Long Acting Injectable Formulations

Abstract

The invention relates to extended-release formulations comprising: (i) a poorly water-soluble active pharmaceutical ingredient; and (ii) a non-aqueous liquid vehicle comprising (a) a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24 fatty acid, or (b) a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide, or (c) a combination of (a) and (b), and (iii) an amphiphilic agent wherein the active pharmaceutical ingredient is dispersed as discrete particles having a D 90 particle size of about 0.5 μm to about 25 μm in the formulation, and wherein the formulation is non-gelling and thixotropic with a viscosity of less than 10 poise at a shear rate of 10/s at 25° C.

1 . A long acting injectable formulation comprising:
 (i) about 1% to about 50% of a poorly water-soluble active pharmaceutical ingredient;   (ii) about 40% to about 99% of a non-aqueous liquid vehicle comprising: (a) a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid, (b) a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide; or a combination of (a) and (b); and   (iii) about 0.1% to about 50% of an amphiphilic agent,   wherein the active pharmaceutical ingredient is dispersed as discrete particles having a D 90  particle size of about 0.5 μm to about 25 μm in the formulation, and   wherein the formulation is non-gelling and thixotropic with a viscosity of less than 10 poise at a shear rate of 10/s at 25° C.   
     
     
         2 . The long acting injectable formulation of  claim 1 , wherein the non-aqueous liquid vehicle comprises a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid. 
     
     
         3 . The long acting injectable formulation of  claim 2 , wherein the hydrophobic lipid is a glyceryl ester of a C 12 -C 18  fatty acid. 
     
     
         4 . The long acting injectable formulation of  claim 1 , wherein the hydrophobic lipid is selected from the group consisting of castor oil, cottonseed oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, coconut oil, palm seed oil, and combinations thereof. 
     
     
         5 . The long acting injectable formulation of  claim 1 , wherein the vehicle comprises a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide. 
     
     
         6 . The long acting injectable formulation of  claim 1 , wherein the hydrophilic organic compound is polyethylene glycol or propylene glycol. 
     
     
         7 . The long acting injectable formulation of  claim 1  any one of  claims 1  to  6 , wherein the active pharmaceutical ingredient is (i) an anti-psychotic drug selected from the group consisting of a free base, salt or ester of lurasidone, aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, risperidone, and ziprasidone, (ii) an analgesic drug selected from the group consisting of the free acid, salt or ester of celecoxib, naproxen, diclofenac, ketoprofen, and meloxicam, (iii) the free acid, salt, or ester of meloxicam, (iv) the free acid, salt, or ester of celecoxib, (v) an antiviral drug selected from the group of the poorly soluble salt or ester of adefovir, entecavir, or lamivudine, (vi) the poorly soluble salt or ester of adefovir, (vii) the poorly soluble salt or ester of entecavir or (viii) the poorly soluble salt or ester of lamivudine, (ix) an antibiotic drug selected from the group consisting of cefditoren and cefpodixime, (x) the free acid, salt or ester of cefditoren, (xi) the free acid, salt or ester of cefpodixime, (xii) a drug for the treatment of Alzheimer's disease selected from the group consisting of free base, poorly soluble salt, or amide of donepezil, galantamine, rivastigmine, and memantine. 
     
     
         8 . The long acting injectable formulation of  claim 7 , wherein the active pharmaceutical ingredient is a free base or salt of lurasidone. 
     
     
         9 - 22 . (canceled) 
     
     
         23 . The long acting injectable formulation of  claim 1 , wherein the active pharmaceutical ingredient has a D 90  particle size of about 0.5 μm to about 15 μm. 
     
     
         24 . The long acting injectable formulation of  claim 1 , wherein the active pharmaceutical ingredient has a D 90  particle size of about 0.5 μm to about 10 μm. 
     
     
         25 . The long acting injectable formulation of  claim 1 , wherein the active pharmaceutical ingredient has a D 50  particle size of about 0.3 μm to about 15 μm. 
     
     
         26 . (canceled) 
     
     
         27 . The long acting injectable formulation of  claim 1 , wherein the active pharmaceutical ingredient has a D 50  particle size of about 0.3 μm to about 5 μm. 
     
     
         28 . The long acting injectable formulation of  claim 1 , wherein the amphiphilic agent is selected from the group consisting of ethanol, benzyl alcohol, N-methyl-2-pyrrolidone, dimethylacetamide, sorbitan esters, polyethoxylated sorbitan esters, fatty alcohol ethoxylates, fatty acid ethoxylates, castor oil based ethoxylates, polyoxyethylene-polyoxypropylene block copolymers, and combinations thereof. 
     
     
         29 . The long acting injectable formulation of  claim 1 , wherein the amphiphilic agent is Vitamin E TPGS. 
     
     
         30 . The long acting injectable formulation of  claim 1 , wherein the vehicle further comprises a preservative selected from the group consisting of benzyl alcohol, butylated hydroxyltoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, methylparaben, propylparaben, tocopherols, and combinations thereof. 
     
     
         31 . The long acting injectable formulation of  claim 1 , wherein the formulation has a viscosity of about 0.5 to about 50 poise at a shear rate of 1/s at 25° C. 
     
     
         32 . (canceled) 
     
     
         33 . The long acting injectable formulation of  claim 1 , wherein the formulation has a viscosity of about 0.5 to about 4 poise at 100/s shear rate at 25° C. 
     
     
         34 . A long acting injectable formulation comprising:
 (i) about 1% to 50% lurasidone as free base or salt;   (ii) about 40% to about 99% of vehicle comprising a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid, and   (iii) about 0.5% to 50% of an amphiphilic agent,   wherein the lurasidone is dispersed as discrete particles having a D 90  particle size of about 0.5 μm to about 25 μm in the vehicle, and   wherein the formulation is non-gelling and thixotropic with a viscosity of less than 10 poise at a shear rate of 10/s at 25° C.   
     
     
         35 - 42 . (canceled) 
     
     
         43 . A process for preparing a long acting injectable formulation, comprising:
 (i) mixing an amphiphilic agent with a non-aqueous liquid vehicle comprising (a) a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid, (b) a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide, or a combination of (a) and (b);   (ii) dispersing a poorly water-soluble active pharmaceutical ingredient in the mixture of (i) and mixing to form a dispersion; and   (iii) milling the dispersion of (ii) to achieve an active pharmaceutical ingredient having a D 90  particle size of about 0.5 μm to about 25 μm to obtain the long acting injectable formulation.   
     
     
         44 - 45 . (canceled) 
     
     
         46 . A process for preparing a long acting injectable formulation, comprising:
 (i) mixing an amphiphilic agent with a non-aqueous liquid vehicle comprising (a) a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid, (b) a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide, or a combination of (a) and (b); and   (ii) dispersing a poorly water-soluble active pharmaceutical ingredient having a D 90  particle size of about 0.5 μm to about 25 μm in the mixture of (i) and mixing to form a uniform dispersion to obtain the long acting injectable formulation.   
     
     
         47 - 48 . (canceled) 
     
     
         49 . An injectable pharmaceutical dosage form, comprising (i) the formulation of any  claim 1 , and (ii) a pre-filled syringe or vial. 
     
     
         50 . A method of administering a poorly soluble active pharmaceutical ingredient to a subject, the method comprising administering intramuscularly or subcutaneously the formulation of  claim 1 . 
     
     
         51 . The method of  claim 50 , wherein the formulation is administered once a week. 
     
     
         52 . The method of  claim 50 , wherein the formulation is administered once a month. 
     
     
         53 . The method of  claim 50 , wherein the formulation is administered once every three months. 
     
     
         54 . (canceled) 
     
     
         55 . A method of treating a psychotic disorder, the method comprising administering intramuscularly or subcutaneously the formulation of  claim 7  (i). 
     
     
         56 - 59 . (canceled) 
     
     
         60 . A long acting injectable formulation comprising:
 (i) about 1% to about 50% of a poorly water-soluble active pharmaceutical ingredient;   (ii) about 40% to about 99% of a non-aqueous liquid vehicle comprising: (a) a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid, (b) a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide; or a combination of (a) and (b); and   (iii) about 0.5% to about 50% of an amphiphilic agent,   wherein the active pharmaceutical ingredient is dispersed as discrete particles having a D 90  particle size of about 0.5 μm to about 25 μm in the formulation, and   wherein the formulation is non-gelling and thixotropic with a viscosity of less than 10 poise at a shear rate of 10/s at 25° C.   wherein administration of said dosage form to a subject increases the ratio of AUC/C max  by at least 5-times that of regular release dosage form.   
     
     
         61 . A long acting injectable formulation comprising:
 (i) about 1% to about 50% of a poorly water-soluble active pharmaceutical ingredient;   (ii) about 40% to about 99% of a non-aqueous liquid vehicle comprising: (a) a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid, (b) a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide; or a combination of (a) and (b); and   (iii) about 0.5% to about 50% of an amphiphilic agent,   wherein the active pharmaceutical ingredient is dispersed as discrete particles having a D 90  particle size of about 0.5 μm to about 25 μm in the formulation, and   wherein the formulation is non-gelling and thixotropic with a viscosity of less than 10 poise at a shear rate of 10/s at 25° C.   wherein administration of said dosage form to a subject increases the half-life by at least 5-times that of regular release dosage form.   
     
     
         62 . A long acting injectable formulation comprising:
 (i) about 1% to about 50% of a poorly water-soluble active pharmaceutical ingredient;   (ii) about 40% to about 99% of a non-aqueous liquid vehicle comprising: (a) a hydrophobic lipid comprising a glyceryl ester of a C 6 -C 24  fatty acid, (b) a hydrophilic organic compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, and dimethylsulfoxide; or a combination of (a) and (b); and   (iii) about 0.5% to about 50% of an amphiphilic agent,   wherein the active pharmaceutical ingredient is dispersed as discrete particles having a D 90  particle size of about 0.5 μm to about 25 μm in the formulation, and   wherein the formulation is non-gelling and thixotropic with a viscosity of less than 10 poise at a shear rate of 10/s at 25° C.   wherein administration of said dosage form to a subject increases the MRT by at least 5-times that of regular release dosage form.