LPXC INHIBITOR, FORMULATIONS, AND USES THEREOF
Provided herein is an LpxC inhibitor compound, as well as pharmaceutical compositions comprising said compound, and methods of use thereof in the treatment of disease that would benefit from treatment with an LpxC inhibitor, including gram-negative bacterial infections such as urinary tract infections and the like.
1 . A pharmaceutical composition, comprising:
(i) (S)-1-(3-(5,6-dihydroxypyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile (Compound A):
or an isotopic variant, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate thereof; and
(ii) at least one pharmaceutically acceptable excipient.
2 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in a dosage form for dosing or administration by injection.
3 .- 9 . (canceled)
10 . The pharmaceutical composition of any one claim 2 , wherein the at least one pharmaceutically acceptable excipient is a complexing agent comprising α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin (MBCD), (2-hydroxypropyl)-β-cyclodextrin (HPβCD), sulfobutylether-β-cyclodextrin (SBEβCD), or a combination thereof.
11 . (canceled)
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13 . The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition comprises from about 1% to about 20% sulfobutylether-β-cyclodextrin (SBEβCD).
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18 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition has a pH of from about 4.0 to about 5.0.
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21 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition comprises from about 0.1 mg/mL to about 100 mg/mL of Compound A, or an isotopic variant, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate thereof.
22 . (canceled)
23 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition comprises from about 15 mg/mL to about 35 mg/mL of Compound A, or an isotopic variant, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate thereof; or wherein the pharmaceutical composition comprises from about 15 mg/a to about 25 mg/a of Compound A, or an isotopic variant, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate thereof.
24 .- 27 . (canceled)
28 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in a dosage form for oral dosing or administration.
29 . (canceled)
30 . The pharmaceutical composition claim 28 , wherein the dosage form is a suspension, solution, syrup, elixir, suspension, nanosuspension, solution, tablet, or capsule.
31 .- 37 . (canceled)
38 . The pharmaceutical composition of claim 28 , wherein Compound A, or an isotopic variant, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate thereof, is in an amorphous solid dispersion.
39 . (canceled)
40 . The pharmaceutical composition of claim 38 , wherein the amorphous solid dispersion further comprising a cellulose polymer excipient comprising cellulose acetate phthalate, carboxymethylcellulose sodium, hydroxypropylcellulose acetate succinate, hydroxypropyl methylcellulose 606(HPMC 606), or hydroxypropyl methylcellulose phthalate (HP-55).
41 . (canceled)
42 . The pharmaceutical composition of claim 28 , wherein the at least one pharmaceutically acceptable excipient is a co-solvent, oil, surfactant, complexing agent, a solubilizing polymer, a P-gp modulator, a buffering agent, or a combination thereof.
43 . The pharmaceutical composition of claim 42 , wherein:
the co-solvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, transcutol, glycerin, or a combination thereof;
the oil comprises sesame oil, soybean oil, vegetable oil, poppyseed oil, safflower oil, peppermint oil, castor oil, oleic acid, maisine CC, capmul MCM, or a combination thereof,
the surfactant comprises polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, Gelucire 44/14, vitamin E TPGS, Cremophor RH40, Cremophore RH60, Labrafil M 1944, Labrafil M 2125, Solutol HS 15, or a combination thereof;
the complexing agent comprises α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin (MBCD), (2-hydroxypropyl)-β-cyclodextrin (HPβCD), sulfobutylether-β-cyclodextrin (SBEβCD), or a combination thereof;
the solubilizing polymer comprises cellulose acetate phthalate, carboxymethylcellulose sodium, hydroxypropylcellulose acetate succinate, hydroxypropyl methylcellulose 606 (HPMC 606), hydroxypropyl methylcellulose phthalate (HP-55), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus, PCL-PVAc-PEG), or poly(propylene oxide)-poly(ethylene oxide)copolymer (Paloxomer);
the P-gp modulator comprises vitamin E TPGS or cyclosporin A; and
the buffering agent comprises phosphate, citrate, lactic acid, proline, histidine, or hydroxide, or a combination thereof.
44 .- 50 . (canceled)
51 . The pharmaceutical composition of claim 28 , wherein the pharmaceutical composition comprises from about 25% to about 50% sulfobutylether-β-cyclodextrin (SBEβCD), from about 0.05% to about 0.5% HPMC606, and from about 1% to about 10% vitamin E TPGS; and wherein the pharmaceutical composition has a pH of from about 3.0 to about 4.5.
52 .- 63 . (canceled)
64 . The pharmaceutical composition of claim 28 , wherein the pharmaceutical composition comprises from about 0.1 mg/mL to about 100 mg/mL of Compound A, or an isotopic variant, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate thereof.
65 . (canceled)
66 . The pharmaceutical composition of claim 28 , wherein the pharmaceutical composition comprises from about 1 mg/mL to about 10 mg/mL of Compound A, or an isotopic variant, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate thereof.
67 .- 69 . (canceled)
70 . A method of treating a gram-negative bacterial infection in a patient in need thereof comprising administering to the patient the pharmaceutical composition of claim 1 .
71 . The method of claim 70 , wherein the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skin infection and urinary tract infection.
72 . The method of claim 70 , wherein the gram-negative bacterial infection is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infections, bladder infections, urethral infections and kidney infections.
73 . (canceled)
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76 . The method of claim 70 , wherein the composition is administered to the patient by I.V. injection or infusion: or wherein the composition is administered to the patient orally.
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