WEAKLY BASIC DRUG AND IONIC POLYMER PHARMACEUTICAL FORMULATIONS AND METHODS OF FORMATION AND ADMINISTRATION THEREOF
The present disclosure relates to pharmaceutical formulations including a weakly basic drug and an ionic polymer in an amorphous solid dispersion, as well as methods of forming such pharmaceutical formulations, and methods of administering such pharmaceutical formulations.
1 . A pharmaceutical formulation comprising:
a weakly basic drug; and
an ionic polymer excipient, together in an amorphous solid dispersion.
2 . The pharmaceutical formulation of claim 1 , wherein the ionic polymer excipient comprises hypromellose acetate succinate
3 . The pharmaceutical formulation of claim 1 , wherein the ionic polymer excipient is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, methacylic acid-co-ethyl acrylate, methacylic acid-co-methyl methacrylate; and combinations thereof.
4 . The pharmaceutical formulation of claim 1 , wherein the weakly basic drug and ionic polymer are present in a weight ratio of between 1:0.25 to 1:50, inclusive.
5 . The pharmaceutical formulation of claim 1 , wherein the amorphous solid dispersion is made up of particles, wherein the average specific surface area of the particles is less than 2.0 (m 2 /g), inclusive, such as wherein the particles of the amorphous solid dispersion have a specific surface area of greater than 0.05 (m 2 /g), inclusive.
6 . (canceled)
7 . The pharmaceutical formulation of claim 1 , wherein the weakly basic drug comprises a primary, secondary or tertiary amine functional group.
8 . The pharmaceutical formulation of claim 1 , wherein the weakly basic drug is selected from the group consisting of BI 639667, ciprofloxacin, mitoxantrone, epirubicin, daunorubicin, doxorubicin, vincristine, vinblastine, lidocaine, chlorpromazine, dibucaine, propranolol, timolol, quinidine, pilocarpine, physostigmine, dopamine, serotonin, imipramine, diphenhydramine, quinine, chloroquine, quinacrine, ritonavir, itraconazole, posaconazole, nevirapine, aprepitant, albendazole, mebendazole, amprenavir, abiraterone, saquinavir, rifabutin, anthracyclines, vinca alkaloids, lamivudine, zalcitabine, didanosine, efavirenz, zidovudine, nelfinavir, indinavir, chloroquine, azathioprine, atazanavir, amiodarone, terfenadine, tamoxifen, velpatasvir, elbasvir and codeine, pharmaceutically acceptable salts thereof, and combinations thereof.
9 . The pharmaceutical formulation of claim 1 , wherein a non-sink, pH-shift dissolution test of the pharmaceutical formulation has a C max, acidic /C eq, neutral ratio less than or equal to 1.10.
10 . A method of forming a pharmaceutical formulation, the method comprising compounding a weakly basic drug and a ionic polymer excipient in a thermokinetic mixer at a temperature less than or equal to 200° C. for less than 300 seconds to form an amorphous solid dispersion of a weakly basic drug and an ionic polymer.
11 . The method of claim 10 , wherein the pharmaceutical formulation is a pharmaceutical formulation comprising a weakly basic drug and an ionic polymer excipient, together in an amorphous solid dispersion.
12 . The method of claim 10 , wherein compounding in the thermokinetic mixer does not cause more than 20% of the weakly basic drug to thermally degrade.
13 . A method of forming a pharmaceutical formulation, the method comprising melt processing a weakly basic drug and an ionic polymer excipient to form an amorphous solid dispersion of the weakly basic drug and the ionic polymer excipient in which less than 20% of the weakly basic drug thermally degrades.
14 . The method of claim 13 , wherein the pharmaceutical formulation is a pharmaceutical formulation comprising a weakly basic drug and an ionic polymer excipient, together in an amorphous solid dispersion.
15 . A method of administering a weakly basic drug, the method comprising orally delivering to a patient, with a stomach having stomach contents, a small intestine having small intestine contents, and blood plasma, a pharmaceutical formulation of claim 1 .
16 . The method of claim 15 , wherein at least 50%, inclusive, of the weakly basic drug dissolves in the small intestine of the patient.
17 . The method of claim 15 , wherein between 0.05% and 30%, inclusive, of the weakly basic drug is dissolved in the stomach of the patient.
18 . The method of claim 15 , wherein the weakly basic drug does not reach a saturation concentration in the stomach contents of the patient.
19 . The method of claim 15 , wherein the weakly basic drug does reach a saturation concentration in the small intestine contents of the patient.
20 . The method of claim 15 , wherein the weakly basic drug reaches a max concentration level of greater than or equal to 1800 ng/mL in the blood plasma.
21 . The method of claim 15 , wherein the weakly basic drug has a AUC 0-24 hr value of greater than or equal to 20,000 (ng×hr)/mL in the blood plasma.