HIGH CONCENTRATION FORMULATIONS
Low-viscosity, high concentration nucleic acid compositions that can be administered by multiple parenteral routes may allow for less frequent dosing than nucleic acid products currently on the market. In particular, low-viscosity defibrotide formulations for subcutaneous, intramuscular, and intraperitoneal administration are more convenient to the patient and/or are administered outside of the hospital setting. Formulations of the invention may be used for the treatment of numerous conditions including for example, treatment of peripheral arteriopathies, treatment of acute renal insufficiency, treatment of acute myocardial ischemia, and treatment and prevention of sinusoidal obstruction syndrome or VOD.
1 - 74 . (canceled)
75 . A pharmaceutical formulation comprising about 80 to about 100 mg/mL of defibrotide, and about 10 to about 40 mM sodium citrate, and wherein the formulation is formulated for subcutaneous delivery to a patient.
76 . The pharmaceutical formulation of claim 75 , wherein the formulation when administered subcutaneously demonstrates extended systemic half-life compared to the same defibrotide formulation administered intravenously.
77 . The pharmaceutical formulation of claim 75 , wherein the formulation exhibits lower peak-to-trough ratios of plasma concentrations compared to the same defibrotide formulation administered intravenously.
78 . The pharmaceutical formulation of claim 75 , wherein the formulation exhibits improved efficacy and/or an improved safety profile compared to the same defibrotide formulation administered intravenously.
79 . The pharmaceutical formulation of claim 75 , that is packaged for self-administration by a patient.
80 . The pharmaceutical formulation of claim 75 , wherein the formulation comprises about 34 mM sodium citrate.
81 . The pharmaceutical formulation of claim 75 , wherein the formulation comprises about 80 mg/mL defibrotide.
82 . The pharmaceutical formulation of claim 75 , wherein the formulation comprises about 80 mg/mL defibrotide and about 34 mM sodium citrate.
83 . A device for subcutaneous administration of a formulation of claim 75 .
84 . The device of claim 83 , wherein the formulation comprises about 80 mg/mL defibrotide and about 34 mM sodium citrate.
85 . A method of treating or preventing a disease or condition comprising administering to a patient the formulation of claim 75 , wherein the disease or condition is selected from thrombosis, Hematopoietic Stem Cell Transplantation (HSCT) related complications including sinusoidal obstruction syndrome or hepatic vaso-occlusive disease (VOD), Graft versus Host Disease (GvHD), Transplant-Associated Thrombotic Microangiopathy (TA-TMA) or Idiopathic Pneumonia Syndrome, other TMAs including Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS), Acute Myocardial Ischemia, Ischemic Stroke, Ischemia Reperfusion Injury, cytokine release syndrome (CRS) or Chimeric Antigen Receptor (CAR)-T Cell Related Encephalopathy Syndrome (CRES), Acute Respiratory Distress Syndrome (ARDS), Sickle Cell Vaso-occlusive Crisis (VOC), Sickle Cell Related Acute Chest Syndrome, Disseminated Intravascular Coagulation (DIC), Sepsis, Renal Insufficiency, other Coronary or Peripheral Artery Diseases, Hematological Malignancies or Solid Tumors.
86 . The method of claim 85 , wherein the formulation is administered at a dosing regimen that provides improved patient quality of life by requiring a reduced administration volume and/or allowing less-frequent administration and/or a shorter duration of administration.
87 . The method of claim 85 , wherein the formulation is self-administered by the patient using a device for subcutaneous administration.
88 . The method of claim 87 , wherein the formulation comprises about 80 mg/mL defibrotide and about 34 mM sodium citrate.
89 . A method of treating or preventing Acute Respiratory Distress Syndrome comprising administering to a patient a pharmaceutical formulation comprising about 80 to about 100 mg/mL of defibrotide.
90 . The method of claim 89 , wherein the formulation comprises about 80 mg/mL defibrotide.
91 . The method of claim 89 , wherein the formulation comprises about 10 to about 40 mM sodium citrate.
92 . The pharmaceutical formulation of claim 91 , wherein the formulation comprises about 80 mg/mL defibrotide and about 34 mM sodium citrate.