Adjunctive Therapy With 25-Hydroxyvitamin D and Articles Therefor

Abstract

Methods, compositions, and kits for adjunctive therapy using 25-hydroxyvitamin D are disclosed. The 25-hydroxyvitamin D may be administered with an agent that increases the risk of hypocalcemia, such as cinacalcet or a salt thereof, and/or an anticancer agent. The adjunctive therapy is effective to treat and prevent iatrogenic hypocalcemia and/or secondary hyperparathyroidism, as well as delay cancer progression and the time to a post-treatment skeletal related event.

What is claimed is: 
     
         1 . A pharmaceutical formulation for oral administration comprising (a) a 25-hydroxyvitamin D compound (b) an agent that increases the risk of hypocalcemia, optionally cinacalcet or a salt thereof, and (c) an anticancer agent. 
     
     
         2 . The pharmaceutical formulation of  claim 1 , comprising a first region comprising the 25-hydroxyvitamin D compound and a second region comprising the agent that increases the risk of hypocalcemia. 
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein the first region comprising the 25-hydroxyvitamin D compound further comprises a pharmaceutically acceptable excipient, or the second region that comprises the agent that increases the risk of hypocalcemia further comprises a pharmaceutically acceptable excipient, or both the first and second regions each further comprises a pharmaceutically acceptable excipient. 
     
     
         4 . The pharmaceutical formulation of  claim 1 , comprising a matrix that releasably binds and controllably releases the 25-hydroxyvitamin D compound. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , comprising a wax matrix comprising the 25-hydroxyvitamin D compound, a controlled release agent, an emulsifier, an absorption enhancer, and a stabilizing agent. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , comprising a matrix comprising the 25-hydroxyvitamin D compound, about 20 wt % paraffin, about 20 wt % to about 25 wt % glycerol monostearate, about 10 wt % a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides, about 30 wt % to about 35 wt % mineral oil, and about 10 wt % to about 15 wt % hydroxyl propyl methylcellulose. 
     
     
         7 . The pharmaceutical formulation of  claim 1 , wherein formulation or region comprising the 25-hydroxyvitamin D compound comprises a coating comprising a mixture of neutral swellable methacrylic acids esters with trimethylammonioethyl methacrylate chlorides. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein formulation or region comprising the 25-hydroxyvitamin D compound comprises a coating comprising a one or more polyvinyl esters, polyvinyl acetals, polyacrylic acid esters, butadiene sytrene copolymers, or mixtures thereof. 
     
     
         9 . The pharmaceutical formulation of  claim 1 , characterized by an in vitro dissolution profile providing release of the 25-hydroxyvitamin D compound of about 20% to about 40% at 2 hours, at least 35% at 6 hours, and at least 70% at 12 hours. 
     
     
         10 . The pharmaceutical formulation of  claim 1 , characterized by an in vitro dissolution profile providing release of the agent that increases the risk of hypocalcemia of at least 50% at 30 minutes. 
     
     
         11 . The pharmaceutical formulation of  claim 1 , wherein the formulation comprises a capsule having a hard shell. 
     
     
         12 . The pharmaceutical formulation of  claim 1 , wherein the formulation comprises a soft capsule. 
     
     
         13 . The pharmaceutical formulation of  claim 1 , comprising the agent that increases the risk of hypocalcemia disposed in a first capsule shell and the 25-hydroxyvitamin D compound disposed in second capsule shell, the second capsule shell being disposed within the first capsule shell. 
     
     
         14 . The pharmaceutical formulation of  claim 1 , comprising the agent that increases the risk of hypocalcemia in granular form. 
     
     
         15 . The pharmaceutical formulation of  claim 1 , comprising a core region comprising the 25-hydroxyvitamin D compound and an outer region comprising the agent that increases the risk of hypocalcemia. 
     
     
         16 . The pharmaceutical formulation of  claim 1 , wherein the agent that increases the risk of hypocalcemia is disposed within a coating. 
     
     
         17 . The pharmaceutical formulation of  claim 16 , wherein the coating is disposed on at least one nonpareil. 
     
     
         18 . The pharmaceutical formulation of  claim 17 , wherein one or more coated nonpareils are blended with the 25-hydroxyvitamin D compound in a non-aqueous solution, the blend being disposed in a capsule shell. 
     
     
         19 . The pharmaceutical formulation of  claim 17 , wherein the 25-hydroxyvitamin D compound is disposed in a first chamber of a two-chamber capsule, and one or more coated nonpareils are disposed in a second chamber of the two-chamber capsule. 
     
     
         20 . The pharmaceutical formulation of  claim 1 , wherein the agent that increases the risk of hypocalcemia is formulated for rapid release. 
     
     
         21 . The pharmaceutical formulation of  claim 1 , wherein the 25-hydroxyvitamin D compound is 25-hydroxyvitamin D 2 , 25-hydroxyvitamin D 3 , or a combination thereof. 
     
     
         22 . The pharmaceutical formulation of  claim 21 , wherein the 25-hydroxyvitamin D compound is 25-hydroxyvitamin D 3 . 
     
     
         23 . The pharmaceutical formulation of  claim 1 , comprising the 25-hydroxyvitamin D compound in an amount between about 1 mcg and about 1000 mcg. 
     
     
         24 . The pharmaceutical formulation of  claim 1 , comprising the 25-hydroxyvitamin D compound in an amount between about 1 mcg and about 100 mcg. 
     
     
         25 . The pharmaceutical formulation of  claim 1 , comprising the agent that increases the risk of hypocalcemia in an amount between about 1 mg and about 100 mg. 
     
     
         26 . The pharmaceutical formulation of  claim 1 , wherein the agent that increases the risk of hypocalcemia comprises cinacalcet or a salt thereof. 
     
     
         27 . The pharmaceutical formulation of  claim 26 , wherein the cinacalcet or salt thereof comprises cinacalcet HCl. 
     
     
         28 . The pharmaceutical formulation of  claim 1 , further comprising a disintegrant, optionally in an amount of about 1 wt % to 10 wt %. 
     
     
         29 . The pharmaceutical formulation of  claim 2 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises from about 10% to about 40% by weight of cinacalcet or a salt thereof, from about 45% to about 85% by weight of at least one diluent, and from about 1% to about 10% by weight of at least one disintegrant, optionally further comprising from about 1% to about 5% by weight of at least one binder, wherein the percentage by weight is relative to the total weight of the region. 
     
     
         30 . The pharmaceutical formulation of  claim 2 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
 (a) from about 10% to about 40% by weight of cinacalcet or salt thereof;   (b) from about 40% to about 75% by weight of microcrystalline cellulose;   (c) from about 5% to about 35% by weight of starch;   (d) from about 1% to about 10% by weight of crospovidone;   (e) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and   (f) from about 0.05% to about 1.5% by weight of magnesium stearate;   wherein the percentage by weight is relative to the total weight of the region.   
     
     
         31 . The pharmaceutical formulation of  claim 2 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
 (a) from about 10% to about 40% by weight of cinacalcet or salt thereof;   (b) from about 40% to about 75% by weight of microcrystalline cellulose;   (c) from about 1% to about 5% by weight of povidone;   (d) from about 5% to about 35% by weight of starch;   (e) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and   (f) from about 0.05% to about 1.5% by weight of magnesium stearate;   wherein the percentage by weight is relative to the total weight of the region.   
     
     
         32 . The pharmaceutical formulation of  claim 2 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
 (a) from about 10% to about 40% by weight of cinacalcet or salt thereof;   (b) from about 40% to about 75% by weight of microcrystalline cellulose;   (c) from about 15% to about 50% by weight of starch;   (d) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and   (e) from about 0.05% to about 1.5% by weight of magnesium stearate;   wherein the percentage by weight is relative to the total weight of the region.   
     
     
         33 . The pharmaceutical formulation of  claim 2 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
 (a) from about 10% to about 40% by weight of cinacalcet or salt thereof;   (b) from about 40% to about 75% by weight of microcrystalline cellulose;   (c) from about 1% to about 5% by weight of povidone;   (d) from about 1% to about 10% by weight of a disintegrant selected from the group consisting of croscarmellose, sodium starch glycolate, crosslinked cellulose, crosslinked polymers, crosslinked starches, and combinations thereof;   (e) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and   (f) from about 0.05% to about 1.5% by weight of magnesium stearate;   wherein the percentage by weight is relative to the total weight of the region.   
     
     
         34 . The pharmaceutical formulation of  claim 2 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
 (a) from about 10% to about 40% by weight of cinacalcet or salt thereof;   (b) from about 40% to about 75% by weight of microcrystalline cellulose;   (c) from about 1% to about 5% by weight of a binder selected from the group consisting of gelatin, acacia, tragacanth, alginic acid, cellulose, methyl cellulose, ethyl cellulose, HPMC, HPC, sodium carboxy methyl cellulose, PEG, PVA, polymethacrylate, polyvinylcaprolactam, and combinations thereof;   (d) from about 5% to about 35% by weight of starch;   (e) from about 1% to about 10% by weight of crospovidone;   (f) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and   (g) from about 0.05% to about 1.5% by weight of magnesium stearate;   wherein the percentage by weight is relative to the total weight of the region.   
     
     
         35 . A method of managing iatrogenic hypocalcemia and secondary hyperparathyroidism in a patient receiving therapy with cinacalcet or a salt thereof, comprising administering to said patient a pharmaceutical formulation of  claim 1 . 
     
     
         36 . The method of  claim 35 , wherein the patient has impaired renal function, optionally associated with Chronic Kidney Disease Stage 1, 2, 3, 4, or 5. 
     
     
         37 . The method of  claim 35 , wherein the patient is receiving dialysis. 
     
     
         38 . The method of  claim 35 , wherein the patient is not on dialysis. 
     
     
         39 . The method of  claim 35 , wherein the amount of 25-hydroxyvitamin D is effective to restore or maintain the patient's serum calcium level to at least about 8.0 mg/dL, optionally in a range of about 8.3 mg/dL to about 11.6 mg/dL. 
     
     
         40 . The method of  claim 35 , wherein the amount of 25-hydroxyvitamin D is effective to safely increase the patient's serum level of 25-hydroxyvitamin D to at least 30 ng/mL, optionally in a range of about 30 ng/mL to about 100 ng/mL. 
     
     
         41 . The method of  claim 35 , wherein the amount of 25-hydroxyvitamin D is effective to decrease the patient's serum parathyroid hormone level, optionally by 30% or more. 
     
     
         42 . The method of  claim 35 , wherein the amount of 25-hydroxyvitamin D is administered in an oral modified release formulation, optionally a sustained release formulation. 
     
     
         43 . The method of  claim 35 , wherein the 25-hydroxyvitamin D is co-administered with an oral formulation comprising cinacalcet or a salt thereof. 
     
     
         44 . The method of  claim 35 , wherein the 25-hydroxyvitamin D comprises 25-hydroxyvitamin D 3 , 25-hydroxyvitamin D 2 , or a combination thereof. 
     
     
         45 . The method of  claim 44 , wherein the 25-hydroxyvitamin D comprises 25-hydroxyvitamin D 3 . 
     
     
         46 . The method of  claim 35 , wherein the 25-hydroxyvitamin D is administered in a dosage of 1 mcg to 1000 mcg per day. 
     
     
         47 . The method of  claim 35 , wherein the cinacalcet or salt thereof comprises cinacalcet HCl. 
     
     
         48 . The method of  claim 35 , wherein the patient is receiving cinacalcet administered in a dosage of 1 mg to 400 mg per day. 
     
     
         49 . A method of treating hypercalcemia in a patient with parathyroid carcinoma, comprising administering to said patient an effective amount of a 25-hydroxyvitamin D compound by modified release and an effective dose of cinacalcet or a salt thereof in an amount of less than 360 mg daily, wherein said effective amount of cinacalcet or a salt thereof is a reduced dose compared to the effective dose of cinacalcet in the absence of said 25-hydroxyvitamin D administration, and an anticancer agent. 
     
     
         51 . The method of  claim 49 , comprising an initial dose of cinacalcet in a rage of about 20 mg to about 25 mg once daily. 
     
     
         52 . The method of  claim 49 , wherein the amount of 25-hydroxyvitamin D is in a range of about 100 mcg to about 300 mcg. 
     
     
         53 . The pharmaceutical formulation of  claim 1 , wherein the anticancer agent comprises one or more agents in the groups including aromatase inhibitors; anti-estrogens; anti-androgens; gonadorelin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; retinoids, carotenoids, tocopherols; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antimetabolites; platin compounds; methionine aminopeptidase inhibitors; bisphosphonates; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; Flt-3 inhibitors; Hsp90 inhibitors; kinesin spindle protein inhibitors; MEK inhibitors; antitumor antibiotics; nitrosoureas, compounds targeting/decreasing protein or lipid kinase activity, compounds targeting/decreasing protein or lipid phosphatase activity, antiangiogenic compounds, azacitidine, axathioprine, bevacizumab, bleomycin, capecitabine, carboplatin, chlorabucil, cisplatin, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fluorouracil, gemcitabine, herceptin, idarubicin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, tafluposide, teniposide, tioguanine, retinoic acid, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, and receptor tyrosine kinase inhibitors. 
     
     
         54 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more aromatase inhibitors. 
     
     
         55 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more anti-estrogens. 
     
     
         56 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more anti-androgens. 
     
     
         57 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more gonadorelin agonists. 
     
     
         58 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or moretopoisomerase I inhibitors. 
     
     
         59 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more topoisomerase II inhibitors. 
     
     
         60 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more microtubule active agents. 
     
     
         61 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more alkylating agents. 
     
     
         62 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more retinoids. 
     
     
         63 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more carotenoids. 
     
     
         64 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more tocopherols. 
     
     
         65 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more cyclooxygenase inhibitors. 
     
     
         66 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more MMP inhibitors. 
     
     
         67 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more mTOR inhibitors. 
     
     
         68 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more antimetabolites. 
     
     
         69 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more platin compounds. 
     
     
         70 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more methionine aminopeptidase inhibitors. 
     
     
         71 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more bisphosphonates. 
     
     
         72 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more antiproliferative antibodies. 
     
     
         73 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more heparanase inhibitors. 
     
     
         74 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more inhibitors of Ras oncogenic isoforms. 
     
     
         75 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more telomerase inhibitors. 
     
     
         76 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more proteasome inhibitors. 
     
     
         77 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more Flt-3 inhibitors. 
     
     
         78 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more Hsp90 inhibitors. 
     
     
         79 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more kinesin spindle protein inhibitors. 
     
     
         80 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more MEK inhibitors. 
     
     
         81 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more antitumor antibiotics. 
     
     
         82 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more nitrosoureas. 
     
     
         83 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more compounds targeting/decreasing protein or lipid kinase activity. 
     
     
         84 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more compounds targeting/decreasing protein or lipid phosphatase activity. 
     
     
         85 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more antiangiogenic compounds. 
     
     
         86 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises azacitidine. 
     
     
         87 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises axathioprine. 
     
     
         88 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises bevacizumab. 
     
     
         89 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises bleomycin. 
     
     
         90 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises capecitabine. 
     
     
         91 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises carboplatin. 
     
     
         92 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises chlorabucil. 
     
     
         93 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises cisplatin. 
     
     
         94 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises cyclophosphamide. 
     
     
         95 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises cytarabine. 
     
     
         96 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises daunorubicin. 
     
     
         97 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises docetaxel. 
     
     
         98 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises doxifluridine. 
     
     
         99 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises doxorubicin. 
     
     
         100 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises epirubicin. 
     
     
         101 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises etoposide. 
     
     
         102 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises fluorouracil. 
     
     
         103 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises gemcitabine. 
     
     
         104 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises herceptin. 
     
     
         105 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises idarubicin. 
     
     
         106 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises mechlorethamine. 
     
     
         107 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises melphalan. 
     
     
         108 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises mercaptopurine. 
     
     
         109 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises methotrexate. 
     
     
         110 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises mitoxantrone. 
     
     
         111 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises oxaliplatin. 
     
     
         112 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises paclitaxel. 
     
     
         113 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises tafluposide. 
     
     
         114 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises teniposide. 
     
     
         115 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises tioguanine. 
     
     
         116 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises retinoic acid. 
     
     
         117 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises valrubicin. 
     
     
         118 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises vinblastine. 
     
     
         119 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises vincristine. 
     
     
         120 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises vindesine. 
     
     
         121 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises vinorelbine. 
     
     
         122 . The pharmaceutical formulation of  claim 53 , wherein the anticancer agent comprises one or more receptor tyrosine kinase inhibitors.