Intravenous formulations of coenzyme Q10 (CoQ10) and methods of use thereof
Inventors
Narain, Niven Rajin • McCook, John Patrick
Assignees
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Publication Number
US-11400058-B2
Publication Date
2022-08-02
Expiration Date
Abstract
Disclosed herein are formulations suitable for parenteral administration of certain hydrophobic active agents such as Coenzyme Q10. Methods of preparing the same and methods of treatment of oncological disorders using the same are also provided herein. The formulations comprise an aqueous solution; a hydrophobic active agent dispersed to form a colloidal nano-dispersion of particles; and at least one of a dispersion stabilizing agent and an opsonization reducer wherein the colloidal nano-dispersion of the active agent is dispersed into nano-dispersion particles having a mean size of less than 200-nm. Methods of preparing the parenteral formulations comprise dispersing the hydrophobic active agent by high pressure homogenization by (1) adding hydrophobic active agent to a 65° C. bath of water and mixing to form a hydrophobic active agent/water mixture; (2) adding a dispersion stabilizing agent to the hydrophobic active agent/water mixture and mix at 65° C. to form a hydrophobic active agent/water/stabilizer mixture; (3) adding an opsonization reducer to form a hydrophobic active agent/water/stabilizer/reducer mixture; (4) pre-heating a Microfluidizer to 65° C.; and (5) processing by mixing the hydrophobic active agent/water/stabilizer/reducer mixture in the Microfluidizer at 65° C. such that a hydrophobic active agent colloidal nano-dispersion having a mean particle size less than 200-nm is formed. Provided herein are also methods of treating oncological disorders by administering formulations described herein to a subject such that treatment or prevention of the oncological disorder occurs.
Core Innovation
The invention relates to a therapeutic formulation suitable for intravenous administration comprising an aqueous solution, coenzyme Q10, dimyristoylphosphatidyl choline, and poloxamer 188. Coenzyme Q10 is dispersed into a colloidal nano-dispersion of particles having a mean size of less than 50 nm, and the formulation addresses the poor water solubility of coenzyme Q10 and the requirement to nanosize the dispersion to achieve a stable colloidal nano-dispersion suitable for intravenous delivery.
The formulation provides coenzyme Q10-containing colloidal nano-dispersions in defined particle-size ranges, using dispersion stabilizers and opsonization reducers. Dimyristoylphosphatidyl choline is used as a dispersion component together with poloxamer 188, and coenzyme Q10 is described in crystalline form or super-cooled melt form.
Optional lyophilization produces crystalline or super-cooled melt forms using nutritive sugar lyoprotectants. Characterization is described using XRDP and PLM, and biological evaluation includes pharmacokinetic tissue/liver/spleen accumulation and therapeutic effects in tumor models and cell assays.
Claims Coverage
The independent claims center on an intravenous aqueous formulation containing coenzyme Q10, dimyristoylphosphatidyl choline, and poloxamer 188, where coenzyme Q10 forms colloidal nano-dispersion particles having a mean size of less than 50 nm. The claims also specify fixed wt % amounts and a 4:3:0.5-1.5 ratio, and one independent claim further specifies liposomes.
Intravenous nano-dispersion aqueous formulation with CoQ10, DMPC, and poloxamer 188
A therapeutic formulation suitable for intravenous administration comprising an aqueous solution, coenzyme Q10, dimyristoylphosphatidyl choline, and poloxamer 188, wherein coenzyme Q10 is dispersed into a colloidal nano-dispersion of particles having a mean size of less than 50 nm, with coenzyme Q10 present at 4 wt %, dimyristoylphosphatidyl choline present at 3 wt %, and poloxamer 188 selected from 0.5 wt %, 1.0 wt %, and 1.5 wt %.
Liposome nano-dispersion embodiment with CoQ10, DMPC, and poloxamer 188
A therapeutic formulation suitable for intravenous administration comprising an aqueous solution, coenzyme Q10 dispersed to form a colloidal nano-dispersion of particles, dimyristoylphosphatidyl choline, and poloxamer 188, wherein coenzyme Q10 is dispersed into liposomes having a mean size of less than 50 nm, with coenzyme Q10 present at 4 wt %, dimyristoylphosphatidyl choline present at 3 wt %, and poloxamer 188 selected from 0.5 wt %, 1.0 wt %, and 1.5 wt %.
Ratio-defined intravenous formulation with sub-50 nm colloidal nano-dispersion
A therapeutic formulation suitable for intravenous administration comprising an aqueous solution, coenzyme Q10, dimyristoylphosphatidyl choline, and poloxamer 188, wherein coenzyme Q10 is dispersed into a colloidal nano-dispersion of particles having a mean size of less than 50 nm, with coenzyme Q10 present at 4 wt %, dimyristoylphosphatidyl choline present at 3 wt %, and wherein the ratio of coenzyme Q10, dimyristoylphosphatidyl choline, and poloxamer 188 is 4:3:0.5-1.5, respectively.
The independent claims collectively cover an intravenous aqueous therapeutic formulation containing coenzyme Q10 with dimyristoylphosphatidyl choline and poloxamer 188, where coenzyme Q10 forms sub-50 nm colloidal nano-dispersion particles. One independent claim specifies coenzyme Q10 dispersed into liposomes with mean size below 50 nm, and another independent claim specifies a ratio of 4:3:0.5-1.5 for coenzyme Q10:dimyristoylphosphatidyl choline:poloxamer 188.
Stated Advantages
Stable colloidal nano-dispersion in aqueous media suitable for intravenous administration.
Greater tissue/liver/spleen accumulation is indicated for the nano-dispersion approach described in the document.
Early indications of therapeutic effects in tumor models and cell assays are described.
Documented Applications
In vivo pharmacokinetic and organ distribution studies comparing formulations with and without poloxamer 188, including mouse organ distribution in liver, spleen, lung, pancreas, and brain, and reported differential accumulation.
Use of the formulations in a liver cancer model and a lung cancer model.
Cancer-related apoptosis/efficacy assessment including apoptosis assays and caspase-3 measurements, with reported survival and safety observations.
Nonclinical toxicology and toxicokinetic evaluation in rats, dogs, and macaques, including single-dose and repeat-dose toxicity and assessment of tolerability and exposure behavior.
Oncological disorders, including tumor cell growth inhibition in tumor models and cell assays are described.
Therapeutic effects and pharmacokinetic accumulation after intravenous administration in preclinical biological evaluation are described.
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