Claims for Patent: 10,758,532

Summary for Patent: 10,758,532

Title:	Compositions, devices, and methods for treating or preventing headaches
Abstract:	Disclosed herein are pharmaceutical compositions, devices, their combinations, and their uses thereof for example in treating or preventing headaches.
Inventor(s):	John KOLLINS, Fumiyoshi IWASHIMA, Detlef Albrecht, Robert David Schultz
Assignee:	Satsuma Pharmaceuticals Inc
Application Number:	US16/710,538
Patent Claims:	1. A method of treatment or prevention of a headache, comprising administering to a human subject a powdery pharmaceutical composition that comprises an active agent, wherein said active agent is present in 4.5 mg to about 6 mg in a unit dose of said pharmaceutical composition and is selected from the group consisting of a compound having a formula of a pharmaceutically acceptable salt thereof, a complex thereof, a chelate thereof, and an ion pair thereof, wherein R12 is hydrogen or halogen in said formula, wherein said administering results in a time to reach a peak plasma concentration (Tmax) of 90 minutes or longer for a metabolite of said active agent, when determined from measurement of a human plasma concentration of said metabolite by liquid chromatography-tandem mass spectrometry with automated extraction, wherein said metabolite is of Formula (I) in which R12 is —OH, and wherein: R1 is hydrogen, (C1-C4) alkyl, or (C1-C4) perfluoroalkyl; each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —OR101, —NR102R103, —CONR104R105, or —CO2R106; R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy; R5, R6, and R7 are independently hydrogen, (C1-C3) alkyl, or (C1-C3) perfluoroalkyl; R8 and R9 are independently hydrogen, (C1-C4) alkyl, or benzyl; R10, R11, and R14 are independently hydrogen, halogen, —OH, (C1-C4) alkyl, —CO2R108, or —CONR109R110; R13 is hydrogen or halogen; R101, R102, R103, R104, R105, R106, R108, R109, and R110 are independently hydrogen, halogen, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl; and n is 0, 1, 2, or 3. 2. The method of claim 1, wherein said Tmax is at least about 2 hours. 3. The method of claim 1, wherein a peak plasma concentration (Cmax) of said metabolite is less than about 250 pg/ml. 4. The method of claim 1, wherein a peak plasma concentration (Cmax) of said metabolite is less than about 15% of a Cmax of said active agent measured following said administration to said human subject. 5. The method of claim 1, wherein a plasma concentration of said metabolite is less than about 5% of a plasma concentration of said active agent measured within about 30 minutes following said administration to said human subject, or wherein a plasma concentration of said metabolite is less than about 2% of a plasma concentration of said active agent measured within about 15 minutes following said administration to said human subject. 6. The method of claim 1, wherein a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect is less than 20% binding activity at an adrenergic, dopaminergic, or 5-HT receptor or receptor subtype as measured by a radioligand competitive binding assay. 7. The method of claim 1, wherein a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect in said human subject is manifested by a reduced transcutaneous partial O2 pressure as measured at the back of a foot, a reduced venous constrictive effect as determined using a venous occlusion mercury strain gauge, a less decreased diameter or compliance of a brachial artery wall, a decreased constrictive effect on a human coronary artery, meningeal artery, or saphenous vein, a less decreased venous diameter at a fixed occlusion pressure, a change in peripheral circulatory capacitance, or any combination thereof. 8. A method of treatment or prevention of a headache, comprising administering to a human subject a pharmaceutical composition that comprises an active agent, wherein said active agent is present in 4.5 mg to about 6 mg in a unit dose of said pharmaceutical composition and is selected from the group consisting of a compound having a formula of a pharmaceutically acceptable salt thereof, a complex thereof, a chelate thereof, and an ion pair thereof, wherein said administering results in: 1) a Cmax of about 1 to about 2.5 ng/ml, or a plasma concentration of at least 1 ng/mL at about 10 minutes or shorter, 2) a Tmax of about 30 minutes or less, and 3) an AUC value selected from the group consisting of an AUC0-30min of about 500 to about 1000 h*pg/ml, an AUC0-60min of about 1000 to about 2000 h*pg/ml, an AUC0-120min of about 2000 to about 3000 h*pg/ml, and an AUC0-inf of about 10000 to about 12000 h*pg/ml, when determined from measurement of a human plasma concentration of said active agent by liquid chromatography-tandem mass spectrometry with automated extraction, and wherein: R1 is hydrogen, (C1-C4) alkyl, or (C1-C4) perfluoroalkyl; each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —OR101, —NR102R103, —CONR104R105, or —CO2R106; R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy; R5, R6, and R7 are independently hydrogen, (C1-C3) alkyl, or (C1-C3) perfluoroalkyl; R8 and R9 are independently hydrogen, (C1-C4) alkyl, or benzyl; R10, R11, R12, and R14 are independently hydrogen, halogen, —OH, (C1-C4) alkyl, —CO2R108, or —CONR109R110; R13 is hydrogen or halogen; R101, R102, R103, R104, R105, R106, R108, R109, and R110 are independently hydrogen, halogen, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl; and n is 0, 1, 2, or 3. 9. The method of claim 8, further providing a half-life of said active agent from about 12 hours to about 13 hours. 10. The method of claim 8, wherein said administering results in a time to reach a peak plasma concentration (Tmax) of 90 minutes or longer for a metabolite of said active agent, when determined from measurement of a human plasma concentration of said metabolite by liquid chromatography-tandem mass spectrometry with automated extraction, wherein R12 is hydrogen or halogen in said formula of said active agent, and wherein said metabolite is of Formula (I) in which R12 is —OH. 11. A method of treatment or prevention of a headache, comprising administering to a human subject a pharmaceutical composition that comprises an active agent, wherein said active agent is present in 4.5 mg to about 6 mg in a unit dose of said pharmaceutical composition and is selected from the group consisting of a compound having a formula of a pharmaceutically acceptable salt thereof, a complex thereof, a chelate thereof, and an ion pair thereof, wherein said administering results in an apparent clearance (CL/F) value of said active agent from about 100 L/hr to about 1000 L/hr, and wherein: R1 is hydrogen, (C1-C4) alkyl, or (C1-C4) perfluoroalkyl; each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —OR101, —NR102R103, —CONR104R105, or —CO2R106; R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy; R5, R6, and R7 are independently hydrogen, (C1-C3) alkyl, or (C1-C3) perfluoroalkyl; R8 and R9 are independently hydrogen, (C1-C4) alkyl, or benzyl; R10, R11, R12, and R14 are independently hydrogen, halogen, —OH, (C1-C4) alkyl, —CO2R108, or —CONR109R110; R13 is hydrogen or halogen; R101, R102, R103, R104, R105, R106, R108, R109, and R110 are independently hydrogen, halogen, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl; and n is 0, 1, 2, or 3. 12. The method of claim 1, wherein said R3 and said R4 are both hydrogen. 13. The method of claim 12, wherein said active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof. 14. The method of claim 1, wherein said metabolite is 8′-hydroxy dihydroergotamine. 15. The method of claim 1, wherein said pharmaceutical composition further comprises about 6 mg to about 7 mg of a sugar alcohol. 16. The method of claim 1, wherein said active agent is in an amorphous form. 17. The method of claim 1, wherein said headache is a migraine. 18. The method of claim 1, wherein said headache comprises a migraine headache with aura, a migraine headache without aura, cluster headache, post-traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, refractory migraine, migraine attack when treatment is initiated at least 1-24 hours after an onset of attack, migraine attack when treatment is initiated at the earliest premonitory sign or symptom, pediatric migraine, status migraine, chronic daily headache, a migraine attack with allodynia, menstrually-associated migraine, menstrual migraine, migraine-upon-awakening, rapid-onset migraine, or any combination thereof. 19. The method of claim 1, wherein said administration comprises delivering two or more doses of said pharmaceutical composition in two or more devices to said human subject. 20. The method of claim 19, wherein a first dose and a second dose of said two or more doses are separated by about 2 hours or longer. 21. The method of claim 1, wherein said pharmaceutical composition further comprises a carrier that is at least partially adhesive to mucus. 22. The method of claim 1, wherein said pharmaceutical composition further comprises a carrier, and wherein the carrier is at least partially adhesive to mucus and present in an amount at least partially effective to result in said Tmax. 23. The method of claim 1, wherein said pharmaceutical composition further comprises a carrier, and wherein the carrier is at least partially adhesive to mucus and present in at least 12 mg in a unit dose of said pharmaceutical composition. 24. The method of claim 1, wherein said administering comprises delivering said pharmaceutical composition in a delivery device that comprises a poppet valve and a retainer that holds the poppet valve. 25. The method of claim 1, wherein said active agent comprises a pharmaceutically acceptable salt of dihydroergotamine. 26. The method of claim 1, wherein said active agent comprises dihydroergotamine mesylate. 27. The method of claim 26, wherein at least one of the following applies: said Tmax is at least about 2 hours; a peak plasma concentration (Cmax) of said metabolite is less than about 250 pg/ml; a peak plasma concentration (Cmax) of said metabolite is less than about 15% of a Cmax of said active agent measured following said administration to said human subject; a plasma concentration of said metabolite is less than about 5% of a plasma concentration of said active agent measured within about 30 minutes following said administration to said human subject, or wherein a plasma concentration of said metabolite is less than about 2% of a plasma concentration of said active agent measured within about 15 minutes following said administration to said human subject; a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect is less than 20% binding activity at an adrenergic, dopaminergic, or 5-HT receptor or receptor subtype as measured by a radioligand competitive binding assay; or a reduced presence of said metabolite results in a reduced pharmacological effect from said metabolite in said human subject, and wherein said reduced pharmacological effect in said human subject is manifested by a reduced transcutaneous partial O2 pressure as measured at the back of a foot, a reduced venous constrictive effect as determined using a venous occlusion mercury strain gauge, a less decreased diameter or compliance of a brachial artery wall, a decreased constrictive effect on a human coronary artery, meningeal artery, or saphenous vein, a less decreased venous diameter at a fixed occlusion pressure, a change in peripheral circulatory capacitance, or any combination thereof. 28. The method of claim 8, wherein said active agent comprises dihydroergotamine mesylate. 29. The method of claim 28, further providing a half-life of said active agent from about 12 hours to about 13 hours, or wherein said administering results in a time to reach a peak plasma concentration (Tmax) of 90 minutes or longer for a metabolite of said active agent, when determined from measurement of a human plasma concentration of said metabolite by liquid chromatography-tandem mass spectrometry with automated extraction, wherein R12 is hydrogen or halogen in said formula of said active agent, and wherein said metabolite is of Formula (I) in which R12 is —OH. 30. The method of claim 11, wherein said active agent comprises dihydroergotamine mesylate. 31. The method of claim 1, wherein said active agent is dihydroergotamine mesylate, and wherein said metabolite comprise 8′-hydroxy dihydroergotamine. 32. The method of claim 1, wherein said Tmax is a mean value from a human clinical study. 33. The method of claim 2, wherein said Tmax is a mean value from a human clinical study. 34. The method of claim 8, wherein said Cmax, Tmax and AUC value are mean values from a human clinical study. 35. The method of claim 11, wherein said CL/F value is a mean value from a human clinical study.