In situ activation of microcapsules
AssigneeThe United States of America as represented by the Administrator of the National Aeronautics and Space Administration
InventorsDennis R. Morrison, Benjamin Mosier
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Abstract
Disclosed are microcapsules comprising a polymer shell enclosing two or more immiscible liquid phases in which a drug, or a prodrug and a drug activator are partitioned into separate phases, or prevented from diffusing out of the microcapsule by a liquid phase in which the drug is poorly soluble. Also disclosed are methods of using the microcapsules for in situ activation of drugs, where upon exposure to an appropriate energy source the internal phases mix and the drug is activated in situ.
Claims76
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal liquids, wherein each internal liquid is immiscible with the other internal liquids, and all of the internal liquids are enclosed together in a single polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- wherein one of said internal liquid phases is an aqueous phase and one of said internal liquid phases is a hydrocarbon or oil phase,
- wherein said aqueous phase is in contact with the polymer membrane,
- wherein the drug precursor is more soluble in the hydrocarbon or oil phase than in the aqueous phase and the activated drug is more soluble in the aqueous phase than in the hydrocarbon or oil phase,
- wherein the pair consisting of said drug precursor and drug is chosen from the group consisting of papaverine and papaverine HCl, genoscopolamine and scopolamine, hematoporphyrin and dihematoporphyrin ester, and sulfamerazine sulfate and 2-sulfanilamido-4-methylpyrimidine.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- wherein one of said internal liquid phases is an aqueous phase and one of said internal liquid phases is a hydrocarbon or oil phase,
- wherein said hydrocarbon or oil phase is in contact with the polymer membrane,
- wherein the drug precursor is more soluble in the aqueous phase than in the hydrocarbon or oil phase and the activated drug is more soluble in the hydrocarbon or oil phase than in the aqueous phase,
- wherein the pair consisting of the drug precursor and the drug is chosen from the group consisting of floxuridine and 5-fluorouracil, cocaine hydrochloride and cocaine base, and estrone and estradiol.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source that causes the precursor to assume an active state,
- wherein the pair consisting of said drug precursor and the drug is chosen from the group consisting of dehydrocholesterol and vitamin D.sub.3, testosterone acetate and testosterone, ergosterol and vitamin D.sub.2, nitromethane and 1-methyl-2(1-hydroxy-1 methylethyl) diazene, and .alpha., .alpha.-dinitroketone and a diketone.
A micromixer useful for mixing two or more immiscible liquid phases contained in the micromixer comprising:
- a microcapsule comprising two or more immiscible internal liquid phases enclosed in a polymer shell and a radiant energy source effective to generate liquid flow within the microcapsule,
- said microcapsule formed by a method comprising:
- formulating a first phase comprising a first solvent, a first polymer soluble in said first phase and immiscible in a second phase, a co-solvent, oil, and water;
- formulating said second phase immiscible with said first phase, said second phase comprising a second solvent, a second polymer soluble in said second phase and immiscible in said first phase, a surface active agent, and a salt;
- said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first polymer;
- said second polymer having a hydrophilic/lipophilic balance value lower than that of said surface active agent;
- creating an interface between said first and second phases in a manner that limits fluid shear, and
- maintains adsorptive surface characteristics at said interface.
A composition comprising a drug or drug precursor contained in a microcapsule comprising two or more concentric, immiscible internal liquid phases enclosed in a polymer shell, wherein a first of said internal liquid phases is in contact with said polymer shell, and wherein a second of said internal liquid phases is separated from said polymer shell by said first internal liquid phase, and further wherein said drug or drug precursor is associated with said second internal liquid phase,
- wherein said microcapsule is formed by a method comprising:
- formulating a first phase comprising a first solvent, a first polymer soluble in said first phase and immiscible in a second phase, a co-solvent, oil, and water;
- formulating said second phase immiscible with said first phase, said second phase comprising a second solvent, a second polymer soluble in said second phase and immiscible in said first phase, a surface active agent, and a salt;
- said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first polymer;
- said second polymer having a hydrophilic/lipophilic balance value lower than that of said surface active agent;
- creating an interface between said first and second phases in a manner that limits fluid shear, and
- maintains adsorptive surface characteristics at said interface.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- wherein the microcapsule also contains a radiocontrast media.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- wherein the drug precursor is a proenzyme.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- wherein the drug precursor is selected from the group consisting of a pro-thrombolytic enzyme, a pro-urokinase and a pro-tissue plasminogen activator.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- wherein the energy is near infrared light of about 700-900 nanometer wavelength.
A method of in situ activation of a drug comprising:
- providing a micro capsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- wherein the energy is ultraviolet light of about 220-390 nanometer wavelength.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source in an amount effective to promote physical mixing of the immiscible liquid phases and to increase the activation kinetics of activation of the drug precursor,
- further defined as comprising administering said microcapsules to a subject, allowing said microcapsules to reach a target site and applying said energy to the subject.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases, wherein neither internal immiscible liquid phase is enclosed separately by a polymer shell but wherein the internal immiscible liquid phases are enclosed together in a single polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source that causes the precursor to assume an active state.
A composition comprising a drug or drug precursor contained in a microcapsule consisting of two or more concentric, immiscible internal liquid phases, wherein neither internal immiscible liquid phase is enclosed separately by a polymer shell but wherein the internal immiscible liquid phases are enclosed together in a single polymer shell, wherein a first of said internal liquid phases is in contact with said polymer shell, and wherein a second of said internal liquid phases is separated from said polymer shell by said first internal liquid phase, and further wherein said drug or drug precursor is associated with said second internal liquid phase.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source that causes the precursor to assume an active state,
- wherein the microcapsule also contains a radiocontrast media.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source that causes the precursor to assume an active state,
- wherein the microcapsule contains the radiocontrast media a halogenated oil.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source that causes the precursor to assume an active state,
- wherein the energy source is near infrared light of about 700-900 nanometer wavelength.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source that causes the precursor to assume an active state,
- wherein the energy source is ultraviolet light of about 220-390 nanometer wavelength.
A method of in situ activation of a drug comprising:
- providing a microcapsule wherein the microcapsule comprises two or more internal immiscible liquid phases enclosed in a polymer shell, a drug precursor associated with at least one internal liquid phase;
- and
- exposing the microcapsule to an energy source that causes the precursor to assume an active state,
- further defined as comprising administering said microcapsules to a subject, allowing said microcapsules to reach a target site and applying said energy to the subject.
A micromixer useful for mixing two or more immiscible liquid phases contained in the micromixer comprising:
- a microcapsule consisting of two or more immiscible internal liquid phases, wherein neither internal immiscible liquid phase is enclosed separately by a polymer shell but wherein the internal immiscible liquid phases are enclosed together in a single polymer shell and a radiant energy source effective to generate liquid flow within the microcapsule.
A micromixer useful for mixing two or more immiscible liquid phases contained in the micromixer comprising:
- a microcapsule comprising two or more immiscible internal liquid phases enclosed in a polymer shell and a radiant energy source effective to generate liquid flow within the microcapsule,
- wherein the energy source is a source of ultraviolet light at 220 to 390 nanometers wavelength.
Dependencies are inferred from the claim text.