Treatment using dantrolene
Provided are low-volume, safe for injection formulations of dantrolene yielding significant advantages over the currently approved and marketed dantrolene for malignant hyperthermia (MH) threatening anesthetic crisis. Once dantrolene can be made immediately available to patients triggered of MH, the anesthesiologist will be able to focus exclusively on the management of the patient's physiologic status in this complex and evolving crisis, not on the laborious and time consuming reconstitution process of the rescue agent. The low volume, safe for injection formulations of dantrolene have significant advantages over currently used approaches to the prevention and treatment of pumphead, and other neurological, cognitive and motor dysfunction incident to iatrogenically or trauma induced situations of altered blood flow, including those incurred during surgical procedures involving CPB or related procedures, as well as those incurred during non-normothermic episodes caused iatrogenically or by disease.
1. A formulation comprising:
a salt of dantrolene;
a polyvinylpyrrolidone; and
water;
wherein the formulation includes up to 500 mg of dantrolene in a volume of less than or equal to about 150 mL and wherein the concentration of dantrolene is 30-80 mg/mL;
wherein the formulation is in the form of a stable colloidal suspension, and
wherein the particles of the colloidal suspension are less than about 2 microns in average diameter.
2. The formulation of claim 1 , wherein the salt of dantrolene is a sodium, potassium, ammonium, calcium, or magnesium salt.
3. The formulation of claim 1 , wherein the salt of dantrolene is a sodium salt.
4. The formulation of claim 1 , wherein the volume is less than or equal to about 100 mL.
5. The formulation of claim 1 , wherein the volume is less than or equal to about 30 mL.
6. The formulation of claim 1 , wherein the volume is less than or equal to about 5 mL.
7. The formulation of claim 1 , wherein the particles are less than 0.8microns in average diameter.
8. The formulation of claim 1 , wherein the particles are less than 0.45microns in average diameter.
9. The formulation of claim 1 , further comprising lactose, trehalose, sorbitol, sucrose, dextrose, or mannitol.
10. A method of treating a non-normothermic state in a mammal comprising intravenously administering to the mammal a formulation of claim 1 .
11. The method of claim 10 , wherein the non-normothermic state is malignant hyperthermia.
12. The method of claim 10 , wherein the non-normothermic state is heat stroke.
13. A lyophilized formulation comprising up to 500 mg of dantrolene or a salt of dantrolene, polyvinylpyrrolidone, and optionally, lactose, trehalose, sorbitol, sucrose, dextrose, or mannitol.
14. The lyophilized formulation of claim 13 , comprising up to 500 mg of dantrolene.
15. The lyophilized formulation of claim 13 , comprising up to 300 mg of dantrolene.
16. The lyophilized formulation of claim 13 , comprising mannitol.
17. A method of treating a non-normothermic state in a mammal comprising reconstituting the lyophilized formulation of claim 13 to provide an injectable, colloidal suspension wherein the concentration of dantrolene is 30-80mg/mL, and the particles of the colloidal suspension are less than about 2 microns in average diameter; and
intravenously administering to the mammal the colloidal suspension.
18. The method of claim 17 , wherein the particles are less than 0.8 microns in average diameter.
19. The method of claim 17 wherein the particles are less than 0.45microns in average diameter.
20. The method of claim 17 , wherein the non-normothermic state is malignant hyperthermia.
21. The method of claim 17 , wherein the non-normothermic state is heat stroke.