Alprostadil Concentrate Solvent System for PAD Infusion
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Solution Overview
Problem
Current alprostadil preparations for treating peripheral arterial disease (PAD) face challenges with intra-arterial administration due to the instability of alprostadil and the use of cyclodextrins, which can cause local intolerance and nephrotoxicity, limiting their effectiveness and safety, especially in advanced stages of PAD.
Innovation Solution
A liquid pharmaceutical composition of alprostadil dissolved in a pharmaceutically acceptable organic solvent or solvent mixture with water, optimized for intra-arterial infusion, which enhances local tolerability and stability, avoiding cyclodextrins and minimizing ethanol content to reduce vascular and renal toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If alprostadil is administered intra-arterially to achieve high local concentration for effective PAD treatment, then therapeutic effectiveness is improved, but local intolerance and nephrotoxicity increase due to cyclodextrin excipients
Solution Approach 1:
The patent removes cyclodextrin excipients from the alprostadil formulation, extracting the harmful component while retaining the therapeutic active ingredient. This is achieved by using alternative solvents such as ethanol, propylene glycol, or polyethylene glycol to dissolve alprostadil without requiring cyclodextrins, thereby eliminating nephrotoxicity and local intolerance associated with cyclodextrin administration
Solution Approach 2:
The patent changes the chemical parameters of the formulation by substituting cyclodextrin-based solubilization with alternative solvent systems. This involves modifying the solvent composition (e.g., using ethanol/water mixtures or propylene glycol) to achieve adequate alprostadil solubility and stability without the harmful cyclodextrin excipients, thereby maintaining therapeutic effectiveness while reducing toxicity
2Stability of the object's composition
If alprostadil is stabilized using cyclodextrins to improve shelf life and stability, then storage stability is improved, but vascular and renal toxicity increase
Solution Approach 1:
The patent extracts and removes cyclodextrin excipients from the formulation, eliminating the source of vascular and renal toxicity while maintaining alprostadil stability through alternative solvent systems that do not require cyclodextrin inclusion complexes
Solution Approach 2:
The patent employs composite solvent systems (e.g., ethanol/water mixtures, propylene glycol/water combinations, or polyethylene glycol formulations) to achieve both stability and safety. These composite materials provide the necessary solubility and stability for alprostadil without the toxic effects of cyclodextrins
3Object-affected harmful factors
If ethanol content is reduced in the formulation to minimize toxicity, then safety is improved, but alprostadil stability and solubility may be compromised
Solution Approach 1:
The patent modifies the solvent composition parameters by introducing alternative solvents with different chemical properties (propylene glycol, polyethylene glycol, or ethanol/water mixtures) that provide adequate solubility and stability for alprostadil at lower ethanol concentrations, thereby maintaining stability while reducing toxicity
Solution Approach 2:
The patent uses composite solvent formulations combining multiple components (e.g., ethanol with water, or propylene glycol with polyethylene glycol) to achieve synergistic effects that maintain alprostadil stability and solubility while minimizing the concentration of any single potentially toxic component, particularly ethanol
Data Source
AI summary
The invention relates to a liquid pharmaceutical composition in the form of a concentrate for preparing an infusion solution, containing, in particular consisting of alprostadil (prostaglandin E1) as an active substance, dissolved in a pharmaceutically acceptable organic solvent or in a solvent mixture made from at least one pharmaceutically acceptable organic solvent and water, for the use in the treatment of the peripheral arterial disease (pAVK) by means of intra-arterieller (i.a) infusion.