Recombinant VWF formulations

{
  "publication_number": "US11191837B2",
  "country": "US",
  "kind": "B2",
  "title": "Recombinant VWF formulations",
  "abstract": "The present invention provides long-term stable pharmaceutical formulations of recombinant von-Willebrand Factor (rVWF) and methods for making and administering said formulations.",
  "claims": [
    "1. A stable liquid pharmaceutical formulation of a recombinant von Willebrand Factor (rVWF) comprising: (a) a rVWF; (b) a buffer; (c) one or more salts; (d) optionally a stabilizing agent; and (e) optionally a surfactant; wherein said rVWF causes agglutination of stabilized platelets in the presence of ristocetin; wherein said rVWF comprises a polypeptide selected from the group consisting of: a) the amino acid sequence set out in SEQ ID NO: 3; b) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by the polynucleotide set out in SEQ ID NO: 1; and c) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by a polynucleotide that hybridizes to the polynucleotide set out in SEQ ID NO: 1 under moderately stringent hybridization conditions; wherein said buffer comprises sodium citrate at a concentration of 15 mM and a pH range of 6.5 to 7.3; wherein said one or more salts are calcium chloride at a concentration of 10 mM and sodium chloride at a concentration of 0.5 mM to 100 mM; wherein said stabilizing agent is at a concentration of 0.1 to 1000 mM and is selected from the group consisting of mannitol, sorbitol, xylitol, sucrose, trehalose, mannose, maltose, lactose, glucose, raffinose, cellobiose, gentiobiose, isomaltose, arabinose, glucosamine, fructose, and combinations of these stabilizing agents; and wherein said surfactant is at a concentration of 0.01 g/L to 0.5 g/L.",
    "2. The formulation of claim 1 wherein the rVWF comprises the amino acid sequence set out in SEQ ID NO: 3.",
    "3. The formulation of claim 1 wherein the pH is 7.0.",
    "4. The formulation of claim 1 wherein the rVWF comprises the amino acid sequence set out in SEQ ID NO: 3; and wherein the pH is 7.0.",
    "5. The formulation of claim 1 wherein the rVWF comprises the amino acid sequence set out in SEQ ID NO: 3; wherein the pH is 7.0; and wherein the sodium chloride is at a concentration of 100 mM.",
    "6. The formulation of claim 1 wherein the sodium chloride is at a concentration of 30 mM.",
    "7. The formulation of claim 1 wherein the stabilizing agents are trehalose at a concentration of 7.8 mM and mannitol at a concentration of 58.6 mM.",
    "8. The formulation of claim 1 wherein the surfactant is selected from the group consisting of digitonin, Triton X-100, Triton X-114, TWEEN-20, TWEEN-80 and combinations of these surfactants.",
    "9. The formulation of claim 1 wherein the surfactant is TWEEN-80 at 0.03 g/L.",
    "10. A stable liquid pharmaceutical formulation of a recombinant von Willebrand Factor (rVWF) comprising: (a) a rVWF; (b) a buffer; (c) one or more salts; (d) optionally a stabilizing agent; and (e) optionally a surfactant; wherein the rVWF causes agglutination of stabilized platelets in the presence of ristocetin; wherein said rVWF comprises a polypeptide selected from the group consisting of: a) the amino acid sequence set out in SEQ ID NO: 3; b) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by the polynucleotide set out in SEQ ID NO: 1; and c) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by a polynucleotide that hybridizes to the polynucleotide set out in SEQ ID NO: 1 under moderately stringent hybridization conditions; wherein said buffer comprises sodium citrate at a concentration of 15 mM and a pH range of 6.5 to 7.3; wherein said one or more salts are calcium chloride at a concentration of 10 mM and sodium chloride at a concentration of 0.5 mM to 100 mM; wherein said stabilizing agent is at a concentration of 0.1 to 1000 mM; and wherein said surfactant is at a concentration of 0.01 g/L to 0.5 g/L.",
    "11. A stable liquid pharmaceutical formulation of a recombinant von Willebrand Factor (rVWF) comprising: (a) a rVWF; (b) a buffer; and (c) one or more salts; wherein the rVWF causes agglutination of stabilized platelets in the presence of ristocetin; wherein said rVWF comprises a polypeptide selected from the group consisting of: a) the amino acid sequence set out in SEQ ID NO: 3; b) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by the polynucleotide set out in SEQ ID NO: 1; and c) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by a polynucleotide that hybridizes to the polynucleotide set out in SEQ ID NO: 1 under moderately stringent hybridization conditions; wherein said buffer comprises sodium citrate at a concentration of 15 mM and a pH range of 6.5 to 7.3; wherein said one or more salts are calcium chloride at a concentration of 10 mM and sodium chloride at a concentration of 100 mM.",
    "12. A stable liquid pharmaceutical formulation of a recombinant von Willebrand Factor (rVWF) comprising: (a) a rVWF; (b) a buffer; and (c) one or more salts; wherein the rVWF causes agglutination of stabilized platelets in the presence of ristocetin; wherein said rVWF comprises a polypeptide selected from the group consisting of: a) the amino acid sequence set out in SEQ ID NO: 3; b) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by the polynucleotide set out in SEQ ID NO: 1; and c) a polypeptide having the amino acid sequence set out in SEQ ID NO: 3 and encoded by a polynucleotide that hybridizes to the polynucleotide set out in SEQ ID NO: 1 under moderately stringent hybridization conditions; wherein said buffer comprises sodium citrate at a concentration of 15 mM and a pH of 7.0; wherein said one or more salts are calcium chloride at a concentration of 10 mM and sodium chloride at a concentration of 100 mM."
  ],
  "description_excerpt": "This application claims priority of U.S. Provisional Application No. 61/017,418, filed Dec. 28, 2007, and U.S. Provisional Application No. 61/017,881 filed Dec. 31, 2007, each of which is incorporated by reference herein in its entirety.\n\nGenerally, the invention relates to formulations of recombinant VWF and methods for making a composition comprising recombinant VWF.\n\nVon Willebrand factor (VWF) is a glycoprotein circulating in plasma as a series of multimers ranging in size from about 500 to 20,000 kD. Multimeric forms of VWF are composed of 250 kD polypeptide subunits linked together by disulfide bonds. VWF mediates initial platelet adhesion to the sub-endothelium of the damaged vessel wall. Only the larger multimers exhibit hemostatic activity. It is assumed that endothelial cells secrete large polymeric forms of VWF and those forms of VWF which have a low molecular weight (low molecular weight VWF) arise from proteolytic cleavage. The multimers having large molecular masses are stored in the Weibel-Pallade bodies of endothelial cells and liberated upon stimulation.\n\nVWF is synthesized by endothelial cells and megakaryocytes as prepro-VWF that consists to a large extent of repeated domains. Upon cleavage of the signal peptide, pro-VWF dimerizes through disulfide linkages at its C-terminal region. The dimers serve as protomers for multimerization, which is governed by disulfide linkages between the free end termini. The assembly to multimers is followed by the proteolytic removal of the propeptide sequence (Leyte et al., Biochem. J. 274 (1991), 257-261).",
  "cpc": [
    "A61K 47/26",
    "A61K 38/1709",
    "A61K 38/36",
    "A61K 38/37",
    "A61K 47/02",
    "A61K 47/10",
    "A61K 47/12",
    "A61K 47/18",
    "A61K 47/20",
    "A61K 47/22",
    "A61K 47/36",
    "A61K 9/0019",
    "A61K 9/08",
    "A61P 7/04"
  ],
  "ipc": [
    "A61K 38/17",
    "A61K 47/02",
    "A61K 47/10",
    "A61K 47/12",
    "A61K 47/18",
    "A61K 47/20",
    "A61K 47/22",
    "A61K 47/26",
    "A61K 38/36",
    "A61K 9/00",
    "A61K 9/08"
  ],
  "assignees": [
    "Takeda Pharmaceutical Co Ltd"
  ],
  "inventors": [
    "Peter Matthiessen",
    "Peter Turecek",
    "Hans-Peter Schwarz",
    "Kurt Schnecker"
  ],
  "filing_date": "2015-04-22",
  "publication_date": "2021-12-07",
  "grant_date": "2021-12-07",
  "priority_date": "2007-12-28",
  "application_number": "US-201514693078-A",
  "family_id": "40591819",
  "cited_by_count": 9,
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