# US 8,785,168 B2 · Formulations for lysosomal enzymes > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,168 B2 - Document ID: US8785168B2 - Status: Granted - Kind: B2 - Application number: 13/378,745 - Filed: 2010-06-17 - Published: 2012-06-14 - Granted: 2014-07-22 - Earliest claimed: 2009-06-17 - Assignees: Biomarin Pharmaceutical Inc. - Applicants: Jonathan LeBowitz; Byeong Chang - Inventors: Jonathan LeBowitz; Byeong Chang - Web page: https://patentgrep.com/patent/US8785168B2 ## CPC - A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} - A61K 38/30: Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 {(insulin-like growth factor binding protein A61K38/1754)} - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) - A61P 21/00: Drugs for disorders of the muscular or neuromuscular system - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention provides improved formulations for lysosomal enzymes useful for enzyme replacement therapy. Among other things, the present invention provides formulations that preserve or enhance the stability and/or efficacy of a lysosomal enzyme such as acid alpha-glucosidase. ## Claims ### Claim 1 A pharmaceutical composition for treating Pompe disease comprising a recombinant human acid alpha-glucosidase (GAA) in a formulation comprising: a) a buffering agent selected from the group consisting of histidine, sodium acetate, citrate, phosphate, succinate, Tris and combinations thereof; b) a stabilizing agent selected from the group consisting of sucrose, arginine, sorbitol, mannitol, glycine, trehalose and combinations thereof; c) a tonicity modifier selected from the group consisting of glycine, sorbitol, sucrose, mannitol, sodium chloride, dextrose, arginine and combinations thereof; d) a bulking agent selected from the group consisting of sucrose, mannitol, glycine, sodium chloride, dextran, trehalose and combinations thereof; and e) a poloxamer, wherein the poloxamer is Pluronic® F-68 at a concentration ranging between 0.001% and 0.2%, wherein the pH ranges from approximately 4.0 to 7.0. ### Claim 2 (depends on 1) The pharmaceutical composition of claim 1, wherein the pH is approximately 6.0. ### Claim 3 (depends on 1) The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in a form suitable for parenteral administration. ### Claim 4 (depends on 1) The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a lyophilized mixture. ### Claim 5 (depends on 1) The pharmaceutical composition of claim 1, wherein the recombinant human GAA is produced from CHO cells. ### Claim 6 (depends on 1) The pharmaceutical composition of claim 1, wherein the recombinant human GAA has modified glycosylation levels as compared to naturally-occurring human GAA. ### Claim 7 (depends on 6) The pharmaceutical composition of claim 6, wherein the recombinant human GAA contains increased mannose-6-phosphates as compared to naturally-occurring human GAA. ### Claim 8 (depends on 1) The pharmaceutical composition of claim 1, wherein the recombinant human GAA is a fusion protein comprising recombinant human GAA and a lysosomal targeting peptide having an amino acid sequence having at least 70% identity to the amino acid sequence of mature human IGF-II (SEQ ID NO:1), wherein the fusion protein comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 2. ### Claim 9 (depends on 8) The pharmaceutical composition of claim 8, wherein the lysosomal targeting peptide is an IGF-II mutein and comprises a mutation within a region corresponding to amino acids 34-40 of SEQ ID NO:1 such that the mutation abolishes at least one furin protease cleavage site. ### Claim 10 (depends on 8) The pharmaceutical composition of claim 8, wherein the lysosomal targeting peptide is an IGF-II mutein that has diminished binding affinity for the IGF-I receptor relative to the affinity of naturally-occurring human IGF-II for the IGF-I receptor and/or has diminished binding affinity for the insulin receptor relative to the affinity of naturally-occurring human IGF-II for the insulin receptor. ### Claim 11 (depends on 8) The pharmaceutical composition of claim 8, wherein the fusion protein comprises the amino acid sequence set forth in SEQ ID NO:2. ### Claim 12 (depends on 1) The pharmaceutical composition of claim 1, wherein the recombinant human GAA is in a formulation containing approximately 50 mM citrate, 4% mannitol, 1% trehalose, and 0.1% Pluronic® F-68 at a pH of approximately 6.0. ### Claim 13 A pharmaceutical composition comprising a lyophilized mixture of a recombinant human acid alpha-glucosidase (GAA), sodium citrate, mannitol, trehalose, and Pluronic® F-68. ### Claim 14 (depends on 13) The pharmaceutical composition of claim 13, wherein the recombinant human GAA is produced from CHO cells. ### Claim 15 (depends on 13) The pharmaceutical composition of claim 13, wherein the recombinant human GAA has modified glycosylation levels as compared to naturally-occurring human GAA. ### Claim 16 (depends on 13) The pharmaceutical composition of claim 13, wherein the recombinant human GAA contains increased mannose-6-phosphates as compared to naturally-occurring human GAA. ### Claim 17 (depends on 13) The pharmaceutical composition of claim 13, wherein the recombinant human GAA is a fusion protein comprising recombinant human GAA and a lysosomal targeting peptide having an amino acid sequence having at least 70% identity to the amino acid sequence of mature human IGF-II (SEQ ID NO:1), wherein the fusion protein comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 2. ### Claim 18 (depends on 17) The pharmaceutical composition of claim 17, wherein the lysosomal targeting peptide is an IGF-II mutein and comprises a mutation within a region corresponding to amino acids 34-40 of SEQ ID NO:1 such that the mutation abolishes at least one furin protease cleavage site. ### Claim 19 (depends on 17) The pharmaceutical composition of claim 17, wherein the lysosomal targeting peptide is an IGF-II mutein that has diminished binding affinity for the IGF-I receptor relative to the affinity of naturally-occurring human IGF-II for the IGF-I receptor and/or has diminished binding affinity for the insulin receptor relative to the affinity of naturally-occurring human IGF-II for the insulin receptor. ### Claim 20 (depends on 17) The pharmaceutical composition of claim 17, wherein the fusion protein comprises the amino acid sequence set forth in SEQ ID NO:2. ### Claim 21 (depends on 12) A method of treating Pompe disease comprising administering to a subject in need of treatment the pharmaceutical composition of claim 12.