Pharmaceutical compositions
Inventors
Sharma, Shubh • Van Der Ploeg, Leonardus H. T. • Henderson, Bart
Assignees
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Publication Number
US-11129869-B2
Publication Date
2021-09-28
Expiration Date
Abstract
The present invention relates to an ionic complex comprising a cationic polypeptide and an anionic excipient selected from: a PEG-carboxylic acid; a fatty acid having 10 or more carbon atoms; an anionic phospholipid; and a combination thereof. The invention also relates to a pharmaceutical composition comprising the ionic complex of the invention and a pharmaceutically acceptable carrier. The cationic polypeptide of the ionic complex has pharmacological activity and the complex can provide a more desirable pharmacokinetic profile for the cationic polypeptide of the complex as compared to the cationic polypeptide alone following administration. As such, the invention also relates to the use of the ionic complex and pharmaceutical composition comprising same to treat a subject suffering from a disease or disorder that is responsive to the cationic polypeptide of the ionic complex.
Core Innovation
The invention relates to an ionic complex comprising a cationic polypeptide represented by a structural formula, methoxy(polyethylene glycol 2,000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG-2,000-DSPE), and carboxymethylcellulose (CMC). The ionic complex is defined by a molar ratio of the cationic peptide to the mPEG-2,000-DSPE between 1:3 to 1:6. In some embodiments, the ionic complex includes D-mannitol in addition to the cationic polypeptide, mPEG-2,000-DSPE, and CMC.
The document describes cyclic cationic polypeptides evaluated for MC receptor binding and cAMP signaling, including MC1R, MC3R, MC4R, and MC5R. It provides peptide testing rationale based on radioligand binding with reported Kd/IC50-type displacement behavior and downstream cAMP measurement, including EC50 results, across MC receptor subtypes. This establishes that the described cationic cyclic polypeptides are evaluated for MC receptor binding and functional cAMP responses.
The invention also ties the ionic complex composition to a functional drug-delivery behavior by specifying that the ionic complex forms a drug depot in a physiological environment or when delivered subcutaneously. The document further describes ionic-complex/pharmaceutical formulations that include Peptide 1 with anionic excipients such as CMC and an anionic phospholipid component, and provides examples of ionic complex compositions and formulation components, including optional D-mannitol.
Claims Coverage
The independent claims define an ionic complex built from a cationic polypeptide, mPEG-2,000-DSPE, and CMC with a cationic peptide:mPEG-2,000-DSPE molar ratio constraint. The claim set also includes a depot-formation property for certain variants and a constrained consisting essentially of making process. Overall, the claims cover four inventive features.
Ionic complex with specified peptide-to-mPEG-2,000-dsPE ratio
An ionic complex comprising a cationic polypeptide represented by the structural formula, methoxy(polyethylene glycol 2,000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG-2,000-DSPE), and carboxymethylcellulose (CMC), wherein the molar ratio of the cationic peptide to the mPEG-2,000-DSPE is between 1:3 to 1:6.
Drug depot forming ionic complex
An ionic complex comprising a cationic polypeptide represented by the structural formula, mPEG-2,000-DSPE, and CMC, wherein the molar ratio is between 1:3 to 1:6, and wherein the ionic complex forms a drug depot in a physiological environment or when delivered subcutaneously.
Ionic complex made by mixing mPEG-2,000-dsPE with CMC and adding the cationic polypeptide
An ionic complex comprising a cationic polypeptide represented by the structural formula, mPEG-2,000-DSPE, and CMC, wherein the molar ratio is between 1:3 to 1:6, and the ionic complex is made in a process consisting essentially of preparing a mixture of mPEG-2,000-DSPE and CMC in an aqueous solution; and adding the cationic polypeptide to the mixture.
Ionic complex including d-mannitol
An ionic complex comprising a cationic polypeptide represented by the structural formula, mPEG-2,000-DSPE, CMC, and D-mannitol, wherein the molar ratio of the cationic peptide to the mPEG-2,000-DSPE is between 1:3 to 1:6.
The claims center on an ionic complex comprising a cationic polypeptide, mPEG-2,000-DSPE, and CMC with a defined molar ratio range, optionally including D-mannitol. Some claims further require drug depot formation in a physiological environment or upon subcutaneous delivery, and one claim limits the process of making the complex by mixing and addition.
Stated Advantages
Improves pharmacokinetics, including sustained/extended release versus the polypeptide alone.
Can form a drug depot upon injection.
Potential improved selectivity/potency for MC4R/MC3R and reduced side effects.
Documented Applications
Treatment of diseases/conditions responsive to MC4R modulation, including type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, inflammation, anxiety, and male erectile dysfunction.
Drug-delivery context in which the ionic complex forms a drug depot in a physiological environment or when delivered subcutaneously.
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