Fast dissolving pharmaceutical compositions
Inventors
Brisander, Magnus • Meijer, Thomas • Söderberg, Victor
Assignees
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Publication Number
US-11529351-B2
Publication Date
2022-12-20
Expiration Date
Abstract
The present disclosure relates to the field of pharmaceutical compositions. Furthermore, the present invention relates to an immediate release pharmaceutical composition in the form of a non-effervescent tablet composition comprising dasatinib and a gas generating agent.
Core Innovation
The invention relates to an immediate release pharmaceutical composition in the form of a non-effervescent tablet comprising dasatinib in an amorphous solid dispersion with copovidone and a defined set of excipients. The tablet includes mannitol, at least one gas generating agent comprising sodium bicarbonate, crospovidone, at least one acidic pH modifier comprising fumaric acid, sodium stearyl fumarate, and colloidal silicon dioxide, and the stated amounts are based on the total weight of the composition.
The composition optionally comprises a coating layer and is defined by specific weight percentage ranges for dasatinib, copovidone, mannitol, sodium bicarbonate, crospovidone, fumaric acid, sodium stearyl fumarate, and colloidal silicon dioxide. A mole ratio of the at least one gas generating agent to the at least one acidic pH-modifier is defined, and the tablet is configured so that a dasatinib dose of 100 mg provides a fed/AUC(0-24h) to fasted AUC(0-24h) ratio from about 95% to about 100%.
The background and summary content describe variability and food- and pH-dependent performance when comparing to Sprycel (dasatinib monohydrate). The composition is intended to improve solubility and dissolution across pH conditions and to reduce intra- and inter-subject variability, including avoiding anomalously low exposure, with clinical pharmacokinetic results and dissolution results provided as support.
The disclosed use includes therapeutic treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (Ph+ ALL) in adult patient populations defined by resistance or intolerance to prior therapy including imatinib. Documented data also includes a food-effect analysis and a gastric acid reducing agent drug-drug interaction evaluation including omeprazole, with reporting of pharmacokinetic parameters such as Cmax and AUC.
Claims Coverage
The document includes one independent composition claim and at least one independent treating method claim. The inventive features concentrate on the specific non-effervescent immediate release tablet composition with defined drug/excipient relationships, pharmacokinetic behavior under fed versus fasted conditions, and treatment of specified Ph+ CML and Ph+ ALL adult populations.
Non-effervescent immediate release tablet with amorphous solid dispersion and defined excipient system
A non-effervescent immediate release tablet comprising an amorphous solid dispersion comprising dasatinib and copovidone, and mannitol, at least one gas generating agent comprising sodium bicarbonate, crospovidone, at least one acidic pH modifier comprising fumaric acid, sodium stearyl fumarate, and colloidal silicon dioxide, with stated amounts based on total weight, and optionally a coating layer.
Defined gas-agent/acid-multiplier mole ratio
A mole ratio of the at least one gas generating agent to the at least one acidic pH-modifier is defined.
Fed/fasted exposure equivalence for 100 mg dasatinib dose
A dasatinib dose of 100 mg provides an AUC(0-24h) fed/AUC(0-24h) fasted ratio of from about 95% to about 100%.
Treating specific Ph+ CML and Ph+ ALL adult populations with the composition
A method for treating a proliferative disorder by administering a therapeutically effective amount of the composition, including newly diagnosed adults with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, adults with Ph+ CML in chronic accelerated or myeloid or lymphoid blast phases with resistance or intolerance to prior therapy including imatinib, and adults with Ph+ ALL with resistance or intolerance to prior therapy.
Co-administration of gastric acid reducing agent classes
The method further includes co-administering a gastric acid reducing agent that is either an antacid, an H2 antagonist, or a proton pump inhibitor.
Dose pairing bioequivalence to Sprycel
Administering dasatinib using a dose X that achieves bioequivalence to a dasatinib dose Y for Sprycel, with paired dose values including 15 mg/20 mg, 36 mg/50 mg, 50 mg/70 mg, 57 mg/80 mg, and 70 mg/100 mg.
Cmax constraint for a 100 mg dasatinib dose
Using a dasatinib dose of 100 mg that yields a Cmax of about 241 ng/mL.
Across the composition claim and dependent claim features, the key inventive elements are a specific non-effervescent immediate release tablet composition built on an amorphous solid dispersion of dasatinib with copovidone plus defined excipients, a defined gas generating agent to acidic pH modifier mole ratio, and a fed/fasted AUC(0-24h) ratio constraint for a 100 mg dose. Dependent claim coverage further narrows treatment to specified Ph+ CML and Ph+ ALL adult subpopulations, includes gastric acid reducing agent co-administration, and constrains bioequivalent dose pairing to Sprycel and a Cmax endpoint for a 100 mg dose.
Stated Advantages
Improves solubility and dissolution and reduces pH-dependent dissolution variability compared with Sprycel (dasatinib monohydrate).
Reduces intra-subject and inter-subject variability compared with Sprycel and avoids anomalously low exposure.
Produces a reduced food effect, with fed/fasted AUC(0-24h) ratios within about 95% to about 100% for a 100 mg dose.
Shows no clinically relevant drug-drug interaction with omeprazole (proton pump inhibitor) in the described study.
Documented Applications
Therapeutic treatment of Philadelphia chromosome-positive chronic myeloid leukemia, including adults newly diagnosed with chronic phase disease, and adults with chronic accelerated or myeloid or lymphoid blast phases with resistance or intolerance to prior therapy including imatinib.
Therapeutic treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults with resistance or intolerance to prior therapy.
Use in the presence of gastric acid reducing agents, including antacid, H2 antagonist, or proton pump inhibitor co-administration (omeprazole evaluated).
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