Amorphous AMG 706 Solid-State Formulation for Rapid Dissolution
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Solution Overview
Problem
AMG 706, a therapeutic agent for angiogenesis-mediated disorders, faces challenges in formulation as a rapid-onset oral dosage form due to low solubility in aqueous media, leading to slow drug absorption and bioavailability issues.
Innovation Solution
Development of an amorphous form of AMG 706 with the use of crystallization inhibitors to create a stable amorphous drug substance that enhances bioavailability through rapid dissolution, utilizing processes like spray drying and lyophilization, and forming composites with polymers to maintain the amorphous state.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If crystalline form of AMG 706 is used, then manufacturing stability is maintained, but dissolution rate and bioavailability are reduced
Solution Approach 1:
The patent changes the physical state parameter of AMG 706 from crystalline to amorphous form. This parameter change enables the drug to achieve rapid dissolution and enhanced bioavailability while maintaining compositional stability through controlled amorphous structure, directly resolving the contradiction between dissolution rate and structural stability
Solution Approach 2:
The patent creates a composite system by combining amorphous AMG 706 with specific excipients and formulation components. This composite approach allows the amorphous drug substance to maintain its high dissolution rate while the formulation matrix provides structural stability and prevents premature crystallization, solving the contradiction between productivity and stability
2Reliability
If amorphous form of AMG 706 is used, then bioavailability and dissolution rate are improved, but manufacturing complexity increases
Solution Approach 1:
The patent utilizes parameter changes in the formulation process, specifically controlling temperature, humidity, and processing conditions to transform and maintain AMG 706 in amorphous form. By optimizing these parameters, the patent achieves high bioavailability while managing manufacturing complexity through controlled process conditions
Solution Approach 2:
The patent introduces intermediary substances and formulation components that facilitate the creation and stabilization of amorphous AMG 706. These intermediaries act as carriers or stabilizing agents that simplify the manufacturing process by providing a framework for maintaining the amorphous state, thus improving bioavailability without proportionally increasing complexity
3Loss of time
If rapid-onset oral dosage form is prepared, then therapeutic response time is reduced, but solubility requirements are not met
Solution Approach 1:
The patent changes the physical state of AMG 706 to amorphous form, which fundamentally alters its solubility parameters. This parameter change enables the drug to achieve rapid dissolution in aqueous media, meeting the solubility requirements for rapid-onset oral dosage forms and reducing therapeutic response time
Solution Approach 2:
The patent utilizes phase transition principles by controlling the transformation between crystalline and amorphous states of AMG 706. By maintaining the drug in the amorphous phase, the patent achieves rapid dissolution and fast therapeutic response while satisfying aqueous solubility requirements, directly addressing the contradiction between response time and solubility
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 amorphous form of AMG 706 exhibits increased bioavailability, faster therapeutic onset, and improved solubility, achieving higher maximum blood serum concentration and shorter time to reach that maximum, addressing the limitations of crystalline forms.
Implementation Method 1
AMG 706 presents certain challenges for formulation as a rapid-onset dosage form, particularly as a rapid-onset oral dosage form. For example, AMG 706 has low solubility in aqueous media and therefore may not have rapid absorption
Implementation Method 2
utilizing processes like spray drying and lyophilization
Implementation Method 3
spray drying
Implementation Method 4
lyophilization
Implementation Method 5
utilizing processes like spray drying and lyophilization
Implementation Method 6
lyophilization
Implementation Method 7
Development of an amorphous form of AMG 706 with the use of crystallization inhibitors to create a stable amorphous drug substance
Data Source
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AI summary
The present invention relates to the compound AMG 706, of formula (I) and in particular to solid-state forms of that drug, to pharmaceutical compositions comprising such solid-state forms, and to processes for preparing them.