Precipitation resistant small molecule drug formulations
Embodiments of the invention are directed to formulations that provide a solution to the problem of small molecule (e.g., diazepam) precipitation at the injection site when administered as a highly-concentrated formulation. In certain aspects the formulations include at least one surfactant in a non-aqueous formulation, which prevents small molecule precipitation and improves the bioavailability of the drug by enhancing absorption into the systemic circulation.
1. A stable precipitation resistant formulation for parenteral injection comprising:
(a) a biocompatible non-aqueous solvent selected from dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, n-methyl pyrrolidone (NMP), dimethyl acetamide (DMA), propylene carbonate, or mixtures thereof; and
(b) a small molecule drug, selected from levothyroxine, sumatriptan, or a salt thereof, solubilized within the non-aqueous solvent; and
(c) 1% to 30% w/w of a surfactant selected from sodium deoxycholate, polysorbate 80, polysorbate 20, dodecyl maltoside, or sodium dodecyl sulfate, wherein the surfactant attenuates the precipitation of the small molecule drug when injected into a subject and wherein the surfactant is present at a molar ratio of surfactant:small molecule drug of 0.5:1 to 4:1.
2. The formulation of claim 1 , wherein the surfactant is present at a molar ratio of surfactant:small molecule drug of 1:1 to 2:1.
3. The formulation of claim 1 , wherein the formulation comprises less than 10% by weight moisture content.
4. The formulation of claim 1 , wherein the volume of the formulation to be parenterally injected is 3 mL or less.
5. The formulation of claim 1 , further comprised within a device for dispensing the formulation.
6. The formulation of claim 5 , wherein the device is a syringe, a pen injection device, an auto-injector device, an external or implantable pump, or a perfusion bag.
7. The formulation of claim 1 , wherein the aprotic polar solvent is DMSO, NMP, or a mixture thereof.
8. The formulation of claim 1 , wherein the formulation includes from 0.5 mg/mL to 750 mg/mL of the small molecule drug.
9. The formulation of claim 1 , wherein the volume of the formulation to be parenterally injected is from 1 μL to 10 μL.
10. The formulation of claim 1 , wherein the volume of the formulation to be parenterally injected is from 10 μL to 100 μL.
11. The formulation of claim 1 , wherein the volume of the formulation to be parenterally injected is from 100 μL to 1 mL.
12. The formulation of claim 1 , wherein the small molecule drug is levothyroxine.
13. The formulation of claim 1 , wherein the small molecule drug is sumatriptan.
14. A method of administering the formulation of claim 1 to a subject in need thereof comprising parenterally injecting the formulation to the subject.
15. The method of claim 14 , wherein injecting is by parenteral injection or intracutaneous injection.
16. The method of claim 14 , wherein the formulation is not diluted prior to administration.
17. A method for treating a condition, wherein the condition is an indication for which levothyroxine or sumatriptan is approved, comprising parenterally administering to a subject in need thereof the formulation of claim 1 in an amount effective to treat the condition.
18. The method of claim 17 , further comprising the injectable volume within a device for dispensing the formulation.
19. The method of claim 18 , wherein the device is a syringe, a pen injection device, an auto-injector device, an external or implantable pump, or a perfusion bag.
20. The method of claim 18 , wherein the volume of the formulation to be parenterally injected is from 1 μL to 10 μL.
21. The method of claim 18 , wherein the volume of the formulation to be parenterally injected is from 10 μL to 100 μL.
22. The method of claim 18 , wherein the volume of the formulation to be parenterally injected is from 100 μL to 1 mL.
23. The method of claim 17 , wherein the formulation is not diluted prior to administration.
24. The method of claim 17 , wherein the small molecule drug is levothyroxine or a salt thereof, and the approved indication is hypothyroidism.
25. The method of claim 17 , wherein the small molecule drug is sumatriptan or a salt thereof, and the approved indication is migraine.