Low-Viscosity Defibrotide Formulations for Outpatient Dosing
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Solution Overview
Problem
Current defibrotide administration methods, particularly for hepatic veno-occlusive disease and other conditions, are inconvenient for patients due to the need for frequent intravenous infusions and large volumes, making outpatient dosing challenging.
Innovation Solution
Development of low-viscosity, high-concentration nucleic acid formulations of defibrotide that can be administered via various routes, including subcutaneous, intravenous, and oral, allowing for reduced dosing frequency and duration, and enabling self-administration through compatible devices.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If defibrotide is administered via traditional intravenous infusion, then the therapeutic effect is achieved, but the dosing frequency is high and the liquid volume is large, making outpatient dosing inconvenient
Solution Approach 1:
The patent changes the concentration parameter of defibrotide formulation from traditional low concentration to high concentration (at least 50 mg/mL, preferably 100-400 mg/mL). This parameter change reduces the liquid volume required for dosing while maintaining therapeutic efficacy, enabling convenient outpatient and self-administration
2Quantity of substance
If defibrotide concentration is increased, then the liquid volume for dosing is reduced, but the viscosity increases making administration difficult
Solution Approach 1:
The patent optimizes multiple formulation parameters simultaneously: uses specific buffers (phosphate, citrate, acetate, TRIS, HEPES, MES, or amino acid buffers at pH 5-9), controls ionic strength (0.1-1.0 M), and adjusts temperature (20-40°C during administration). These parameter changes enable high concentration formulations to maintain low viscosity (<100 cP, preferably <50 cP) for easy administration
3Loss of time
If defibrotide is administered via intravenous infusion, then the therapeutic effect is achieved, but the dosing duration is long (2-hour infusions), increasing time burden on patients and hospitals
Solution Approach 1:
The patent formulates high concentration defibrotide solutions that can be administered via subcutaneous injection or rapid intravenous infusion. The high concentration allows the same therapeutic dose to be delivered in smaller volumes and shorter times, reducing dosing duration from 2 hours to much shorter periods and enabling less frequent dosing regimens
Data Source
AI summary
Low-viscosity nucleic acid compositions that can be administered by oral or 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, intradermal, 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.