Stabilization and acoustic activation of polymeric micelles for drug delivery

A method for manufacture of a stabilized micelle delivery system for a lipophilic or hydrophilic substance comprising:

• stabilizing micelles comprising a block polymer having a hydrophobic block and a hydrophilic block where the hydrophobic block forms a core of the micelle with corona from the hydrophilic block, the method comprising polymerizing a hydrogel with a temperature-responsive low critical solution temperature (LCST) in the micelle core to form an interpenetrating network in the core, using an initiator that is hydrophobic such that polymerization of hydrogel occurs in the core, with only a minor amount occurring outside of the core;
• controlling the temperature of the micelles to achieve a first temperature which is below the LCST such that the hydrogel in the core of the micelle is in a swollen state sufficient to swell the core of the micelle;
• loading substances into the micelles to diffuse the substance into the swollen cores of the micelles, and
• controlling the temperature of the micelles to achieve a second temperature of the micelles above the LCST at which the gel collapses to a dense phase to form dense core in which the substance is retained in the core.

A method for administering a hydrophobic drug to a patient, the method comprising:

• stabilizing micelles comprising a block polymer having a hydrophobic block and a hydrophilic block where the hydrophobic block forms a core of the micelle with corona from the hydrophilic block, the method comprising polymerizing a hydro gel with a temperature-responsive low critical solution temperature (LCST) in the micelle core to form an interpenetrating network in the core, using an initiator that is hydrophobic such that polymerization of hydrogel occurs in the core, with only a minor amount occurring outside of the core,
• controlling the temperature of the micelles to achieve a first temperature which is below the LCST such that the hydrogel in the core of the micelle is in a swollen state sufficient to swell the core of the micelle,
• loading the drugs into the micelles to diffuse drug into the swollen cores of the micelles,
• controlling the temperature of the micelles to achieve a second temperature near the temperature of the body, which temperature is above the LCST at which the gel collapses to a dense phase to form dense core in which drug is retained in the core,
• administering the micelles into the patient's bloodstream or desired site in the patient's body, and
• subjecting a region of the body to which the drug is to be administered to pulsed ultrasound signal in which pulses are timed to release the drug when the ultrasound is on.

A method for manufacturing a stabilized micelle delivery system for a lipophilic or hydrophilic substance, the method comprising:

• stabilizing micelles comprising a block polymer having a hydrophobic block and a hydrophilic block where the hydrophobic block forms a core of the micelle with a corona from the hydrophilic block, said stabilizing comprising polymerizing a hydrogel with a temperature-responsive low critical solution temperature (LCST) in the micelle core to form an interpenetrating network in the core, using an initiator that is hydrophobic such that polymerization of the hydrogel occurs in the core, with only a minor amount occurring outside of the core, wherein the hydrogel is selected from the group consisting of N-isopropylacrylamide, N,N-diethylacrylamide N,N-diethylmethacrylamide, N-isopropylmethacrylamide, N-n-butylacrylamide, other mono- and di-alkyl substituted acrylamides, acrylic acid, methacrylic acid, and mixtures thereof;
• controlling the temperature of the micelles to achieve a first temperature which is below the LCST such that the hydrogel in the core of the micelle is in a swollen state sufficient to swell the core of the micelle;
• loading substances into the micelles to diffuse the substance into the swollen cores of the micelles, and
• controlling the temperature of the micelles to achieve a second temperature of the micelles above the LCST at which the gel collapses to a dense phase to form dense core in which the substance is retained in the core.

A method for manufacturing a stabilized micelle delivery system for a lipophilic or hydrophilic substance, the method comprising:

• stabilizing micelles comprising a block polymer having a hydrophobic block and a hydrophilic block where the hydrophobic block forms a core of the micelle with a corona from the hydrophilic block, said stabilizing comprising polymerizing a hydrogel with a temperature-responsive low critical solution temperature (LCST) in the micelle core to form an interpenetrating network in the core, using an initiator that is hydrophobic such that polymerization of the hydrogel occurs in the core, with only a minor amount occurring outside of the core, wherein the hydrogel is copolymerized with acrylic acid to shift the LCST upward;
• controlling the temperature of the micelles to achieve a first temperature which is below the LCST such that the hydrogel in the core of the micelle is in a swollen state sufficient to swell the core of the micelle;
• loading substances into the micelles to diffuse the substance into the swollen cores of the micelles, and
• controlling the temperature of the micelles to achieve a second temperature of the micelles above the LCST at which the gel collapses to a dense phase to form dense core in which the substance is retained in the core.

A method for manufacturing a stabilized micelle delivery system for a lipophilic or hydrophilic substance, the method comprising:

• stabilizing micelles comprising a block polymer having a hydrophobic block and a hydrophilic block where the hydrophobic block forms a core of the micelle with a corona from the hydrophilic block, said stabilizing comprising polymerizing a hydrogel with a temperature-responsive low critical solution temperature (LCST) in the micelle core to form an interpenetrating network in the core, using an initiator that is hydrophobic such that polymerization of the hydrogel occurs in the core, with only a minor amount occurring outside of the core, wherein the hydrogel is copolymerized with hydrophobic butyl acrylate to shift the LCST downward;
• controlling the temperature of the micelles to achieve a first temperature which is below the LCST such that the hydrogel in the core of the micelle is in a swollen state sufficient to swell the core of the micelle;
• loading substances into the micelles to diffuse the substance into the swollen cores of the micelles, and
• controlling the temperature of the micelles to achieve a second temperature of the micelles above the LCST at which the gel collapses to a dense phase to form dense core in which the substance is retained in the core.

A method for manufacturing a stabilized micelle delivery system for a lipophilic or hydrophilic substance, the method comprising:

• stabilizing micelles comprising a block polymer having a hydrophobic block and a hydrophilic block where the hydrophobic block forms a core of the micelle with a corona from the hydrophilic block, said stabilizing comprising polymerizing a hydrogel with a temperature-responsive low critical solution temperature (LCST) in the micelle core to form an interpenetrating network in the core, using an initiator that is hydrophobic such that polymerization of the hydrogel occurs in the core, with only a minor amount occurring outside of the core, wherein the hydrogel is copolymerized with acylamide, acrylic, or methacrylic comonomer to change the LCST;
• controlling the temperature of the micelles to achieve a first temperature which is below the LCST such that the hydrogel in the core of the micelle is in a swollen state sufficient to swell the core of the micelle;
• loading substances into the micelles to diffuse the substance into the swollen cores of the micelles, and
• controlling the temperature of the micelles to achieve a second temperature of the micelles above the LCST at which the gel collapses to a dense phase to form dense core in which the substance is retained in the core.

A method for manufacturing a stabilized micelle delivery system for a drug, wherein the drug is released from the stabilized micelle by subjecting the stabilized micelle to a pulsed ultrasound signal, the method comprising:

• stabilizing micelles comprising a block polymer having a hydrophobic block and a hydrophilic block where the hydrophobic block forms a core of the micelle with a corona from the hydrophilic block, said stabilizing comprising polymerizing a hydrogel with a temperature-responsive low critical solution temperature (LCST) in the micelle core to form an interpenetrating network in the core, using an initiator that is hydrophobic such that polymerization of the hydrogel occurs in the core, with only a minor amount occurring outside of the core;
• controlling the temperature of the micelles to achieve a first temperature which is below the LCST such that the hydrogel in the core of the micelle is in a swollen state sufficient to swell the core of the micelle;
• loading the drug into the micelles to diffuse the drug into the swollen cores of the micelles;
• and
• controlling the temperature of the micelles to achieve a second temperature of the micelles above the LCST at which the gel collapses to a dense phase to form dense core in which the drug is retained in the core.