SAHA Form I Polymorph Oral Bioavailability
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Solution Overview
Problem
Current treatments for cancer, particularly solid tumors, are often ineffective and toxic, with existing histone deacetylase inhibitors requiring continuous intravenous administration due to poor pharmacokinetic profiles, limiting their therapeutic effectiveness.
Innovation Solution
Development of a Form I polymorph of suberoylanilide hydroxamic acid (SAHA) with specific X-ray diffraction and Differential Scanning Calorimetry characteristics, formulated with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, which allows for oral administration and sustained high blood levels of the active compound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If continuous intravenous administration is used to maintain therapeutic blood levels of HDAC inhibitors, then therapeutic effectiveness is improved, but treatment complexity and patient burden increase
Solution Approach 1:
The patent applies parameter changes by developing a specific polymorph form (Form I) of SAHA with distinct crystallographic properties that enables oral bioavailability. This changes the physical-chemical parameters of the drug formulation, allowing it to be administered orally rather than requiring intravenous injection, thereby reducing treatment complexity while maintaining therapeutic effectiveness through sustained blood levels
Solution Approach 2:
The patent uses an oral formulation with specific excipients (microcrystalline cellulose, croscarmellose sodium, magnesium stearate) as intermediaries to deliver the active compound SAHA. This formulation acts as a mediator that enables the drug to be administered orally while achieving the same therapeutic blood levels that previously required intravenous administration
2Ease of operation
If oral formulation is developed to reduce administration complexity, then ease of operation is improved, but bioavailability and sustained blood levels may be compromised
Solution Approach 1:
The patent changes the physical parameters of SAHA by crystallizing it in a specific polymorph form (Form I) with space group P212121 and specific unit cell dimensions. This parameter change in crystal structure dramatically improves oral bioavailability and enables sustained blood levels, making the oral formulation as reliable as intravenous administration
3Reliability
If higher doses are administered to achieve therapeutic blood levels, then therapeutic effectiveness is improved, but toxicity increases
Solution Approach 1:
The patent achieves continuous therapeutic action by formulating SAHA in a polymorph form that provides sustained release and maintenance of blood levels over extended periods. This continuous action allows for lower individual doses to be administered less frequently, reducing peak-to-trough fluctuations and minimizing toxicity while maintaining therapeutic effectiveness
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 formulation provides a safe, daily dosing regimen with high oral bioavailability, maintaining therapeutically effective plasma concentrations of SAHA for extended periods, reducing toxicity and improving treatment efficacy by selectively inducing terminal differentiation and apoptosis of neoplastic cells.
Implementation Method 1
characterized by an X-ray diffraction pattern substantially similar to that set forth in FIG. 13A
Implementation Method 2
X-ray diffraction pattern including characteristic peaks at about 9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0, and 43.3 degrees 2θ
Implementation Method 3
characterized by a Differential Scanning Calorimetry (DSC) thermogram having a single maximum value at about 164.4±2.0
Data Source
AI summary
The present invention provides methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylase (HDAC) by administration of pharmaceutical compositions comprising potent HDAC inhibitors. The oral bioavailability of the active compounds in the pharmaceutical compositions of the present invention is surprisingly high. Moreover, the pharmaceutical compositions unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo. The present invention also provides a novel Form I polymorph of SAHA, characterized by a unique X-ray diffraction pattern and Differential Scanning Calorimetry profile, as well a unique crystalline structure.