Cepharanthine Salt Polymorphs for Filovirus Solubility
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Solution Overview
Problem
Current therapies for filovirus infections, such as those caused by Ebolavirus, lack effectiveness due to the limited solubility of medicinal alkaloids like Cepharanthine and Tetrandrine in their free base forms, hindering their development as oral therapeutics or alternative administration routes.
Innovation Solution
The preparation of pharmaceutically acceptable salt forms of Cepharanthine and Tetrandrine with improved solubility, specifically the Cepharanthine dihydrochloride (Cepharanthine.2HCl) salt, which is recrystallized to form a mixture of polymorphs and combined with a polymer in a water-soluble organic solvent to create an enteric formulation with an amorphous liquid crystal form, enhancing solubility and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the free base form of Cepharanthine or Tetrandrine is used, then the medicinal activity is maintained, but the solubility is very limited (≤1 mg/mL)
Solution Approach 1:
The patent applies parameter changes by converting the free base form of the alkaloids into salt forms (e.g., hydrochloride salts). This chemical modification changes the physical and chemical parameters of the compound, specifically improving water solubility from ≤1 mg/mL to significantly higher levels, thereby enabling diverse routes of administration including oral, IV, IP, and IM.
Solution Approach 2:
The patent creates composite material systems by formulating the alkaloid salt forms into various pharmaceutical formulations including enteric-coated tablets, capsules, and liquid preparations. These composite formulations combine the active ingredient with excipients, coatings, and other materials to achieve both improved solubility and appropriate delivery characteristics for different administration routes.
2Ease of manufacture
If the free base form is used, then the medicinal properties are preserved, but the development as oral therapeutics is hindered
Solution Approach 1:
By changing the chemical form from free base to salt (parameter change), the patent enables oral therapeutic development. The salt form exhibits significantly improved solubility and stability characteristics that are essential for oral formulation development, while maintaining the medicinal activity of the parent compound.
3Quantity of substance
If salt forms are prepared to improve solubility, then the solubility increases, but the complexity of formulation increases
Solution Approach 1:
The patent simplifies the overall formulation complexity by making a fundamental parameter change - converting to salt forms - which inherently provides improved solubility. This eliminates the need for complex solubilization techniques such as micellar systems, liposomes, or complex co-solvent systems that would otherwise be required for the free base form.
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 improved solubility and bioavailability of the salt forms enable more efficient drug delivery and treatment of filovirus infections, including Ebola and Marburg viruses, through enhanced absorption and distribution in the body.
Implementation Method 1
The preparation of pharmaceutically acceptable salt forms of Cepharanthine and Tetrandrine with improved solubility, specifically the Cepharanthine dihydrochloride (Cepharanthine.2HCl) salt, which is recrystallized to form a mixture of polymorphs
Implementation Method 2
combined with a polymer in a water-soluble organic solvent to create an enteric formulation with an amorphous liquid crystal form, enhancing solubility and bioavailability
Data Source
AI summary
The present disclosure relates to the preparation of polymorphic mixtures of Cepharanthine.2HCl. Mixtures of at least two polymorphic forms can be formed into a mobile liquid phase in organic/aqueous solvent mixtures along with enteric polymer that can be spray dried to produce solid particulate enteric formulations for medicinal drug-treatment applications.