DIHYDROERGOTAMINE MESYLATE FORMULATIONS AND PRE-FILLED INJECTORS FOR THERAPEUTIC DELIVERY OF THE SAME
The present disclosure is directed to formulations and methods for treating or preventing head pain, including migraines, with dihydroergotamine mesylate.
1 . A pre-filled injector comprising:
a pharmaceutically acceptable formulation comprising:
dihydroergotamine mesylate at a concentration of about 3 mg/mL to about 6 mg/mL; and
carbon dioxide at a concentration sufficient to retard oxidative degradation of the dihydroergotamine mesylate.
2 . The pre-filled injector of claim 1 , wherein the pharmaceutically acceptable formulation further comprises caffeine.
3 . The pre-filled injector of claim 2 , wherein the concentration of caffeine is about 5 mg/mL to about 15 mg/mL.
4 . The pre-filled injector of any one of claims 1 - 3 , wherein the pharmaceutically acceptable formulation further comprises an osmotic agent.
5 . The pre-filled injector of claim 4 , where the osmotic agent is selected from the group consisting of: dextrose, glycerin, mannitol, and sucrose, or combinations thereof.
6 . The pre-filled injector of claim 5 , where the osmotic agent is dextrose at a concentration of about 1 mg/mL to about 20 mg/mL.
7 . The pre-filled injector of claim 5 , where the osmotic agent is glycerin at a concentration of about 1 mg/mL to about 20 mg/mL.
8 . The pre-filled injector of claim 5 , where the osmotic agent is mannitol at a concentration of about 20 mg/mL to about 50 mg/mL.
9 . The pre-filled injector of claim 5 , where the osmotic agent is sucrose at a concentration of about 2 mg/mL to about 20 mg/mL.
10 . The pre-filled injector of any one of claims 1 - 9 , where the volume of the pharmaceutically acceptable formulation to be dispensed from the pre-filled injector is adjustable to about 0.1 mL to about 0.3 mL per injection.
11 . The pre-filled injector of any one of claims 1 - 10 , wherein the pharmaceutically acceptable formulation further comprises an antioxidant.
12 . The pre-filled injector of claim 11 , wherein the antioxidant is selected from the group consisting of: methionine, monothioglycerol, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium citrate, and thiourea, or combinations thereof.
13 . The pre-filled injector of claim 12 , wherein the antioxidant is methionine at a concentration of about 1.5 mg/mL to about 5 mg/mL.
14 . The pre-filled injector of claim 13 , wherein the antioxidant is methionine at a concentration of about 1.5 mg/mL.
15 . The pre-filled injector of claim 12 , wherein the antioxidant is monothioglycerol.
16 . The pre-filled injector of claim 15 , wherein the antioxidant is monothioglycerol at a concentration of about 2 mg/mL to about 3 mg/mL.
17 . The pre-filled injector of claim 15 or claim 16 , wherein the antioxidant is monothioglycerol at a concentration of about 2 mg/mL.
18 . The pre-filled injector of claim 12 , wherein the antioxidant is sodium metabisulfite at a concentration of about 0.2 mg/mL to about 4.0 mg/mL.
19 . The pre-filled injector of claim 12 , wherein the antioxidant is sodium citrate at a concentration of about 0.1 mg/mL to about 4.0 mg/mL.
20 . The pre-filled injector of any one of claims 1 - 19 , wherein the pharmaceutically acceptable formulation is contained within an about 3.0 mL sterilized cartridge.
21 . The pre-filled injector of any one of the claims 1 - 20 , wherein the pharmaceutically acceptable formulation has a pH of about 2.5 to about 4.5.
22 . The pre-filled injector of any one of claims 1 - 21 , wherein the pharmaceutically acceptable formulation further comprises a preservative.
23 . The pre-filled injector of claim 22 , wherein the preservative is an isomer of cresol selected from the group consisting of o-cresol, m-cresol, and p-cresol, or combinations thereof.
24 . The pre-filled injector of claim 23 , wherein the preservative is o-cresol.
25 . The pre-filled injector of claim 23 , wherein the preservative is m-cresol.
26 . The pre-filled injector of claim 25 , wherein m-cresol is present at a concentration of about 1 mg/mL to about 5 mg/mL.
27 . The pre-filled injector of claim 25 or claim 26 , wherein m-cresol is present at a concentration of about 1 mg/mL to about 2.5 mg/mL.
28 . The pre-filled injector of any one of claims 25 - 27 , wherein m-cresol is present at a concentration of about 1.5 mg/mL.
29 . The pre-filled injector of claim 23 , wherein the preservative is p-cresol.
30 . The pre-filled injector of claim 22 , wherein the preservative is benzyl alcohol.
31 . The pre-filled injector of claim 30 , wherein benzyl alcohol is present at a concentration of about 5 mg/mL to about 100 mg/mL.
32 . The pre-filled injector of claim 31 , wherein benzyl alcohol is present at a concentration of about 10 mg/mL.
33 . The pre-filled injector of claim 22 , wherein the preservative is a composition of one or more parabens.
34 . The pre-filled injector of claim 33 , wherein the composition of one or more parabens comprises methylparaben.
35 . The pre-filled injector of claim 33 or claim 34 , wherein the composition of one or more parabens comprises propylparaben.
36 . The pre-filled injector of any one of claims 33 - 35 , wherein the composition of one or more parabens comprises methylparaben and propylparaben.
37 . The pre-filled injector of any one of claims 1 - 36 , wherein the pharmaceutically acceptable formulation is stable.
38 . A pharmaceutically acceptable formulation comprising:
about 3 mg/mL to about 6 mg/mL dihydroergotamine mesylate;
about 3 mg/mL to about 10 mg/mL of a pharmaceutically acceptable alcohol;
about 5 mg/mL to about 15 mg/mL caffeine;
about 1 mg/mL to about 3 mg/mL an isomer of cresol selected from the group consisting of o-cresol, m-cresol, and p-cresol, or combinations thereof;
carbon dioxide at a concentration sufficient to retard oxidative degradation of the dihydroergotamine mesylate; and
an osmotic agent selected from the group consisting of:
dextrose, glycerin, mannitol, and sucrose , or combinations thereof.
39 . The pharmaceutically acceptable formulation of claim 38 , where the pharmaceutically acceptable alcohol is selected from the group consisting of: propylene glycol, ethanol, and a pharmaceutically acceptable polyethylene glycol, or combinations thereof.
40 . The pharmaceutically acceptable formulation of claim 39 , where the pharmaceutically acceptable alcohol is ethanol.
41 . The pharmaceutically acceptable formulation of any one of claims 38 - 40 , where the isomer of cresol is o-cresol.
42 . The pharmaceutically acceptable formulation of any one of claims 38 - 40 , where the isomer of cresol is m-cresol.
43 . The pharmaceutically acceptable formulation of any one of claims 38 - 40 , where the isomer of cresol is p-cresol.
44 . The pharmaceutically acceptable formulation of any one of claims 38 - 43 , where the osmotic agent is dextrose at a concentration of about 1 mg/mL to about 20 mg/mL.
45 . The pharmaceutically acceptable formulation of any one of claims 38 - 43 , where the osmotic agent is glycerin at a concentration of about 1 mg/mL to about 20 mg/mL.
46 . The pharmaceutically acceptable formulation of any one of claims 38 - 43 , where the osmotic agent is mannitol at a concentration of about 20 mg/mL to about 50 mg/mL.
47 . The pharmaceutically acceptable formulation of any one of claims 38 - 43 , where the osmotic agent is sucrose at a concentration of about 2 mg/mL to about 20 mg/mL.
48 . The pharmaceutically acceptable formulation of any one of claims 38 - 47 , wherein the pharmaceutically acceptable formulation further comprises an antioxidant.
49 . The pharmaceutically acceptable formulation of claim 48 , wherein the antioxidant is selected from the group consisting of: methionine, monothioglycerol, sodium bisulfate, sodium metabisulfite, sodium thiosulfate, sodium citrate, and thiourea, or combinations thereof.
50 . The pharmaceutically acceptable formulation of claim 49 , where in the antioxidant is methionine at a concentration of about 1.5 mg/mL to about 5 mg/mL.
51 . The pharmaceutically acceptable formulation of claim 49 or claim 50 , where in the antioxidant is methionine at a concentration of about 1.5 mg/mL.
52 . The pharmaceutically acceptable formulation of claim 49 , where in the antioxidant is monothioglycerol at a concentration of about 2 mg/mL to about 3 mg/mL.
53 . The pharmaceutically acceptable formulation of claim 52 , where in the antioxidant is monothioglycerol at a concentration of about 2 mg/mL.
54 . The pharmaceutically acceptable formulation of claim 49 , where in the antioxidant is sodium metabisulfite at a concentration of about 0.2 mg/mL to about 4.0 mg/mL
55 . The pharmaceutically acceptable formulation of claim 49 , where in the antioxidant is sodium citrate at a concentration of about 0.1 mg/mL to 4.0 mg/mL
56 . The pharmaceutically acceptable formulation of any one of claims 38 - 55 , wherein the pharmaceutically acceptable formulation further comprises a cyclodextrin.
57 . The pharmaceutically acceptable formulation of claim 56 , wherein the cyclodextrin is selected from the group consisting of: 2-hydroxypropyl-β-cyclodextrin, O-methyl-β-cyclodextrin, and γ-cyclodextrin, or combinations thereof.
58 . The pharmaceutically acceptable formulation of any one of claims 38 - 57 , wherein the pharmaceutically acceptable formulation is stable.
59 . A pre-filled injector comprising the pharmaceutically acceptable formulation of any one of claims 38 - 58 .
60 . The pre-filled injector of claim 59 , wherein the volume of the formulation to be dispensed from the pre-filled injector is adjustable to about 0.1 mL to about 0.3 mL per injection.
61 . The pre-filled injector of claim 59 or claim 60 , wherein the pharmaceutically acceptable formulation is contained within an about 3.0 mL sterilized cartridge.
62 . A method of treating a migraine or a cluster headache attack in a patient, comprising:
parenterally administering to the patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable formulation comprising:
dihydroergotamine mesylate at a concentration of about 3 mg/mL to about 6 mg/mL; and
carbon dioxide at a concentration sufficient to retard oxidative degradation of the dihydroergotamine mesylate.
63 . The method of claim 62 , wherein the pharmaceutically acceptable formulation further comprises caffeine.
64 . The method of claim 63 , where the concentration of caffeine in the pharmaceutically acceptable formulation is about 5 mg/mL to about 15 mg/mL.
65 . The method of any one of claims 62 - 64 , wherein the pharmaceutically acceptable formulation further comprises an osmotic agent selected from the group consisting of: dextrose, glycerin, mannitol, and sucrose, or combinations thereof.
66 . The method of claim 65 , where the osmotic agent is dextrose at a concentration of about 1 mg/mL to about 20 mg/mL.
67 . The method of claim 65 , where the osmotic agent is glycerin at a concentration of about 1 mg/mL to about 20 mg/mL.
68 . The method of claim 65 , where the osmotic agent is mannitol at a concentration of about 20 mg/mL to about 50 mg/mL.
69 . The method of claim 65 , where the osmotic agent is sucrose at a concentration of about 2 mg/mL to about 20 mg/mL.
70 . The method of any one of claims 62 - 69 , wherein the pharmaceutically acceptable formulation further comprises an antioxidant.
71 . The method of claim 70 , where the antioxidant is selected from the group consisting of: methionine, monothioglycerol, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium citrate, and thiourea, or combinations thereof.
72 . The method of claim 71 , where the antioxidant is methionine at a concentration of about 1.5 mg/mL to about 5 mg/mL.
73 . The method of claim 72 , where the antioxidant is methionine at a concentration of about 1.5 mg/mL.
74 . The method of claim 71 , where the antioxidant is monothioglycerol at a concentration of about 2 mg/mL to about 3 mg/mL.
75 . The method of claim 74 , where the antioxidant is monothioglycerol at a concentration of about 2 mg/mL.
76 . The method of claim 71 , where the antioxidant is sodium metabisulfite at a concentration of about 0.2 mg/mL to about 4.0 mg/mL.
77 . The method of claim 71 , where the antioxidant is sodium citrate at a concentration of about 0.1 mg/mL to about 4.0 mg/mL.
78 . The method of any one of claims 62 - 77 , wherein the pharmaceutically acceptable formulation further comprises a cyclodextrin.
79 . The method of claim 78 , where the cyclodextrin is selected from the group consisting of: 2-hydroxypropyl-β-cyclodextrin, O-methyl-β-cyclodextrin, and γ-cyclodextrin, or combinations thereof.
80 . The method of any one of claims 62 - 79 , wherein the pharmaceutically acceptable formulation further comprises a preservative.
81 . The method of claim 80 , wherein the preservative is an isomer of cresol selected from the group consisting of o-cresol, m-cresol, and p-cresol, or combinations thereof.
82 . The method of claim 81 , wherein the preservative is o-cresol.
83 . The method of claim 81 , wherein the preservative is m-cresol.
84 . The method of claim 83 , wherein m-cresol is present at a concentration of about 1 mg/mL to about 5 mg/mL.
85 . The method of claim 84 , wherein m-cresol is present at a concentration of about 1 mg/mL to about 2.5 mg/mL.
86 . The method of claim 85 , wherein m-cresol is present at a concentration of about 1.5 mg/mL.
87 . The method of claim 81 , wherein the preservative is p-cresol.
88 . The method of claim 80 , wherein the preservative is benzyl alcohol.
89 . The method of claim 88 , wherein benzyl alcohol is present at a concentration of about 5 mg/mL to about 100 mg/mL.
90 . The method of claim 89 , wherein benzyl alcohol is present at a concentration of about 10 mg/mL.
91 . The method of any one of claims 62 - 90 , wherein the pharmaceutically acceptable formulation is administered into the patient subcutaneously, intramuscularly, or intravenously.
92 . The method of any one of claims 62 - 91 , wherein the pharmaceutically acceptable formulation is administered to the patient from an injector pre-loaded with the pharmaceutically acceptable formulation.
93 . The method of claim 91 or claim 92 , wherein the volume of the pharmaceutically acceptable formulation to be dispensed to the patient is about 0.1 mL to about 0.3 mL.
94 . The method of any one of claims 62 - 93 , wherein the treatment reduces the severity, duration, or occurrence of headaches or migraines experienced by the patient.
95 . The method of any one of claims 62 - 94 , wherein the pharmaceutically acceptable formulation is stable and ready-to-use.
96 . A method of manufacturing a pre-filled injector comprising:
preparing a pharmaceutically acceptable formulation comprising:
about 3 mg/mL to about 6 mg/mL dihydroergotamine mesylate;
about 3 mg/mL to about 10 mg/mL of a pharmaceutically acceptable alcohol;
about 5 mg/mL to about 15 mg/mL caffeine;
about 1 mg/mL to about 3 mg/mL an isomer of cresol selected from the group consisting of o-cresol, m-cresol, and p-cresol, or combinations thereof and
an osmotic agent selected from the group consisting of:
dextrose, glycerin, mannitol, and sucrose, or combinations thereof;
loading a sterile cartridge with the pharmaceutically acceptable formulation under a headspace of carbon dioxide at a concentration sufficient to retard oxidation of dihydroergotamine mesylate; and
attaching the sterile cartridge operably to an injector.
97 . The method of claim 96 , where the pharmaceutically acceptable alcohol is selected from the group consisting of: propylene glycol, ethanol, and a pharmaceutically acceptable polyethylene glycol, or combinations thereof.
98 . The method of claim 97 , where the pharmaceutically acceptable alcohol is ethanol.
99 . The method of any one of claims 96 - 98 , where the sterile cartridge has a capacity of about 3.0 mL.
100 . The method of any one of claims 96 - 99 , where the isomer of cresol is o-cresol.
101 . The method of any one of claims 96 - 99 , where the isomer of cresol is m-cresol.
102 . The method of any one of claims 96 - 99 , where the isomer of cresol is p-cresol.
103 . The method of any one of claims 96 - 102 , where the osmotic agent is dextrose at a concentration of about 1 mg/mL to about 20 mg/mL.
104 . The method of any one of claims 96 - 102 , where the osmotic agent is glycerin at a concentration of about 1 mg/mL to about 20 mg/mL.
105 . The method of any one of claims 96 - 102 , where the osmotic agent is mannitol at a concentration of about 20 mg/mL to about 50 mg/mL.
106 . The method of any one of claims 96 - 102 , where the osmotic agent is sucrose at a concentration of about 2 mg/mL to about 20 mg/mL.
107 . The method of any one of claims 96 - 106 , wherein the formulation further comprises a cyclodextrin.
108 . The method of claim 107 , where the cyclodextrin is selected from the group consisting of: 2-hydroxypropyl-β-cyclodextrin, O-methyl-β-cyclodextrin, and γ-cyclodextrin, or combinations thereof.
109 . The method of any one of claims 96 - 108 , where the formulation further comprises an antioxidant.
110 . The method of claim 109 , where the antioxidant is selected from the group consisting of:
methionine, monothioglycerol, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium citrate, and thiourea, or combinations thereof.
111 . The method of claim 110 , where the antioxidant is methionine at a concentration of about 1.5 mg/mL to about 5 mg/mL.
112 . The method of claim 110 , where the antioxidant is monothioglycerol at a concentration of about 2 mg/mL to about 3 mg/mL.
113 . The method of claim 110 , where the antioxidant is sodium metabisulfite at a concentration of about 0.2 mg/mL to about 4.0 mg/mL.
114 . The method of claim 110 , where the antioxidant is sodium citrate at a concentration of about 0.1 mg/mL to about 4.0 mg/mL.
115 . The method of any one of claims 96 - 114 , where the volume of the formulation to be dispensed from the pre-filled injector is adjustable to about 0.1 mL to about 0.3 mL per injection.
116 . The method of any one of claims 96 - 116 , wherein the pharmaceutically acceptable formulation is stable and ready-to-use.