Parenteral and oral formulations of benzimidazoles

Abstract

Provided herein are drug delivery systems comprising nanosuspension formulations suitable for parenteral delivery to a subject. The nanosuspension formulations may comprise a benzimidazole derivative, e.g., mebendazole, and surface stabilizers, such as block copolymer(s), e.g., Pluronic F108, and surfactant(s), e.g., Tween 80, and, optionally, water. Provided are methods for defining nanosuspensions of a benzimidazole derivative as having maximum therapeutic efficacy for a treatment regimen by adjusting and/or selecting particles size(s) based on pharmacokinetic parameters of the derivative in the tissue. Also provided are methods for improving the bioavailability of a benzimidazole derivative during treatment of a pathophysiological condition and for treating a cancer by using formulation(s) combining particle diameters whereby the retention of the benzimidazole derivative within the particles increases as the diameter increases such that, upon administration, release of the benzimidazole derivative from the particles into tissue is continuous over a range of time as determined by the particle diameters.

1 . A drug delivery system, comprising:
 a nanosuspension formulation comprising particles of a benzimidazole derivative at a particle size range of about 5 nm to about 2000 nm.   
   
   
       2 . The drug delivery system of  claim 1 , further comprising two or more surface stabilizers. 
   
   
       3 . The drug delivery system of  claim 2 , wherein the surface stabilizers are one or more block copolymers and one or more surfactants. 
   
   
       4 . The drug delivery system of  claim 3 , wherein the block copolymer is Pluronic F108 
   
   
       5 . The drug delivery system of  claim 3 , wherein the surfactant is Tween-80. 
   
   
       6 . The drug delivery system of  claim 2 , wherein the nanosuspension comprises up to about 10% w/v of block copolymer and up to about 10% w/v of surfactant. 
   
   
       7 . The drug delivery system of  claim 6 , wherein the percent w/v of the block copolymer and of the surfactant is about 5% w/v or about 1% w/v. 
   
   
       8 . The drug delivery system of  claim 1 , further comprising water. 
   
   
       9 . The drug delivery system of  claim 1 , wherein the benzimidazole derivative has the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 3  is selected from the group consisting of H, carboxyl (—CO 2 H), hydroxyl, amino, chloro, difluormethoxy, benzoyl, phenyl-thio, pyridinyl, propyl-thio, diphenyl, 5-methoxy, fluorophenylmethyl-2-chloro, propenyl, chloropropyl or esters (—CO 2 R 4 ) wherein R 4  is selected from the group consisting of alkoxy, haloalkyl, alkenyl, and cycloalkyl, wherein the alkyl groups have from 1-8 carbons, or CH 3 CH 2 (OCH 2 CH 2 ) n —, or CH 3 CH 2 CH 2 (OCH 2 CH 2 CH 2 ) n —, or (CH 3 ) 2 CH(OCH(CH 3 )CH 2 ) n —, wherein n is from 1-3 wherein R 1  is OH, Cl, SH, carbamate or piperidin-4-yl, and R 2  is hydrogen, α-methylvinyl, 3-chloropropyl or piperidin-4-yl, or the pharmaceutically effective organic or inorganic salts thereof, or mixtures thereof; 
   
   
       10 . The drug delivery system of  claim 9 , wherein the benzimidazole derivative is methyl 5-benzoylbenzimidazole-2-carbamate, methyl 5-(phenylthio)-2-carbamate, 
     
       
         
         
             
             
         
       
     
   
   
       11 . The drug delivery system of  claim 1 , wherein the benzimidazole derivative comprises the nanosuspension at any concentration up to about 200 mg/ml. 
   
   
       12 . The drug delivery system of  claim 1 , wherein the particles comprising the nanosuspension have substantially the same sizes or have a combination of sizes. 
   
   
       13 . The drug delivery system of  claim 1 , wherein a particle size range is about 100 nm to about 2000 nm. 
   
   
       14 . The drug delivery system of  claim 1 , wherein the benzimidazole derivative is methyl 5-benzoylbenzimidazole-2-carbamate at any concentration up to about 200 mg/ml. 
   
   
       15 . A drug delivery system, comprising:
 a nanosuspension formulation comprising particles of methyl 5-benzoylbenzimidazole-2-carbamate, Pluronic F108 and Tween-80.   
   
   
       16 . The drug delivery system of  claim 15 , further comprising water. 
   
   
       17 . The drug delivery system of  claim 15 , wherein the nanosuspension comprises up to about 10% w/v of Pluronic F108 and up to about 10% w/v of Tween 80. 
   
   
       18 . The drug delivery system of  claim 17 , wherein the percent w/v of the Pluronic F108 and of the Tween 80 is about 5% w/v or about 1% w/v. 
   
   
       19 . The drug delivery system of  claim 15 , wherein the methyl 5-benzoylbenzimidazole-2-carbamate comprises the nanosuspension at any concentration up to about 200 mg/ml. 
   
   
       20 . The drug delivery system of  claim 15 , wherein the particles comprising the nanosuspension have substantially the same sizes or have a combination of sizes. 
   
   
       21 . The drug delivery system of  claim 15 , wherein a particle size range is about 100 nm to about 2000 nm. 
   
   
       22 . A method for increasing the bioavailability of a benzimidazole derivative in a tissue for treatment of a pathophysiological condition in a subject, comprising:
 formulating a nanosuspension of particles comprising the drug delivery system of  claim 1  such that the particles have a range of sizes wherein retention of the benzimidazole derivative within the particles increases as the particle size increases; and   administering the nanosuspension to the subject such that release of the benzimidazole derivative from the particles into the tissue is continuous and sustained over a range of time as determined by the particle sizes.   
   
   
       23 . The drug delivery system of  claim 22 , wherein the sizes range from about 5 nm to about 2000 nm. 
   
   
       24 . The method of  claim 22 , wherein the pathophysiological condition is a cancer. 
   
   
       25 . The method of  claim 22 , wherein the nanosuspension is administered parenterally. 
   
   
       26 . A method for treating a cancer a subject in need thereof, comprising:
 administering the nanosuspension comprising the drug delivery system of claim to the subject wherein release of the benzimidazole derivative from particles comprising the nanosuspension into a cancerous tissue provides a prolonged therapeutic effect thereby treating the same.   
   
   
       27 . The method of  claim 26 , further comprising:
 formulating the particles comprising the nanosuspension with a range of sizes such that retention of the benzimidazole derivative within the particles increases as the particle size increases, thereby increasing the bioavailability thereof to the tissue.   
   
   
       28 . The method of  claim 26 , wherein the sizes range from about 5 nm to about 2000 nm. 
   
   
       29 . The method of  claim 26 , wherein the nanosuspension is administered parenterally. 
   
   
       30 . A method for defining a nanosuspension of a benzimidazole derivative as having maximum therapeutic efficacy for a treatment regimen of a tissue in a subject, comprising:
 adjusting and/or selecting sizes of particles of the benzimidazole derivative comprising the nanosuspension of  claim 1  based on pharmacokinetic parameters of the benzimidazole derivative in the tissue to be treated; wherein the adjusted particle sizes(s) are effective together to maximize the therapeutic efficacy during treatment, said nanosuspension defined thereby.   
   
   
       31 . The method of  claim 30 , further comprising:
 formulating the nanosuspension with the selected particle diameters; and   parenterally administering the formulation to the individual.   
   
   
       32 . The method of  claim 30 , wherein the pharmacokinetic parameters are one or more of concentration, retention, bioavailability, biodistribution, or toxicity of the benzimidazole derivative in the tissue. 
   
   
       33 . The method of  claim 30 , wherein particle sizes range from about 5 nm to about 2000 nm.