Dry Powder Formulations for Messenger RNA
AssigneeTranslate Bio, Inc.
InventorsFrank DeRosa, Michael Heartlein, Shrirang Karve, Zarna Patel, Ashish Sarode
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Abstract
The present invention provides stable, dry powder messenger RNA formulations for therapeutic use, and methods of making and using the same.
Claims96
A dry powder formulation for delivery of cystic fibrosis conductance regulator (CFTR) messenger RNA (mRNA) comprising a plurality of spray-dried particles comprising
- mRNA encoding a CFTR protein;
- one or more lipids, and
- one or more polymers.
The dry powder formulation of any one of the preceding claims, wherein the CFTR mRNA has an integrity of 90% or greater.
The dry powder formulation of any one of the preceding claims, wherein the mRNA maintains an integrity of 90% or greater upon storage at or under room temperature for 6 months or longer.
The dry powder formulation of any one of the preceding claims, wherein at least 20% of the plurality of spray-dried particles are fine particles.
The dry powder formulation of any one of the preceding claims, wherein the dry powder formulation is inhalable.
The dry powder formulation of any one of the preceding claims, wherein the one or more polymers constitute at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the combined weight of the lipids and polymers.
The dry powder formulation of any one of the preceding claims, wherein the one or more polymers constitute about 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, 15-20%, 15-25%, 15-30%, 15-35%, 15-40%, 15-45%, 15-50%, 15-55%, 15-60%, 15-65%, 15-70%, 15-75%, 15-80%, or 15-90% of the combined weight of the lipids and polymers.
The dry powder formulation of any one of the preceding claims, wherein the one or more polymers constitute no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20% of the combined weight of the lipids and polymers.
The dry powder formulation of any one of the preceding claims, wherein the one or more polymers constitute are selected from a group consisting of chitosan, poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(q-caprolactone (PCL), poly amido amines, polyesters, polycarbonates, poly(hydroxyalkyl L-asparagine), poly(hydroxyalkyl L-glutamine), poly(2-alkyloxazoline) acrylates, modified acrylates and polymethacrylate based polymers, poly-N-(2-hydroxyl-propyl)methacryl amide, poly-2-(methacryloyloxy)ethyl phosphorylcholines, poly(2-(methacryloyloxy)ethyl phosphorylcholine), and poly(dimethylaminoethyl methylacrylate) (pDMAEMA).
The dry powder formulation of any one of the preceding claims, wherein the one or more polymers comprise a polymethacrylate based polymer.
The dry powder formulation of any one of the preceding claims, wherein the one or more polymers comprise Eudragit EPO.
The dry powder formulation of any one of the preceding claims, wherein the one or more lipids comprise a cationic lipid.
The dry powder formulation of any one of the preceding claims, wherein the one or more lipids comprise a PEG-modified lipid.
The dry powder formulation of any one of the preceding claims, wherein the one or more lipids do not comprise a neutral lipid or a cholesterol-based lipid.
The dry powder formulation of any one of the preceding claims, wherein the one or more lipids further comprise a neutral lipid or a cholesterol-based lipid.
The dry powder formulation of any one of the preceding claims, wherein the one or more lipids further comprise a neutral lipid.
The dry powder formulation of any one of the preceding claims, further comprising at least one sugar selected from the group consisting of monosaccharides, disaccharides, polysaccharides, glucose, fructose, galactose, mannose, sorbose, lactose, sucrose, cellobiose, trehalose, raffinose, starch, dextran, maltodextrin, cyclodextrins, inulin, xylitol, sorbitol, lactitol, and mannitol.
The dry powder formulation of any one of the preceding claims, further comprising a pharmaceutically acceptable excipient selected from the group consisting of esters, urethanes, phosphoesters, phosphazenes, amino acids, collagen, chitosan, polysaccharides, albumin, surfactants, buffers, salts, and combinations thereof.
The dry powder formulation of any one of the preceding claims, wherein the CFTR mRNA constitutes about 1-20%, 1-15%, 1-10%, 1-8%, 1-6%, 1-5%, 5-15%, or 5-10% of the total weight of the spray-dried particles.
The dry powder formulation of any one of the preceding claims, wherein the CFTR mRNA constitutes about 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, 12.5%, or 15% of the total weight of the spray-dried particles.
A method of delivering cystic fibrosis conductance regulator (CFTR) messenger RNA (mRNA) for in vivo expression comprising a step of administering to a subject in need thereof the dry powder formulation of any one of the preceding claims.
A dry powder formulation for delivery of messenger RNA (mRNA) comprising a plurality of spray-dried particles comprising
- mRNA encoding a protein or a peptide;
- one or more lipids, and
- one or more polymers.
A dry powder formulation for delivery of messenger RNA (mRNA) comprising a plurality of spray-dried particles comprising
- a. one or more lipid nanoparticles (LNPs) encapsulating mRNA encoding a peptide or polypeptide, and
- b. one or more polymers.
A dry powder formulation for delivery of messenger RNA (mRNA) comprising a plurality of spray-dried particles comprising one or more nanoparticles encapsulating mRNA encoding a peptide or polypeptide, the nanoparticles comprising
- a. one or more lipids, and
- b. one or more polymers.
A method for manufacturing a dry powder formulation, the method comprising:
- providing a mixture comprising an mRNA, one or more lipids and a polymer;
- and
- spray-drying the mixture to form a plurality of particles.
Dependencies are inferred from the claim text.