ELP fusion proteins for controlled and sustained release
Inventors
Jowett, James • Ballance, David James
Assignees
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Publication Number
US-10722590-B2
Publication Date
2020-07-28
Expiration Date
Abstract
The present disclosure provides pharmaceutical formulations for sustained release, and methods for delivering a treatment regimen with a combination of sustained release and long half-life formulations. The pharmaceutical formulations comprise a therapeutic agent including an active agent and an amino acid sequence capable of forming a reversible matrix at the body temperature of a subject. The disclosure provides improved pharmacokinetics for peptide and small molecule drugs.
Core Innovation
The invention relates to a sustained release pharmaceutical formulation for systemic administration that includes a therapeutic agent comprising an active agent and at least 90 elastin-like peptide structural units of SEQ ID NO: 3. The ELP exhibits a transition temperature between 26°C and 37°C, and each Xaa is selected from V, G, and A, with the ratio of V:G:A selected from about 7:2:0, about 7:0:2, or about 6:0:3, together with one or more pharmaceutically acceptable excipients.
The sustained release behavior is attributed to the ELP forming a reversible hydrogen-bond/hydrophobic matrix at body temperature through intra- and inter-molecular hydrogen bonds and hydrophobic contributions/coacervation. At the transition temperature, the ELP undergoes an inverse phase transition to form the matrix, leading to slow depot-like absorption. The resulting exposure profile is described as having a long half-life and a flatter pharmacokinetic profile with lower peak-to-trough and prolonged Tmax, supporting infrequent dosing.
The disclosures also include ELP fusions and reversible-matrix formulations for systemic delivery of therapeutic agents such as GLP-1 receptor agonists, growth hormone, and exendin-4, including ELP fusion constructs and corresponding pharmacokinetic data in cynomolgus monkeys. The therapeutic agent may be a chemical conjugate formed between the active agent and ELP, and the formulation may be defined such that the therapeutic agent does not form a phase-transitioned matrix under storage conditions.
Claims Coverage
The provided claim set includes one independent claim directed to a sustained release pharmaceutical formulation for systemic administration, with seven inventive features refined by dependent claims.
Sustained release systemic formulation with SEQ ID NO: 3 ELP exhibiting a 26-37°C transition temperature
A sustained release pharmaceutical formulation comprising a therapeutic agent for systemic administration, wherein the therapeutic agent comprises an active agent and at least 90 elastin-like peptide structural units of SEQ ID NO: 3, the ELP exhibits a transition temperature between 26°C and 37°C, and the formulation includes one or more pharmaceutically acceptable excipients.
Xaa selection and constrained V:G:A ratio
The ELP of the therapeutic agent has each Xaa selected from V, G, and A, and the ratio of V:G:A is selected from about 7:2:0, about 7:0:2, or about 6:0:3.
Chemical conjugate of active agent and ELP
The therapeutic agent is a chemical conjugate formed between the active agent and ELP.
Therapeutic agent concentration range
The formulation has a therapeutic agent concentration ranging from about 0.5 mg/mL to about 200 mg/mL.
No phase-transitioned matrix under storage conditions
The formulation is defined such that the therapeutic agent does not form a phase-transitioned matrix under storage conditions.
Specific electrolyte and excipient ingredient set
The formulation includes two or more specified electrolyte and excipient ingredients comprising calcium chloride, magnesium chloride, potassium chloride, potassium phosphate monobasic, sodium chloride, polysorbate 20, sodium phosphate, sodium phosphate monobasic, and sodium phosphate dibasic.
Subcutaneous or intramuscular administration route
The formulation is administered subcutaneously or intramuscularly.
The inventive features center on a sustained release systemic formulation using a therapeutic agent containing an active agent and at least 90 ELP structural units of SEQ ID NO: 3 with a 26°C to 37°C transition temperature, constrained Xaa selection and V:G:A ratio. Dependent refinements include a chemical conjugate form, specific concentration, storage stability against phase-transitioned matrix formation, a specified electrolyte/excipient set, and subcutaneous or intramuscular administration.
Stated Advantages
The exposure profile has a long half-life and a flatter pharmacokinetic profile with lower peak-to-trough and prolonged Tmax, supporting infrequent dosing.
Documented Applications
Systemic delivery of therapeutic agents such as GLP-1 receptor agonists, growth hormone, and exendin-4.
ELP fusion constructs and corresponding pharmacokinetic data in cynomolgus monkeys.
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