US2020330432A1PendingUtilityA1

Therapeutics for preterm labor management

45
Assignee: UNIV TEXASPriority: Dec 18, 2015Filed: Jul 2, 2020Published: Oct 22, 2020
Est. expiryDec 18, 2035(~9.4 yrs left)· nominal 20-yr term from priority
Inventors:Jerrie S. RefuerzoBiana GodinMonica Longo
A61K 47/62A61K 31/405A61K 38/095A61K 9/1271A61P 15/06A61K 9/127A61P 15/00A61K 9/0019A61K 47/6911C07K 7/16
45
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Claims

Abstract

Methods and compositions are provided for treating and preventing preterm labor using liposome encapsulated tocolytic agents, such as indomethacin. In certain aspects, targeted liposomes are provided that allow delivery of tocolytic agents directly to the uterus, such as by targeting to the oxytocin receptor.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A pharmaceutical composition comprising a tocolytic agent encapsulated in a liposome, wherein the liposome comprises a targeting moiety that binds to an oxytocin receptor. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the tocolytic agent is an agent that crosses the placenta. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the tocolytic agent comprises β2-adrenergic agonist, a calcium-channel blocker, a oxytocin receptor antagonist (ORA), prostaglandin F2α receptor inhibitor, a nitric oxide donor or a nonsteroidal anti-inflammatory drug (NSAID). 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the β2-adrenergic agonist comprises terbutaline, ritodrine, fenoterol, salbutamol, bedoradrine sulfae, MN-221, isoxsuprine, hexoprenaline, nylidrine salbutamol or fenoterol. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein the calcium-channel blocker comprises nifedipine or nicardipine. 
     
     
         6 . The pharmaceutical composition of  claim 3 , wherein the ORA comprises atosiban, retosiban, barusiban or epelsiban. 
     
     
         7 . The pharmaceutical composition of  claim 3 , wherein the ORA comprises carbetocin, TC OT 39, WAY 267464 dihydrochloride, [Thr4]OT, [HO1][Thr4]OT, [Thr4,Gly7]OT and [HO1][Thr4,Gly7]OT. 
     
     
         8 . The pharmaceutical composition of  claim 3 , wherein the prostaglandin F2α receptor inhibitor comprises OBE-001, OBE-002 or PDC-31. 
     
     
         9 . The pharmaceutical composition of  claim 3 , wherein the NSAID comprises indomethacin, sulindac, ketorolac, celecoxib, rofecoxib or nimesulide. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the composition comprises indomethacin. 
     
     
         11 . The pharmaceutical composition of  claim 3 , wherein the Nitric oxide donor comprises sildenafil, nitric oxide or nitroglycerin. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the tocolytic agent comprises magnesium sulfate, progesterone or ethanol. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the targeting moiety comprises an oxytocin receptor agonist or antagonist. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the oxytocin receptor agonist is oxytocin, carbetocin, TC OT 39, WAY 267464 dihydrochloride, [Thr 4 ]-oxytocin peptide, [HO 1 ][Thr 4 ]-oxytocin peptide, [Thr 4 ,Gly 7 ]-oxytocin peptide, or [HO 1 ][Thr 4 ,Gly 7 ]-oxytocin peptide. 
     
     
         15 . The pharmaceutical composition of  claim 13 , wherein the oxytocin receptor agonist is oxytocin. 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the oxytocin receptor antagonist is atosiban, retosiban, barusiban or epelsiban. 
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the oxytocin receptor antagonist is atosiban. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the targeting moiety comprises a protein, an antibody, a peptide, an aptamer, or a thioaptamer. 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the targeting moiety is conjugated to the surface of the liposome. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the targeting moiety is conjugated to a phospholipid in the liposome. 
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein the targeting moiety is conjugated to a PEGylated lipid. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the targeting moiety is conjugated to a PEGylated phospholipid. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the PEGylated phospholipid comprises 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE). 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the PEGylated phospholipid comprises DSPE-PEG(2000) carboxylic acid. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the targeting moiety comprises DSPE-PEG(2000)-atosiban ( FIG. 5B ). 
     
     
         26 . The pharmaceutical composition of  claim 19 , wherein the targeting moiety is conjugated by a carbodiimide crosslinker. 
     
     
         27 . The pharmaceutical composition of  claim 19 , wherein the targeting moiety is conjugated by a 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) crosslinker. 
     
     
         28 . The pharmaceutical composition of  claim 1 , wherein the liposome comprises at least a first phospholipid. 
     
     
         29 . The pharmaceutical composition of  claim 1 , wherein the liposome comprises at least a PEGylated lipid. 
     
     
         30 . The pharmaceutical composition of  claim 1 , wherein the liposome comprises at least a first cationic, anionic or zwitterionic lipid. 
     
     
         31 . The pharmaceutical composition of  claim 1 , wherein the liposome comprises cholesterol. 
     
     
         32 . The pharmaceutical composition of  claim 1 , wherein the composition comprises a plurality of liposomes having an average diameter of about 50 to 500 nm. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the liposomes have an average diameter of about 100 to 200 nm. 
     
     
         34 . The pharmaceutical composition of  claim 1 , wherein the tocolytic agent comprises indomethacin and the targeting moiety comprises an oxytocin receptor antagonist that is conjugated to the liposome. 
     
     
         35 . A composition in accordance with any one of  claims 1 - 34  for use in treatment of a patent. 
     
     
         36 . The composition of  claim 35 , wherein the patient is pregnant and is entering, or at risk for entering, pre-term labor. 
     
     
         37 . A method of treating a pregnant patient to slow or prevent preterm labor comprising administering the patient and effective amount of a tocolytic agent encapsulated in a liposome. 
     
     
         38 . The method of  claim 37 , wherein the patient is a human patient. 
     
     
         39 . The method of  claim 37 , wherein the patient is a domestic or livestock animal. 
     
     
         40 . The method of  claim 37 , wherein the liposome comprises a targeting moiety that targets the liposome to the uterus. 
     
     
         41 . The method of  claim 37 , wherein the liposome comprises a targeting moiety that binds to an oxytocin receptor. 
     
     
         42 . The method of  claim 37 , wherein the tocolytic agent is an agent that crosses the placenta. 
     
     
         43 . The method of  claim 37 , wherein the tocolytic agent comprises β2-adrenergic agonist, a calcium-channel blocker, an oxytocin receptor antagonist (ORA), prostaglandin F2α receptor inhibitor, a nitric oxide donor or a nonsteroidal anti-inflammatory drug (NSAID). 
     
     
         44 . The method of  claim 43 , wherein the β2-adrenergic agonist comprises terbutaline, ritodrine, fenoterol, salbutamol, bedoradrine sulfae, MN-221, isoxsuprine, hexoprenaline, nylidrine salbutamol or fenoterol. 
     
     
         45 . The method of  claim 37 , wherein the calcium-channel blocker comprises nifedipine or nicardipine. 
     
     
         46 . The method of  claim 43 , wherein the ORA comprises atosiban, retosiban, barusiban or epelsiban. 
     
     
         47 . The method of  claim 43 , wherein the ORA comprises carbetocin, TC OT 39, WAY 267464 dihydrochloride, [Thr4]OT, [HO1][Thr4]OT, [Thr4,Gly7]OT and [HO1][Thr4,Gly7]OT. 
     
     
         48 . The method of  claim 43 , wherein the prostaglandin F2α receptor inhibitor comprises OBE-001, OBE-002 or PDC-31. 
     
     
         49 . The method of  claim 43 , wherein the NSAID comprises indomethacin, sulindac, ketorolac, celecoxib, rofecoxib or nimesulide. 
     
     
         50 . The method of  claim 49 , wherein the composition comprises indomethacin. 
     
     
         51 . The method of  claim 43 , wherein the Nitric oxide donor comprises sildenafil, nitric oxide or nitroglycerin. 
     
     
         52 . The method of  claim 37 , wherein the tocolytic agent comprises magnesium sulfate, progesterone or ethanol. 
     
     
         53 . The method of  claim 37 , wherein the targeting moiety comprises a oxytocin receptor agonist or antagonist. 
     
     
         54 . The method of  claim 53 , wherein the oxytocin receptor agonist is oxytocin. 
     
     
         55 . The method of  claim 53 , wherein the oxytocin receptor antagonist is atosiban, retosiban, barusiban or epelsiban. 
     
     
         56 . The method of  claim 53 , wherein the oxytocin receptor antagonist is atosiban. 
     
     
         57 . The method of  claim 41 , wherein the targeting moiety comprises an antibody or apatmer. 
     
     
         58 . The method of  claim 40 , wherein the targeting moiety is conjugated to the surface of the liposome. 
     
     
         59 . The method of  claim 58 , wherein the targeting moiety is conjugated to a phospholipid in the liposome. 
     
     
         60 . The method of  claim 58 , wherein the targeting moiety is conjugated to a PEGylated lipid. 
     
     
         61 . The method of  claim 60 , wherein the targeting moiety is conjugated to a PEGylated phospholipid. 
     
     
         62 . The method of  claim 61 , wherein the PEGylated phospholipid comprises 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE). 
     
     
         63 . The method of  claim 62 , wherein the PEGylated phospholipid comprises DSPE-PEG(2000) carboxylic acid. 
     
     
         64 . The method of  claim 63 , wherein the targeting moiety comprises DSPE-PEG(2000)-atosiban ( FIG. 5B ). 
     
     
         65 . The method of  claim 58 , wherein the targeting moiety is conjugated by a carbodiimide crosslinker. 
     
     
         66 . The method of  claim 58 , wherein the targeting moiety is conjugated by a 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) crosslinker. 
     
     
         67 . The method of  claim 37 , wherein the liposome comprises at least a first phospholipid. 
     
     
         68 . The method of  claim 37 , wherein the liposome comprises at least a PEGylated lipid. 
     
     
         69 . The method of  claim 37 , wherein the liposome comprises at least a first cationic, anionic or zwitterionic lipid. 
     
     
         70 . The method of  claim 37 , wherein the liposome comprises cholesterol. 
     
     
         71 . The method of  claim 37 , wherein the composition comprises a plurality of liposomes having an average diameter of about 50 to 500 nm. 
     
     
         72 . The method of  claim 71 , wherein the liposomes have an average diameter of about 100 to 200 nm. 
     
     
         73 . The method of  claim 41 , wherein the tocolytic agent comprises indomethacin and the targeting moiety comprises an oxytocin receptor antagonist that is conjugated to the liposome.

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