Pyrimethamine-based pharmaceutical compositions and methods for fabricating thereof
Pharmaceutical compositions that include aqueous suspensions of a therapeutically effective quantity of a diaminopyrimidine compound (such as pyrimethamine) are provided herein. Methods for fabricating the compositions and using them are also described.
1. A pharmaceutical composition formulated as a suspension comprising:
(a) a dispersed phase consisting of particles comprising a therapeutically effective quantity of at least one diaminopyrimidine compound, or derivatives or analogs thereof;
(b) at least one pharmaceutically acceptable surfactant or solubilizing and suspending agent;
(c) optionally, at least one derivative of folic acid; and
(d) an anhydrous dispersion medium,
wherein the dispersed phase is dispersed within the dispersion medium.
2. The pharmaceutical composition of claim 1 , wherein the diaminopyrimidine compound is selected from the group consisting of pyrimethamine, trimetrexate, iclaprim, trimethoprim, 2,4-diaminopyrimidine, 4,5-diaminopyrimidine, piritrexim, and any combination thereof.
3. The pharmaceutical composition of claim 2 , wherein the diaminopyrimidine compound is pyrimethamine.
4. The pharmaceutical composition of claim 1 , wherein the derivative of folic acid is leucovorin.
5. The pharmaceutical composition of claim 1 , wherein the anhydrous dispersion medium comprises at least one vegetable oil, at least one medium chain triglyceride, or any combination thereof.
6. The pharmaceutical composition of claim 5 , wherein the at least one vegetable oil is selected from the group consisting of castor oil, soybean oil, coconut oil, avocado oil, olive oil, almond oil, and any combination thereof.
7. The pharmaceutical composition of claim 5 , wherein the at least one medium chain triglyceride is a triglyceride having at least two fatty acid moieties that are derived from saturated open-chain fatty acids having between 6 and 12 carbon atoms.
8. The pharmaceutical composition of claim 7 , wherein the saturated open-chain fatty acids are selected from the group consisting of caprylic acid and caproic acid.
9. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable surfactant or solubilizing and suspending agent is selected from the group consisting of non-ionic polyoxyethlene-polyoxypropylene block copolymers, a water-soluble derivative of cellulose, optionally partially cross-linked polyacrylates, polyoxyethylene sorbitan monolaurates, glyceryl distearate, triglycerol monooleate, polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitan monostearates, and polyoxyethylene sorbitan monooleates.
10. The pharmaceutical composition of claim 9 , wherein the non-ionic polyoxyethlene-polyoxypropylene block copolymer is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol).
11. The pharmaceutical composition of claim 9 , wherein the water-soluble derivative of cellulose is selected from the group consisting of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.
12. The pharmaceutical composition of claim 9 , wherein the solubilizing and suspending agent is polyoxyethylene (20) sorbitan monooleate.
13. The pharmaceutical composition of claim 3 , wherein the mass concentration of pyrimethamine in the composition is between about 0.1% and about 5.0%.
14. The pharmaceutical composition of claim 1 , wherein the composition retains between about 90% and about 110% of the diaminopyrimidine compound after being stored at room temperature for each of 30, 60, 90 and 150 days, or after being stored at up to about 40° C. for each of 30, 60, and 90 days.
15. A method for treating or alleviating a disease, condition, syndrome, symptom, pathology, or malady in a mammalian subject in need of such treatment comprising oral administration to the subject the composition of claim 1 , wherein the disease being treated is selected from the group consisting of toxoplasmosis, malaria, isosporiasis, cystoisosporiasis, actinomycosis, Pneumocystis jirovecii pneumonia, myelodysplastic syndromes, and amyotrophic lateral sclerosis.
16. A method of enhancing efficacy of an immune checkpoint inhibitor in a mammalian subject in need thereof, comprising administering to the subject the composition of claim 1 prior to, concurrent with, and subsequent to, administering the checkpoint inhibitor.
17. The method of claim 16 , wherein the efficacy of the checkpoint inhibitor comprises one or more endpoints selected from the group consisting of tumor regression, tumor stabilization, reduction in tumor growth, inhibition of metastasis, stabilization of metastasis, reduction of metastatic growth, encapsulation of tumor and/or metastasis, augmentation of cytokines associated with tumor inhibition, decrease in cytokines associated with tumor progression, suppression of angiogenesis, augmentation of tumor infiltrating lymphocytes, switch of intratumoral macrophages from M2 to M1 phenotype, augmentation of tumor infiltrating dendritic cells, reduction of tumor associated T regulatory cells, and reduction in tumor associated myeloid suppressor cells.
18. The method of claim 16 , wherein the checkpoint inhibitor is an agent capable of suppressing expression or activity of a molecule selected from a group consisting of PD-1, PD-L1, CTLA-4, PD-L2, LAG3, Tim3, 2B4, A2aR, ID02, B7-H3, B7-H4, BTLA, CD2, CD20, CD27, CD28, CD30, CD33, CD40, CD52, CD70, CD112, CD137, CD160, CD226, CD276, DR3, OX-40, GALS, GITR, ICOS, HVEM, IDO1, KIR, LAIR, LIGHT, MARCO, PS, SLAM, TIGIT, VISTA, and VTCN1.
19. The method of claim 16 , wherein the composition is administered at a concentration and frequency sufficient to inhibit activity of STAT3.
20. The method of claim 16 , wherein the composition is administered as a liquid suspension.
21. The method of claim 16 , wherein the composition is administered intravenously, intramuscularly, parenterally, nasally, intratumorally or orally.
22. The method of claim 16 , wherein the checkpoint inhibitor is administered intravenously, intramuscularly, parenterally, nasally, intratumorally, or orally.
23. The method of claim 16 , wherein the checkpoint inhibitor is an inhibitor of a checkpoint protein selected from the group consisting of PD-1, PD-L1, and CTLA-4.
24. The method of claim 23 , wherein the inhibitor of PD-1 is an anti-PD-1 antibody selected from the group consisting of nivolumab and pembrolizumab.
25. The method of claim 23 , wherein the inhibitor of PD-L1 is an anti-PD-L1 antibody selected from the group consisting of BMS-936559, durvalumab, atezolizumab, avelumab, MPDL3280A, MEDI4736, MSB0010718C, and MDX1105-01.
26. The method of claim 23 , wherein the inhibitor of CTLA-4 is an anti-CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.
27. The method of claim 16 , wherein the composition is administered at a dose and frequency sufficient to inhibit activity of STAT3.