US2019031730A1PendingUtilityA1

Formulation of mk2 inhibitor peptides

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Assignee: MOERAE MATRIX INCPriority: Jan 8, 2015Filed: Aug 21, 2018Published: Jan 31, 2019
Est. expiryJan 8, 2035(~8.5 yrs left)· nominal 20-yr term from priority
Inventors:Cynthia LanderColleen BrophyCaryn Peterson
A61P 43/00A61P 9/00A61K 9/0075A61K 47/02A61K 38/1709A61K 9/0019A61K 9/145A61K 47/32A61K 9/0078C07K 14/4703A61K 47/26A61K 38/00
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Claims

Abstract

The described invention provides pharmaceutical formulations comprising a polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof with improved stability and bioavailability.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A pharmaceutical formulation for delivery by inhalation comprising a therapeutic amount of an MK2i polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof, up to 5% w/w solids before drying, up to 7.3% glycerin, and a pharmaceutically acceptable carrier, wherein the formulation:
 (a) is isosmotic and non-buffered;   (b) has a stable pH of about 7.0 for at least 2 weeks at 60° C.; and   (c) is effective to preserve at least about 93% stability of physical, chemical, microbiological, therapeutic, and toxicological specifications of the MK2i polypeptide for at least 2 weeks at 60° C., and bioavailability of the MK2i polypeptide.   
     
     
         2 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation is a particulate pharmaceutical formulation. 
     
     
         3 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation is an aerosolized pharmaceutical formulation. 
     
     
         4 . The pharmaceutical formulation according to  claim 1 , wherein the formulation is prepared by a process of spray drying. 
     
     
         5 . The pharmaceutical formulation according to  claim 2 , wherein the pharmaceutical formulation comprises 1% w/w solids before drying. 
     
     
         6 . The pharmaceutical formulation according to  claim 2 , wherein the pharmaceutical formulation comprises 5% w/w solids before drying. 
     
     
         7 . The pharmaceutical formulation according to  claim 1  further comprising trehalose. 
     
     
         8 . The pharmaceutical formulation according to  claim 1 , wherein the functional equivalent is made from a fusion between a first polypeptide that is a protein transduction domain (PTD) and a second polypeptide that is a therapeutic domain (TD). 
     
     
         9 . The pharmaceutical formulation according to  claim 8 , wherein the protein transduction domain (PTD) is selected from the group consisting of a polypeptide of amino acid sequence YARAAARQARA (SEQ ID NO: 11), FAKLAARLYR (SEQ ID NO: 16), and KAFAKLAARLYR (SEQ ID NO: 17), and a second polypeptide that is a therapeutic domain (TD) of amino acid sequence KALARQLGVAA (SEQ ID NO: 2). 
     
     
         10 . The pharmaceutical formulation according to  claim 1 , wherein the pharmaceutical formulation is delivered to a subject via a dry powder inhalation device (DPI). 
     
     
         11 . The pharmaceutical formulation according to  claim 3  further comprising saline before drying. 
     
     
         12 . The pharmaceutical formulation according to  claim 11 , wherein the saline is NaCl. 
     
     
         13 . The pharmaceutical formulation according to  claim 12 , wherein the polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or the functional equivalent thereof is at a concentration of 0.7 mg/mL. 
     
     
         14 . The pharmaceutical formulation according to  claim 12 , wherein the polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or the functional equivalent thereof is at a concentration of 7.0 mg/mL. 
     
     
         15 . The pharmaceutical formulation according to  claim 3 , wherein the pharmaceutical formulation is formulated to be used via a nebulizer. 
     
     
         16 . The pharmaceutical formulation according to  claim 1 , comprising an ionic complex of the MK2i polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof and a nano-polyplex polymer, wherein the ionic complex dissociates in intracellular compartments selected by intracellular pH conditions such that bioactivity and stability of the peptide is preserved. 
     
     
         17 . The pharmaceutical formulation according to  claim 16 , wherein the nano-polyplex polymer is anionic and endosomolytic. 
     
     
         18 . The pharmaceutical formulation according to  claim 17 , wherein the nano-polyplex polymer is poly(propylacrylic acid) (PPAA). 
     
     
         19 . The pharmaceutical formulation according to  claim 16 , wherein the pharmaceutical formulation comprises a charge ratio (CR) of the MK2i polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof to PPAA selected from the group consisting of 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 and 1:10. 
     
     
         20 . The pharmaceutical formulation according to  claim 19 , wherein the charge ratio (CR) is 1:3. 
     
     
         21 . The pharmaceutical formulation according to  claim 16 , wherein the functional equivalent is made from a fusion between a first polypeptide that is a protein transduction domain (PTD) and a second polypeptide that is a therapeutic domain (TD). 
     
     
         22 . The pharmaceutical formulation according to  claim 21 , wherein the protein transduction domain (PTD) is selected from the group consisting of a polypeptide of amino acid sequence YARAAARQARA (SEQ ID NO: 11), FAKLAARLYR (SEQ ID NO: 16), and KAFAKLAARLYR (SEQ ID NO: 17), and a second polypeptide that is a therapeutic domain (TD) of amino acid sequence KALARQLGVAA (SEQ ID NO: 2). 
     
     
         23 . The pharmaceutical formulation according to  claim 16 , wherein the pharmaceutical formulation is delivered to a subject via an implantation device. 
     
     
         24 . The pharmaceutical formulation according to  claim 16 , wherein the pharmaceutical formulation is delivered to a subject topically. 
     
     
         25 . The pharmaceutical formulation according to  claim 16 , wherein the pharmaceutical formulation is delivered to a subject parenterally. 
     
     
         26 . A method for treating a vascular graft-induced intimal hyperplasia in a subject in need of such treatment, the method comprising administering the pharmaceutical formulation of  claim 16  comprising a therapeutic amount of a polypeptide of amino sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof, and a nano-polyplex polymer, wherein the therapeutic amount is effective to inhibit MK2; and to treat a vascular graft-induced intimal hyperplasia. 
     
     
         27 . The method according to  claim 26 , wherein the nano-polyplex polymer is anionic and endosomolytic. 
     
     
         28 . The method according to  claim 27 , wherein the nano-polyplex polymer is poly(propylacrylic acid) (PPAA). 
     
     
         29 . The method according to  claim 26 , wherein the pharmaceutical formulation comprises a charge ratio (CR) of the polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof to PPAA selected from the group consisting of 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 and 1:10. 
     
     
         30 . The method according to  claim 29 , wherein the charge ratio (CR) is 1:3. 
     
     
         31 . The method according to  claim 29 , wherein the nano-polyplex polymer is poly(acrylic acid) (PAA). 
     
     
         32 . The method according to  claim 26 , wherein the functional equivalent is made from a fusion between a first polypeptide that is a protein transduction domain (PTD) and a second polypeptide that is a therapeutic domain (TD). 
     
     
         33 . The method according to  claim 32 , wherein the protein transduction domain (PTD) is selected from the group consisting of a polypeptide of amino acid sequence YARAAARQARA (SEQ ID NO: 11), FAKLAARLYR (SEQ ID NO: 16), and KAFAKLAARLYR (SEQ ID NO: 17), and a second polypeptide that is a therapeutic domain (TD) of amino acid sequence KALARQLGVAA (SEQ ID NO: 2). 
     
     
         34 . The method according to  claim 26 , wherein the administering is by an implantation device. 
     
     
         35 . The method according to  claim 26 , wherein the administering is by topical administration. 
     
     
         36 . The method according to  claim 26 , wherein the administering is by parenteral administration.

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