PHARMACEUTICAL PRODRUGS AND METHODS OF THEIR PREPARATION AND USE
The disclosure provides compounds of Formula (I), wherein X, Y, and Z are defined herein. The disclosure also provides particles comprising one or more compounds described herein, compositions comprising one or more compounds or particles described herein and a pharmaceutically acceptable carrier, and methods of treating a subject in need thereof comprising administering one or more compounds, particles, or compositions described herein to the subject. X—Y—Z (I)
1 . Particles comprising a compound of Formula (I):
X—Y—Z (I)
wherein:
X is a biologically active moiety derived from a water-soluble, biologically active compound having a water solubility of 0.0001 to greater than or equal to about 1000 mg/mL;
Y comprises a first pH sensitive linker that is an optionally substituted histidine; and
Z is a hydrophobic moiety selected from an optionally substituted C 2-30 alkyl, C 2-30 alkenyl, or C 2-30 alkynyl;
Y is cleaved from the water-soluble, biologically active moiety upon exposure to a target pH which is less than about 7; and
the compound of Formula (I) is encapsulated in the particles.
2 . The particles of claim 1 , wherein the partition coefficient (log P) of the water-soluble, biologically active compound is about 7 or less or about 7 or greater.
3 . The particles of claim 1 , wherein the water-soluble, biologically active compound is an anti-inflammatory agent, anti-psychotic agent, anti-viral agent, chemotherapeutic agent, or dopamine modulating agent, or is indicated for the treatment of migraine or pain.
4 . The particles of claim 1 , wherein the water-soluble biologically active compound is actinomycin, azacitidine, belinostat, bendamustine, bleomycin, bortezomib, cabazitaxel, cadarbazine, cladribine, clofarabine, cytarabine, cyproterone, daunorubicin, decitabine, docetaxel, doxorubicin, epirubicin, eribulin, etoposide, floxuridine, fludarabine, gemcitabine, idarubicin, irinotecan, ixabepilone, levodopa, melphalan, methotrexate, mitomycin, mitoxantrone, nelarabine, paclitaxel, pemetrexed, pentostatin, pixantrone, pralatreate, raltitrexed, streptozocin, temozolomide, temsirolimus, teniposide, topotecan, trabectedin, treosulfan, vincristine, vindesine, vinflunine, or a salt thereof.
5 . The particles of claim 1 , wherein the water-soluble, biologically active compound comprises a nucleoside.
6 . The particles of claim 1 , wherein the target pH is about 5 to about 7.
7 . The particles of claim 1 , wherein Y further comprises a second pH sensitive linker.
8 . The particles of claim 8 , wherein the second pH sensitive linker is an optionally substituted tetrahydropyranyl ether, an optionally substituted tetrahydropyranyl ester, an optionally substituted azide, an optionally substituted histidine, an optionally substituted hydrazone, or an optionally substituted β-amino ester.
9 . The particles of claim 8 , wherein the second pH sensitive linker is -(tetrahydropyran ether)-(azide), -(hydrazone)-, -(hydrazone)-(azide)-, -(β-amino ester)-, -(β-amino ester)-(azide)-, or -(tetrahydropyran ester)-.
10 . The particles of claim 1 , wherein the compound of formula I is cleaved to produce the water-soluble biological compound after crossing the cell membrane of a cell.
11 . The particles of claim 1 , further comprising a low molecular weight polymer.
12 . The particles of claim 11 , wherein the polymer is a diblock or triblock copolymer.
13 . The particles of claim 12 , wherein at least one block of the copolymer comprises a water-soluble polymer.
14 . The particles of claim 13 , wherein the water-soluble polymer is a polyethylene glycol, optionally having a molecular weight of about 400 to about 5,000 Da.
15 . The particles of claim 13 , wherein a second block of the copolymer is a biodegradable, hydrophobic polymer, optionally having a molecular weight of about 1,000 to about 50,000 Da.
16 . The particles of claim 13 , wherein a second block of the copolymer is a poly(ethylene glycol)-b-poly(lactic acid) polymer, poly(lactic-co-glycolic acid), poly(caprolactone), or combinations thereof.
17 . The particles of claim 13 , wherein a second block of the copolymer comprises a pH-sensitive polymer or two blocks of the copolymer are linked with a pH-sensitive linker.
18 . The particles of claim 1 , which are nanoparticles, optionally having an average particle size of about 10 to about 200 nm, or microparticles, optionally having an average particle size of about 1 to about 200 μm.
19 . A composition comprising the particles of claim 1 and a pharmaceutically acceptable carrier.
20 . A method of treating a subject in need thereof, comprising administering the particles of claim 1 to the subject.