Compositions and methods to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol

Abstract

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol.

What is claimed is: 
     
         1 . A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising an alternative selected from the group consisting of:
 (a) a therapeutically effective quantity of a modified therapeutic agent or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent, wherein the modified therapeutic agent or the derivative, analog or prodrug of the therapeutic agent or modified therapeutic agent possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent;   (b) a composition comprising:
 (i) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent; and 
 (ii) at least one additional therapeutic agent, therapeutic agent subject to chemosensitization, therapeutic agent subject to chemopotentiation, diluent, excipient, solvent system, or drug delivery system, wherein the composition possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent; 
   (c) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent, or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent that is incorporated into a dosage form, wherein the therapeutic agent, the modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent incorporated into the dosage form possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent;   (d) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent, or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent that is incorporated into a dosage kit and packaging, wherein the therapeutic agent, the modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent incorporated into the dosage kit and packaging possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent; and   (e) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent, or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent that is subjected to a bulk drug product improvement, wherein the therapeutic agent, the modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent subject to the bulk drug product improvement possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent; wherein the therapeutic agent or modified therapeutic agent is a substituted hexitol, wherein the substituted hexitol is selected from the group consisting of dianhydrogalactitol and diacetyldianhydrogalactitol.   
     
     
         2 . The composition of  claim 1  wherein the composition comprises a drug combination comprising:
 (a) dianhydrogalactitol or diacetyldianhydrogalactitol; and 
 (b) an alkylating agent selected from the group consisting of BCNU, BCNU wafers, CCNU, bendamustine (Treanda), and temozolomide (Temodar). 
 
     
     
         3 . The composition of  claim 1  wherein the composition comprises a drug combination comprising:
 (a) dianhydrogalactitol or diacetyldianhydrogalactitol; and 
 (b) a biotherapeutic that is an antibody selected from the group consisting of bevacizumab (Avastin), trastuzumab (Herceptin), rituximab (Rituxan), and cetuximab (Erbitux). 
 
     
     
         4 . The composition of  claim 1  wherein the therapeutic agent is dianhydrogalactitol or diacetyldianhydrogalactitol and the dianhydrogalactitol or diacetyldianhydrogalactitol is subjected to a bulk drug product improvement, wherein the bulk drug product improvement is selected from the group consisting of:
 (i) salt formation; 
 (ii) preparation as a homogeneous crystal structure; 
 (iii) preparation as a pure isomer; 
 (iv) increased purity; 
 (v) preparation with lower residual solvent content; and 
 (vi) preparation with lower residual heavy metal content. 
 
     
     
         5 . The composition of  claim 1  wherein the therapeutic agent is dianhydrogalactitol or diacetyldianhydrogalactitol and the composition further comprises at least one additional therapeutic agent to form a multiple drug system, wherein the at least one additional therapeutic agent is selected from the group consisting of:
 (i) an inhibitor of multi-drug resistance; 
 (ii) a specific drug resistance inhibitor; 
 (iii) a specific inhibitor of a selective enzyme; 
 (iv) a signal transduction inhibitor; 
 (v) an inhibitor of a repair enzyme; and 
 (vi) a topoisomerase inhibitor with non-overlapping side effects. 
 
     
     
         6 . A method to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising the steps of:
 (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the drug therapy; and   (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the drug therapy, wherein the suboptimally administered drug therapy comprises administration of a substituted hexitol selected from the group consisting of dianhydrogalactitol and diacetyldianhydrogalactitol, and wherein the factor or parameter is an additional indication selected from the group consisting of:
 (i) use for treatment of benign prostatic hyperplasia; 
 (ii) use for treatment of psoriasis; 
 (iii) use for treatment of gout; 
 (iv) use for treatment of transplantation rejections; 
 (v) use for prevention of restenosis in cardiovascular disease; 
 (vi) use in bone marrow transplantation; 
 (vii) use as an anti-infective agent; and 
 (viii) use for treatment of AIDS. 
   
     
     
         7 . A method to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising the steps of:
 (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the drug therapy; and   (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the drug therapy, wherein the suboptimally administered drug therapy comprises administration of a substituted hexitol selected from the group consisting of dianhydrogalactitol and diacetyldianhydrogalactitol, and wherein the factor or parameter is selected from the group consisting of:
 (i) dose modification; 
 (ii) selection of disease stage; 
 (iii) other indications; 
 (iv) pharmacokinetic/pharmacodynamic monitoring; 
 (v) chemosensitization; 
 (vi) chemopotentiation; 
 (vii) bulk drug product improvement; 
 (viii) use of a diluent; 
 (ix) use of a solvent system; 
 (x) use of an excipient; 
 (xi) use of a dosage form; 
 (xii) biotherapeutic enhancement; 
 (xiii) biotherapeutic resistance modulation; and 
 (xiv) radiation therapy enhancement. 
   
     
     
         8 . The method of  claim 7  wherein the improvement is made by dose modification, and wherein the dose modification is a modification selected from the group consisting of:
 (i) continuous i.v. infusion for hours to days; 
 (ii) biweekly administration; 
 (iii) doses greater than 5 mg/m 2 /day; 
 (iv) progressive escalation of dosing from 1 mg/m 2 /day based on patient tolerance; 
 (v) use of caffeine to modulate metabolism; 
 (vi) use of isoniazid to modulate metabolism; 
 (vii) selected and intermittent boosting of dosage administration; 
 (viii) administration of single and multiple doses escalating from 5 mg/m 2 /day via bolus; 
 (ix) oral dosages of below 30 mg/m 2 ; and 
 (x) oral dosages of above 130 mg/m 2 . 
 
     
     
         9 . The method of  claim 7  wherein the improvement is made by selection of disease stage, and wherein the selection of disease stage is selected from the group consisting of:
 (i) use for the treatment of localized polyp stage colon cancer; 
 (ii) use for leukoplakia in the oral cavity; 
 (iii) use for angiogenesis inhibition to prevent or limit metastatic spread of a malignancy; and 
 (iv) use for treatment of HIV with a therapy selected from the group consisting of azidothymidine (AZT), dideoxyadenosine (DDI), and reverse transcriptase inhibitors. 
 
     
     
         10 . The method of  claim 7  wherein the improvement is made by other indications, and wherein the other indication is selected from the group consisting of:
 (i) use as an anti-infective agent; 
 (ii) use as an antiviral agent; 
 (iii) use as an antibacterial agent; 
 (iv) use as an agent to treat pleural effusion; 
 (v) use as an antifungal agent; 
 (vi) use as an anti-parasitic agent; 
 (vii) use as an agent to treat eczema; 
 (viii) use as an agent to treat herpes zoster (shingles); 
 (ix) use as an agent to treat condylomata; 
 (x) use as an agent to treat HPV; and 
 (xi) use as an agent to treat HSV. 
 
     
     
         11 . The method of  claim 7  wherein the improvement is made by pharmacokinetic/pharmacodynamic monitoring, and wherein the pharmacokinetic/pharmacodynamic monitoring is performed by a method selected from the group consisting of:
 (i) multiple determinations of blood plasma levels; and 
 (ii) multiple determinations of at least one metabolite in blood or urine. 
 
     
     
         12 . The method of  claim 7  wherein the improvement is made by chemosensitization, and wherein the chemosensitization comprises the use of dianhydrogalactitol or diacetyldianhydrogalactitol as a chemosensitizer in combination with an agent selected from the group consisting of:
 (i) topoisomerase inhibitors; 
 (ii) fraudulent nucleosides; 
 (iii) fraudulent nucleotides; 
 (iv) thymidylate synthetase inhibitors; 
 (v) signal transduction inhibitors; 
 (vi) cisplatin or platinum analogs; 
 (vii) alkylating agents; 
 (viii) anti-tubulin agents; 
 (ix) antimetabolites; 
 (x) berberine; 
 (xi) apigenin; 
 (xii) amonafide; 
 (xiii) vinca alkaloids; 
 (xiv) 5-fluorouracil; 
 (xv) curcumin; 
 (xvi) NF-κB inhibitors; 
 (xvii) rosmarinic acid; 
 (xviii) mitoguazone; and 
 (xix) tetrandrine. 
 
     
     
         13 . The method of  claim 7  wherein the improvement is made by chemopotentiation, and wherein the chemopotentiation comprises the use of dianhydrogalactitol or diacetyldianhydrogalactitol as a chemopotentiator in combination with an agent selected from the group consisting of:
 (i) topoisomerase inhibitors; 
 (ii) fraudulent nucleosides; 
 (iii) fraudulent nucleotides; 
 (iv) thymidylate synthetase inhibitors; 
 (v) signal transduction inhibitors; 
 (vi) cisplatin or platinum analogs; 
 (vii) alkylating agents; 
 (viii) anti-tubulin agents; 
 (ix) antimetabolites; 
 (x) berberine; 
 (xi) apigenin; 
 (xii) amonafide; 
 (xiii) vinca alkaloids; 
 (xiv) 5-fluorouracil; 
 (xv) curcumin; 
 (xvi) NF-κB inhibitors; 
 (xvii) rosmarinic acid; 
 (xviii) mitoguazone; and 
 (xix) tetrandrine. 
 
     
     
         14 . The method of  claim 13  wherein the agent is an alkylating agent, and the alkylating agent is selected from the group consisting of:
 (i) BCNU; 
 (ii) BCNU wafers; 
 (iii) CCNU; 
 (iv) bendamustine (Treanda); and 
 (v) temozolomide (Temodar). 
 
     
     
         15 . The method of  claim 7  wherein the improvement is made by use of a bulk drug product improvement, and wherein the bulk drug product improvement is selected from the group consisting of:
 (i) salt formation; 
 (ii) preparation as a homogeneous crystal structure; 
 (iii) preparation as a pure isomer; 
 (iv) increased purity; 
 (v) preparation with lower residual solvent content; and 
 (vi) preparation with lower residual heavy metal content. 
 
     
     
         16 . The method of  claim 7  wherein the improvement is made by use of a diluent, and wherein the diluent is selected from the group consisting of:
 (i) an emulsion; 
 (ii) dimethylsulfoxide (DMSO); 
 (iii) N-methylformamide (NMF) 
 (iv) DMF; 
 (v) ethanol; 
 (vi) benzyl alcohol; 
 (vii) dextrose-containing water for injection; 
 (viii) Cremophor; 
 (ix) cyclodextrin; and 
 (x) PEG. 
 
     
     
         17 . The method of  claim 7  wherein the improvement is made by use of a solvent system, and wherein the solvent system is selected from the group consisting of:
 (i) an emulsion; 
 (ii) dimethylsulfoxide (DMSO); 
 (iii) N-methylformamide (NMF) 
 (iv) DMF; 
 (v) ethanol; 
 (vi) benzyl alcohol; 
 (vii) dextrose-containing water for injection; 
 (viii) Cremophor; 
 (ix) cyclodextrin; and 
 (x) PEG. 
 
     
     
         18 . The method of  claim 7  wherein the improvement is made by use of an excipient, and wherein the excipient is selected from the group consisting of:
 (i) mannitol; 
 (ii) albumin; 
 (iii) EDTA; 
 (iv) sodium bisulfite; 
 (v) benzyl alcohol; 
 (vi) a carbonate buffer; and 
 (vii) a phosphate buffer. 
 
     
     
         19 . The method of  claim 7  wherein the improvement is made by use of a dosage form, and wherein the dosage form is selected from the group consisting of:
 (i) tablets; 
 (ii) capsules; 
 (iii) topical gels; 
 (iv) topical creams; 
 (v) patches; 
 (vi) suppositories; and 
 (vii) lyophilized dosage fills. 
 
     
     
         20 . The method of  claim 7  wherein the improvement is made by use of biotherapeutic enhancement, and wherein the biotherapeutic enhancement is performed by use of dianhydrogalactitol or diacetyldianhydrogalactitol in combination as sensitizers/potentiators with a therapeutic agent or technique selected from the group consisting of:
 (i) cytokines; 
 (ii) lymphokines; 
 (iii) therapeutic antibodies; 
 (iv) antisense therapies; 
 (v) gene therapies; 
 (vi) ribozymes; and 
 (vii) RNA interference. 
 
     
     
         21 . The method of  claim 20  wherein the biotherapeutic enhancement is performed by use in combination with a therapeutic antibody, and the therapeutic antibody is selected from the group consisting of bevacizumab (Avastin), rituximab (Rituxan), trastuzumab (Herceptin), and cetuximab (Erbitux). 
     
     
         22 . The method of  claim 7  wherein the improvement is made by use of biotherapeutic resistance modulation, and wherein the biotherapeutic resistance modulation comprises use of dianhydrogalactitol or diacetyldianhydrogalactitol against tumors resistant to a therapeutic agent or technique selected from the group consisting of:
 (i) biological response modifiers; 
 (ii) cytokines; 
 (iii) lymphokines; 
 (iv) therapeutic antibodies; 
 (v) antisense therapies; 
 (vi) gene therapies; 
 (vii) ribozymes; and 
 (viii) RNA interference. 
 
     
     
         23 . The method of  claim 22  wherein the biotherapeutic resistance modulation comprises use against tumors resistant to a therapeutic antibody, and the therapeutic antibody is selected from the group consisting of Avastin, Rituxan, Herceptin, and Erbitux. 
     
     
         24 . The method of  claim 7  wherein the improvement is made by use of radiation therapy enhancement, and wherein the radiation therapy enhancement is performed by administration of dianhydrogalactitol or diacetyldianhydrogalactitol with use of an agent or technique selected from the group consisting of:
 (i) hypoxic cell sensitizers; 
 (ii) radiation sensitizers/protectors; 
 (iii) photosensitizers; 
 (iv) radiation repair inhibitors; 
 (v) thiol depleters; 
 (vi) vaso-targeted agents; 
 (vii) DNA repair inhibitors; 
 (viii) radioactive seeds; 
 (ix) radionuclides; 
 (x) radiolabeled antibodies; and 
 (xi) brachytherapy. 
 
     
     
         25 . A method to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising the steps of:
 (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the drug therapy; and   (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the drug therapy, wherein the suboptimally administered drug therapy comprises administration of a substituted hexitol selected from the group consisting of dianhydrogalactitol and diacetyldianhydrogalactitol, and wherein the factor or parameter is patient or disease phenotype, and wherein the patient or disease phenotype is selected from the group consisting of quantity or activity of MGMT, methylation of MGMT promoter, and mutant isocitrate dehydrogenase (IDH).   
     
     
         26 . A method to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising the steps of:
 (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the drug therapy; and   (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the drug therapy, wherein the suboptimally administered drug therapy comprises administration of a substituted hexitol selected from the group consisting of dianhydrogalactitol and diacetyldianhydrogalactitol, and wherein the factor or parameter is drug combinations, wherein the drug combination comprises:
 (i) dianhydrogalactitol or diacetyldianhydrogalactitol; and 
 (ii) an additional therapeutic agent selected from the group consisting of an inhibitor of mutant isocitrate dehydrogenase (IDH), a MGMT inhibitor, and an agent that inhibits NF-κB-enhanced expression of MGMT.