Method for improving the bioavailability of low aqueous solubility drugs
Inventors
Karavas, Evangelos • Koutris, Efthimios • SAMARA, VASILIKI • Diakidou, Amalia • Papanikolaou, Georgia
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9561186-B2
Publication Date
2017-02-07
Expiration Date
Abstract
The present invention relates to the implementation of a new method for manufacturing solid dosage forms for oral administration comprising poorly water soluble active ingredients which overcomes the associated solubility problems and affords improved dissolution profile.
Core Innovation
The invention relates to oral solid dosage forms containing a poorly water soluble active ingredient having a solubility of less than or equal to 0.1 mg/mL in water. The composition includes from about 15% to about 25% by weight of 2-pyrrolidone and from about 5% to about 15% by weight of silicon dioxide, and the approach focuses on improving dissolution and/or pharmacotechnical performance for poorly water soluble actives.
A manufacturing approach described as a Pyrroplus Manufacturing Process forms the dosage form by dissolving and/or mixing the active ingredient with 2-pyrrolidone, then mixing the obtained solution or mixture with silicon dioxide, optionally adding other internal phase excipients. The mixture is processed by wet or dry granulation, optionally with ethanol, and optionally drying the wetted mass if required.
The description includes a proposed rationale involving conversion from a crystalline to an amorphous state and hydrogen-bond interaction between the active ingredient and 2-pyrrolidone. Silicon dioxide contributes via its surface area to formation of a one-phase system on the particle surface and to stabilization of the amorphous state, with heteromolecular hydrogen bonds described as preventing recrystallization.
Claims Coverage
Two independent claims are present: one for a pharmaceutical composition and one for a process for preparation of solid oral dosage forms. Both claims feature the same core quantitative combination of 2-pyrrolidone and silicon dioxide for a poorly water soluble active ingredient (solubility ≤0.1 mg/mL in water).
Poorly water soluble active ingredient with defined 2-pyrrolidone and silicon dioxide levels
A pharmaceutical composition for oral administration comprising a poorly water soluble active ingredient with a solubility of less than or equal to 0.1 mg/mL in water, from about 15% to about 25% by weight of 2-pyrrolidone, and from about 5% to about 15% by weight of silicon dioxide.
Process using 2-pyrrolidone with silicon dioxide followed by wet or dry granulation
A process for the preparation of solid dosage forms for oral administration comprising a poorly water soluble active ingredient (solubility ≤0.1 mg/mL in water) and from about 15% to about 25% by weight of 2-pyrrolidone and from about 5% to about 15% by weight of silicon dioxide, comprising dissolving and/or mixing the active ingredient with 2-pyrrolidone, mixing the obtained solution or mixture with silicon dioxide, and performing wet or dry granulation, optionally with ethanol, and optionally drying the wetted mass if required.
The claim set centers on combining a poorly water soluble active ingredient (solubility ≤0.1 mg/mL in water) with specified weight ranges of 2-pyrrolidone and silicon dioxide, and on a preparation route that mixes the active with 2-pyrrolidone, combines with silicon dioxide, and then applies wet or dry granulation, optionally including ethanol and optional drying.
Stated Advantages
Markedly improved dissolution versus ethanol-based preparation (as described in comparative results).
Reduced solubility when silicon dioxide is omitted (as described in comparative solubility/dissolution findings).
Stabilization of the amorphous state to prevent recrystallization, supported by heteromolecular hydrogen bonds.
Documented Applications
Oral solid dosage forms for poorly water soluble active ingredients (solubility ≤0.1 mg/mL in water), exemplified with tadalafil, leflunomide, raloxifene, and atorvastatin.
Solid dosage forms for oral administration prepared using a Pyrroplus Manufacturing Process with 2-pyrrolidone and silicon dioxide, followed by wet or dry granulation and optional ethanol and drying.
Interested in licensing this patent?