Alvimopan Metal Salt Formulation for Parenteral Solubility
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Solution Overview
Problem
Formulating solid pharmaceuticals for parenteral administration is challenging due to low solubility issues, particularly with zwitterionic compounds like alvimopan, which can cause anaphylactic reactions with solubilizing surfactants and have stability and handling drawbacks in oil-in-water emulsions, and higher costs with complexing agents.
Innovation Solution
A composition comprising a pharmaceutically acceptable metal salt of alvimopan or related compounds, a bulking agent, a weak base, and water, with an initial pH adjusted to at least 10.5 and then adjusted to a final pH range of 9 to 11, to enhance solubility and bioavailability for oral or parenteral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If solubilizing surfactants are used to increase the solubility of the active ingredient, then the solubility is improved, but anaphylactic reactions may occur in susceptible patients
Solution Approach 1:
The patent removes harmful surfactants from the formulation entirely, replacing them with a pH adjustment approach using weak bases to achieve solubility enhancement without the risk of anaphylactic reactions
Solution Approach 2:
The patent changes the pH parameter of the formulation to enhance solubility, specifically adjusting to a pH range that optimizes dissolution of the active ingredient without requiring harmful surfactants
2Quantity of substance
If oil-in-water emulsions are used to improve solubility, then the active ingredient can be administered, but pain at the injection site, poor physical stability, potential for embolisms, and need for strict aseptic handling occur
Solution Approach 1:
The patent eliminates oil-in-water emulsion systems from the formulation, replacing them with a direct pH-adjusted aqueous solution that avoids all associated harms including injection site pain, instability, and embolism risks
Solution Approach 2:
The patent uses pH adjustment as the primary mechanism to achieve solubility enhancement, eliminating the need for emulsion systems and their associated stability and safety problems
3Quantity of substance
If complexing agents such as β-cyclodextrin are used to increase solubility, then the active ingredient solubility is improved, but cost increases and regulatory acceptance is limited
Solution Approach 1:
The patent removes complexing agents like β-cyclodextrin from the formulation, replacing them with a simple pH adjustment approach using weak bases that reduces cost and improves regulatory acceptance
Solution Approach 2:
The patent uses pH parameter adjustment as a cost-effective and regulatorily acceptable method to enhance solubility, avoiding the need for expensive complexing agents
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method improves solubility and bioavailability of alvimopan, reducing the need for solubilizing surfactants and stabilizing agents, while minimizing side effects and costs, making it suitable for injectable formulations.
Implementation Method 1
A composition comprising a pharmaceutically acceptable metal salt of alvimopan or related compounds, a bulking agent, a weak base, and water, with an initial pH adjusted to at least 10.5 and then adjusted to a final pH range of 9 to 11
Data Source
AI summary
Compositions containing opioid antagonists, particularly alvimopan and its active metabolite, with improved solubility and bioavailability for oral or parenteral administration, injectable dosage formulations, kits, and methods of making and using same are disclosed. In preferred embodiments, invention provides injectable formulations containing opioid antagonists, particularly alvimopan and its active metabolite, having low solubility that may be readily prepared, are stable during storage, and provide maximum levels of opioid antagonists when administered parenterally, particularly via injection. The results are achieved by a combination of processing techniques and component selection.