α-methylnortestosterone, norethandrolone, dihydrotestosterone, 5α-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, 17α-methylnortestosterone, norethandrolone, dihydrotestosterone, 5α-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.