Long acting injectable formulations
Inventors
Ahmed, Salah U. • Zu, Yanming • LePREE, Jason • PRAJAPATI, Hetalben • Chowdhury, Tahseen A.
Assignees
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Publication Number
US-11596628-B2
Publication Date
2023-03-07
Expiration Date
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 C6-C24 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 D90 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.
Core Innovation
The invention relates to extended-release non-aqueous long acting injectable formulations comprising a poorly water-soluble active pharmaceutical ingredient dispersed as discrete particles. The formulation uses a non-aqueous liquid vehicle in which lurasidone is dispersed as discrete particles having a D90 particle size of about 0.5 μm to about 25 μm, and the lurasidone is present as a free base or salt.
The formulation includes a hydrophobic lipid vehicle comprising a glyceryl ester of a C6-C24 fatty acid and an amphiphilic agent selected from a defined group. The non-aqueous composition is characterized as non-gelling and thixotropic, with a viscosity of less than 10 poise at a shear rate of 10/s at 25°C and a viscosity greater than 15 poise at a shear rate of less than or equal to about 0.1/s at 25°C.
The document emphasizes that in vivo release of the lurasidone is extended over a period of greater than about 1 week. It further reports that administration of the dosage form increases pharmacokinetic exposure metrics compared with immediate release, including increased half-life, AUC/Cmax-related measures, and MRT.
Claims Coverage
The independent claims define a non-aqueous long acting injectable formulation for lurasidone with discrete particle dispersion, a specified non-aqueous lipid vehicle composition, a selected amphiphilic agent, defined particle size, non-gelling and thixotropic rheology with viscosity thresholds, and extended in vivo release. Across the independent claims, performance requirements further require at least 5-times increases in AUC/Cmax, half-life, or MRT versus immediate release dosage forms.
Non-aqueous long acting injectable formulation with lurasidone discrete particles and defined rheology
A non-aqueous long acting injectable formulation comprising lurasidone as free base or salt; a non-aqueous liquid vehicle comprising a hydrophobic lipid comprising a glyceryl ester of a C6-C24 fatty acid; and an amphiphilic agent selected from the group consisting of ethanol, benzyl alcohol, benzyl benzoate, N-methyl-2-pyrrolidone, dimethylacetamide, sorbitan esters, polyethoxylated sorbitan esters, fatty alcohol ethoxylates, fatty acid ethoxylates, polyoxyethylene polyoxypropylene block copolymers, and combinations thereof, wherein the lurasidone is dispersed as discrete particles having a D90 particle size of about 0.5 μm to about 25 μm 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 and a viscosity of greater than 15 poise at a shear rate of less than or equal to about 0.1/s at 25°C, and wherein in vivo release of the lurasidone is extended over a period of greater than about 1 week.
Non-aqueous long acting injectable formulation with AUC/Cmax increase requirement
A non-aqueous long acting injectable formulation comprising lurasidone as free base or salt; a non-aqueous liquid vehicle comprising a hydrophobic lipid comprising a glyceryl ester of a C6-C24 fatty acid; and an amphiphilic agent selected from the group consisting of ethanol, benzyl alcohol, benzyl benzoate, N-methyl-2-pyrrolidone, dimethylacetamide, sorbitan esters, polyethoxylated sorbitan esters, fatty alcohol ethoxylates, fatty acid ethoxylates, polyoxyethylene polyoxypropylene block copolymers, and combinations thereof, wherein the lurasidone is dispersed as discrete particles having a D90 particle size of about 0.5 μm to about 25 μm, wherein administration of said dosage form to a subject increases the ratio of AUC/Cmax by at least 5-times that of immediate release dosage form, and wherein in vivo release of the lurasidone is extended over a period of greater than about 1 week.
Non-aqueous long acting injectable formulation with half-life increase requirement
A non-aqueous long acting injectable formulation comprising lurasidone as free base or salt; a non-aqueous liquid vehicle comprising a hydrophobic lipid comprising a glyceryl ester of a C6-C24 fatty acid; and an amphiphilic agent selected from the group consisting of ethanol, benzyl alcohol, benzyl benzoate, N-methyl-2-pyrrolidone, dimethylacetamide, sorbitan esters, polyethoxylated sorbitan esters, fatty alcohol ethoxylates, fatty acid ethoxylates, polyoxyethylene polyoxypropylene block copolymers, and combinations thereof, wherein the lurasidone is dispersed as discrete particles having a D90 particle size of about 0.5 μm to about 25 μm, and wherein administration of said dosage form to a subject increases the half-life by at least 5-times that of immediate release dosage form, and wherein in vivo release of the lurasidone active is extended over a period of greater than about 1 week.
Non-aqueous long acting injectable formulation with MRT increase requirement
A non-aqueous long acting injectable formulation comprising lurasidone as free base or salt; a non-aqueous liquid vehicle comprising a hydrophobic lipid comprising a glyceryl ester of a C6-C24 fatty acid; and an amphiphilic agent selected from the group consisting of ethanol, benzyl alcohol, benzyl benzoate, N-methyl-2-pyrrolidone, dimethylacetamide, sorbitan esters, polyethoxylated sorbitan esters, fatty alcohol ethoxylates, fatty acid ethoxylates, polyoxyethylene polyoxypropylene block copolymers, and combinations thereof, wherein the lurasidone is dispersed as discrete particles having a D90 particle size of about 0.5 μm to about 25 μm, wherein the formulation is non-aqueous, non-gelling and thixotropic with a viscosity of less than 10 poise at a shear rate of 10/s at 25°C and a viscosity of greater than 15 poise at a shear rate of less than or equal to about 0.1/s at 25°C, wherein administration of said dosage form to a subject increases the MRT by at least 5-times that of immediate release dosage form, and wherein in vivo release of the lurasidone is extended over a period of greater than about 1 week.
Across the independent claims, the coverage centers on a non-aqueous long acting injectable formulation of lurasidone where lurasidone is dispersed as discrete particles in a non-aqueous lipid vehicle comprising a glyceryl ester of a C6-C24 fatty acid and an amphiphilic agent selected from a defined list. The formulation is required to be non-gelling and thixotropic with viscosity thresholds at specified shear-rate conditions, and to extend in vivo release beyond about 1 week. Dependent performance requirements further require at least 5-times increases in AUC/Cmax, half-life, or MRT versus immediate release dosage forms.
Stated Advantages
The formulation is non-gelling and thixotropic.
The formulation provides in vivo release extended over a period of greater than about 1 week.
Administration increases the ratio of AUC/Cmax by at least 5-times compared to immediate release dosage form.
Administration increases the half-life by at least 5-times compared to immediate release dosage form.
Administration increases the MRT by at least 5-times compared to immediate release dosage form.
Improved stability versus aqueous systems.
Documented Applications
Administration of the non-aqueous long acting injectable formulation to a subject, including dosing comparisons to an immediate release dosage form.
In vivo pharmacokinetic evaluation in rats for lurasidone suspensions versus solution, reporting pharmacokinetic parameter changes.
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