Pharmaceutical compositions comprising a ryanodine receptor modulator and uses thereof
The present disclosure provides a modified-release pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, and a pharmaceutically-acceptable excipient. The present disclosure methods of treating conditions associated with RyRs, including, for example, cardiac disorder or disease, a musculoskeletal disorder or disease, cancer associated muscle weakness, malignant hyperthermia, and diabetes.
1. A method of treating RYR1-related myopathy, comprising administering to a subject in need thereof a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising in a unit dosage form 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable excipient, wherein when administered to the subject, the pharmaceutical composition provides to the subject a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof at a time between about 2 to about 6 hours after administration.
2. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof at a time between about 3 to about 4 hours after administration.
3. The method of claim 1 , wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt, wherein the pharmaceutically-acceptable salt is a hemifumarate salt.
4. The method of claim 1 , wherein the unit dosage form is a modified release dosage form.
5. The method of claim 1 , wherein the unit dosage form is a delayed release dosage form.
6. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject a therapeutically-effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof over a period of time, wherein the period of time occurs after administration, wherein the period of time is at least about 12 hours.
7. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject a therapeutically-effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof over a period of time, wherein the period of time occurs after administration, wherein the period of time is at least about 24 hours.
8. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject an in-vivo mean terminal half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof of about 14 to about 21 hours after administration.
9. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject an accumulation ratio for C max of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof between about 1.4 and about 1.8, wherein said accumulation ratio is calculated as a ratio of C max on Day 28/C max on Day 1, wherein C max is maximum observed plasma concentration.
10. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject an accumulation ratio for AUC of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof between about 1.4 and about 1.8, wherein said accumulation ratio for AUC is calculated as a ratio of AUC tau on Day 28/AUC 0-24 Day 1,
wherein
AUC is area under the concentration-time curve;
AUC tau is area under the concentration-time curve during a dosing interval (tau) at steady-state; and
AUC 0-24 is area under the concentration-time curve, from time 0 to 24 hours post-dose.
11. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject a maximum observed plasma concentration of less than about 35 ug/mL of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof.
12. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject a steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4 (5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof in a range of about 3 to about 7 days after initial administration.
13. The method of claim 1 , wherein the unit dosage form is suitable for oral administration.
14. The method of claim 1 , wherein the unit dosage form is a gastro-resistant tablet.
15. The method of claim 14 , wherein the gastro-resistant tablet does not substantially disintegrate at a pH at or below 5.5, wherein disintegration is determined by measuring dissolution of the gastro-resistant tablet in a medium having a pH at or below 5.5.
16. The method of claim 14 , wherein the gastro-resistant tablet substantially disintegrates at a pH of at least about 6.8, wherein disintegration is determined by measuring dissolution of the gastro-resistant tablet in a medium having a pH of 6.8.
17. The method of claim 1 , wherein the unit dosage form is a gastro-resistant tablet, wherein the gastro-resistant tablet comprises a core and a coating layer substantially covering the core.
18. The method of claim 17 , wherein the coating layer comprises an enteric polymer.
19. The method of claim 18 , wherein the enteric polymer is hypromellose acetate succinate.
20. The method of claim 17 , wherein the gastro-resistant tablet further comprises a sub-coating layer between the core and the coating layer.
21. The method of claim 20 , wherein the sub-coating layer comprises a polymer.
22. The method of claim 21 , wherein the polymer is hypromellose.
23. The method of claim 1 , wherein the pharmaceutical composition is in the form of a tablet, the tablet comprising a core, a sub-coating layer substantially covering the core, and a coating layer substantially covering the sub-coating layer, wherein
the core comprises 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate;
the sub-coating layer comprises hypromellose, microcrystalline cellulose and stearic acid; and
the coating layer comprises hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate and talc.