Somatostatin receptor agonist formulations
Inventors
NISTOR, Catalin • Johnsson, Markus • Tiberg, Fredrik
Assignees
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Publication Number
US-11672843-B2
Publication Date
2023-06-13
Expiration Date
Abstract
The present invention relates to compositions forming a low viscosity mixture of: a) 20-50 wt. % of at least one diacyl glycerol; b) 20-54 wt. % of at least one phosphatidyl choline (PC); c) 5-15 wt. % of at least one biocompatible, organic mono-alcoholic solvent; d) 1 to 20 wt. % polar solvent e) 5 to 150 mg/ml of at least one peptide somatostatin receptor agonist comprising pasireotide; f) optionally at least one antioxidant; wherein the ratio of components a:b is in the range 40:60 to 54:46; wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid. The invention further relates to methods of treatment comprising administration of such compositions, and to pre-filled administration devices and kits containing the formulations.
Core Innovation
The invention relates to a low viscosity lipid pre-formulation depot-precursor comprising diacyl glycerol and phosphatidyl choline (PC), an organic mono-alcohol solvent (ethanol), and a polar solvent (propylene glycol), together with about 30 mg/ml of a peptide somatostatin receptor agonist consisting of pasireotide pamoate calculated as the free base. The pre-formulation is configured such that the ratio of diacyl glycerol to PC is approximately 50:50 and the ethanol and propylene glycol are present in an approximately equal amount. The pre-formulation has a viscosity of 1–1000 mPas at 20°C.
The pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid. In certain embodiments the liquid crystalline phase structure is specified as an L2 phase structure. This phase formation provides a liquid crystalline depot-precursor that transitions in situ when exposed to aqueous body fluids.
A process for forming the low viscosity pre-formulation is also disclosed, where a low viscosity mixture is formed from the specified diacyl glycerol, PC, ethanol, propylene glycol, and pasireotide pamoate (calculated as the free base), with the option of dissolving or dispersing the peptide in the mixture or in one or more of its components prior to forming the low viscosity mixture. The process yields a pre-formulation having a viscosity of 1–1000 mPas at 20°C.
Claims Coverage
The partial claim set contains two independent claims. Both claims focus on a low-viscosity mixture composition for a peptide somatostatin receptor agonist, with one claim directed to the pre-formulation itself and the other directed to a process for forming that pre-formulation.
Low viscosity pre-formulation with liquid crystalline phase formation
A low viscosity mixture comprising diacyl glycerol, phosphatidyl choline (PC), ethanol, propylene glycol, and about 30 mg/ml of a peptide somatostatin receptor agonist consisting of pasireotide pamoate calculated as the free base; wherein the ratio of diacyl glycerol to PC is approximately 50:50; wherein ethanol and propylene glycol are present in an approximately equal amount; wherein the pre-formulation has a viscosity of 1–1000 mPas at 20°C; and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid.
Process for forming a low viscosity pre-formulation for administration
A process comprising forming a low viscosity mixture comprising diacyl glycerol, phosphatidyl choline (PC), ethanol, propylene glycol, and about 30 mg/ml of a peptide somatostatin receptor agonist consisting of pasireotide pamoate calculated as the free base; wherein the ratio of diacyl glycerol to PC is approximately 50:50; wherein ethanol and propylene glycol are present in an approximately equal amount; and dissolving or dispersing at least one peptide somatostatin receptor agonist in the low viscosity mixture, or in one or more of its components prior to forming the low viscosity mixture; wherein the pre-formulation formed has a viscosity of 1–1000 mPas at 20°C.
Across the independent claims, coverage centers on a specified low-viscosity mixture containing diacyl glycerol, PC, ethanol, propylene glycol, and pasireotide pamoate (as free base), requiring approximately equal ethanol and propylene glycol amounts and an approximately 50:50 diacyl glycerol:PC ratio, with a viscosity of 1–1000 mPas at 20°C, and capability to form a liquid crystalline phase structure upon contact with excess aqueous fluid.
Stated Advantages
Easier/narrow-needle injectability compared with polymer depots.
Allows sterile filtration.
High drug loading.
Non-burst or flat pharmacokinetic (PK) profile.
Improved stability.
Documented Applications
Administration to a subject of a peptide somatostatin receptor agonist, with the pre-formulation suitable for administration.
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