HIGHLY CONCENTRATED DRUG PARTICLES, FORMULATIONS, SUSPENSIONS AND USES THEREOF
Highly concentrated drug particle formulations are described, wherein the drug comprises between about 25 wt % and 80 wt % of the particle formulation. The particle formulations of the present invention comprise, for example, macromolecules, such as proteins and/or small molecules (such as steroid hormones). The particle formulation typically further includes one or more additional component, for example, one or more stabilizer (e.g., carbohydrates, antioxidants, amino acids, and buffers). Such concentrated particle formulations can be combined with a suspension vehicle to form suspension formulations. The suspension formulation comprises (i) a non-aqueous, single-phase vehicle, comprising one or more polymer and one or more one solvent, wherein the vehicle exhibits viscous fluid characteristics, and (ii) a highly concentrated drug particle formulation. Devices for delivering the suspension formulations and methods of use are also described. The present invention provides needed improvements in drug formulation and delivery to improve patient compliance and expand drug availability.
1 . A method comprising:
assessing stability of exenatide obtained from an exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle;
the exenatide particle formulation comprising,
25 wt % to 80 wt % exenatide; and
75 wt % to 20 wt % of one or more additional components, wherein the additional components comprise an antioxidant, a carbohydrate, and a buffer; and
the non-aqueous, single-phase suspension vehicle comprising one or more polymer and one or more solvent;
wherein
the exenatide is assessed to comprise less than 0.5% exenatide aggregates upon storage of the exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle for up to 6 months at 25-40° C.
2 . A method comprising:
assessing purity of exenatide obtained from an exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle;
the exenatide particle formulation comprising,
25 wt % to 80 wt % exenatide; and
75 wt % to 20 wt % of one or more additional components, wherein the additional components comprise an antioxidant, a carbohydrate, and a buffer; and
the non-aqueous, single-phase suspension vehicle comprising one or more polymer and one or more solvent;
wherein
the exenatide is assessed to comprise less than 0.5% exenatide aggregates upon storage of the exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle for up to 6 months at 25-40° C.
3 . The method of claim 1 , wherein a detected level of less than 0.5% exenatide aggregates identifies a stable exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle.
4 . The method of claim 2 , wherein a detected level of less than 0.5% exenatide aggregates identifies a pure exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle.
5 . The method of claim 1 , wherein the exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle is obtained from a reservoir of an implantable osmotic delivery device.
6 . The method of claim 5 , wherein the implantable osmotic delivery device provides a sustained in vitro release rate of exenatide of up to 80 μg/day for at least 100 days at 37° C.
7 . The method of claim 1 , further comprising precipitating exenatide from the exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle, prior to assessing.
8 . The method of claim 7 , further comprising combining an extraction solvent with the exenatide particle formulation suspended in a non-aqueous, single-phase suspension vehicle to precipitate the exenatide.
9 . The method of claim 1 , wherein assessing stability of the exenatide comprises using one or more of Size Exclusion Chromatography or Reversed Phase High Performance Liquid Chromatography.
10 . The method of claim 1 , wherein the non-aqueous, single-phase suspension vehicle has a viscosity at 33° C. of about 8,000 to about 25,000 poise, and the exenatide particle formulation is homogeneously dispersed in the non-aqueous, single-phase suspension vehicle.
11 . The method of claim 1 , wherein exenatide particle formulation is a spray dried powder.
12 . The method of claim 1 , wherein the exenatide particle formulation comprises about 40 wt % to about 75 wt % exenatide and the one or more additional component comprises about 60 wt % to about 25 wt %.
13 . The method of claim 1 , wherein the antioxidant is selected from the group consisting of cysteine, methionine, and tryptophan.
14 . The method of claim 13 , wherein the antioxidant is methionine.
15 . The method of claim 1 , wherein the buffer is selected from the group consisting of citrate, histidine, succinate, and mixtures thereof.
16 . The method of claim 15 , wherein the buffer is a citrate.
17 . The method of claim 1 , wherein the carbohydrate is a disaccharide.
18 . The method of claim 1 , wherein the disaccharide is selected from the group consisting of lactose, sucrose, trehalose, cellobiose, and mixtures thereof.
19 . The method of claim 18 , wherein the disaccharide is sucrose.
20 . The method of claim 1 , wherein the antioxidant is methionine, the carbohydrate is sucrose, and the buffer is a citrate.
21 . The method of claim 1 , wherein the one or more polymer is a polymer comprising pyrrolidones.
22 . The method of claim 1 , wherein the one or more solvent is selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof.
23 . The method of claim 1 , wherein the suspension vehicle comprises benzyl benzoate and polyvinylpyrrolidone.
24 . The method of claim 1 , wherein the suspension vehicle is about 50% solvent and about 50% polymer.