Methods for micronization of hydrophobic drugs

Abstract

The invention involves methods and products related to the micronization of hydrophobic drugs. A method of micronizing hydrophobic drugs using a set of solutions including an aqueous solution is provided. The invention also relates to products of micronized hydrophobic drugs and related methods of use.

1 - 49 . (canceled)  
     
     
         50 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, wherein the first solvent is free of polymer, wherein the hydrophobic agent and the solvent form a mixture having a continuous phase,    introducing a second solvent into the mixture, and    introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is selected from the group consisting of anticonvulsant, antidiabetic, antifungal, antihypertensive, anti-infective, antimicrobial, antimycotic, antineoplastic, anti-cancer, anti-epileptic, antiparasitic, antiproliferative, antiviral, blood glucose regulator, diuretic, hormone, hypoglycemic, hypotensive, immunomodulator, immunoregulator, immunosuppressant, mood regulator, psychotropic, dyes, and imaging agents.    
     
     
         51 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, wherein the first solvent is free of polymer, wherein the hydrophobic agent and the solvent form a mixture having a continuous phase,    introducing a second solvent into the mixture, and    introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is an antineoplastic, anti-cancer, or antiproliferative agent.    
     
     
         52 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, wherein the first solvent is free of polymer, wherein the hydrophobic agent and the solvent form a mixture having a continuous phase,    introducing a second solvent into the mixture, and    introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is an antifungal or antimycotic agent.    
     
     
         53 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, wherein the first solvent is free of polymer, wherein the hydrophobic agent and the solvent form a mixture having a continuous phase,    introducing a second solvent into the mixture, and    introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is an anti-infective or antimicrobial agent.    
     
     
         54 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, wherein the first solvent is free of polymer, wherein the hydrophobic agent and the solvent form a mixture having a continuous phase,    introducing a second solvent into the mixture, and    introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is a dye or an imaging agent.    
     
     
         55 . The method of  claim 51 , wherein the anti-cancer agent is Paclitaxel.  
     
     
         56 . The method of  claim 50 , further comprising preparing microparticles by spray drying the micronized hydrophobic agent.  
     
     
         57 . The method of  claim 50 , further comprising preparing microparticles by performing phase inversion nanoencapsulation (PIN) on the micronized hydrophobic agent.  
     
     
         58 . The method of  claim 50 , wherein the second solvent is an alcohol.  
     
     
         59 . The method of  claim 50 , wherein greater than 90% of the micronized hydrophobic agent have a particle size less than 1 micron.  
     
     
         60 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, with a polymer, wherein the hydrophobic agent and the first solvent form a mixture having a continuous phase, introducing a second solvent into the mixture, and introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is selected from the group consisting of anticonvulsant, antidiabetic, antifungal, anti-infective, antimicrobial, antihypertensive, antimycotic, antineoplastic, anti-cancer, anti-epileptic, antiparasitic, antiproliferative, antiviral, blood glucose regulator, diuretic, hormone, hypoglycemic, hypotensive, immunomodulator, immunoregulator, immunosuppressant, mood regulator, psychotropic, dyes, and imaging agents.    
     
     
         61 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, with a polymer, wherein the hydrophobic agent and the first solvent form a mixture having a continuous phase, introducing a second solvent into the mixture, and introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is an antineoplastic, anti-cancer, or antiproliferative agent.    
     
     
         62 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, with a polymer, wherein the hydrophobic agent and the first solvent form a mixture having a continuous phase, introducing a second solvent into the mixture, and introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is an antifungal or antimycotic agent.    
     
     
         63 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, with a polymer, wherein the hydrophobic agent and the first solvent form a mixture having a continuous phase, introducing a second solvent into the mixture, and introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is an anti-infective or antimicrobial agent.    
     
     
         64 . A method for micronizing a hydrophobic agent, comprising: 
 dissolving a hydrophobic agent in an effective amount of a first solvent, with a polymer, wherein the hydrophobic agent and the first solvent form a mixture having a continuous phase, introducing a second solvent into the mixture, and introducing an aqueous solution into the mixture wherein the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less, and wherein the hydrophobic agent is a dye or an imaging agent.    
     
     
         65 . The method of  claim 61 , wherein the anti-cancer agent is Paclitaxel.  
     
     
         66 . The method of  claim 60 , wherein the preparation contains less than 5% polymer.  
     
     
         67 . The method of  claim 60 , further comprising preparing microparticles by performing phase inversion nanoencapsulation on the micronized hydrophobic agent.  
     
     
         68 . The method of  claim 60 , wherein the second solvent is an alcohol.  
     
     
         69 . The method of  claim 60 , wherein greater than 90% of the micronized hydrophobic agent have a particle size less than 1 micron.  
     
     
         70 . A preparation of micronized hydrophobic agent prepared according to the method of  claim 50 .  
     
     
         71 . A preparation of micronized hydrophobic agent prepared according to the method of  claim 60 .  
     
     
         72 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer carrier and is free of surfactant, and wherein the hydrophobic agent is selected from the group consisting of anticonvulsant, antidiabetic, antifingal, antihypertensive, anti-infective, antimicrobial, antimycotic, antineoplastic, anti-cancer, anti-epileptic, antiparasitic, antiproliferative, antiviral, blood glucose regulator, diuretic, hormone, hypoglycemic, hypotensive, immunomodulator, immunoregulator, immunosuppressant, mood regulator, psychotropic, dyes, and imaging agents.  
     
     
         73 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer carrier and is free of surfactant, and wherein the hydrophobic agent is an antineoplastic, anti-cancer, or antiproliferative agent.  
     
     
         74 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer carrier and is free of surfactant, and wherein the hydrophobic agent is an antifungal or antimycotic agent.  
     
     
         75 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer carrier and is free of surfactant, and wherein the hydrophobic agent is an anti-infective or antimicrobial agent.  
     
     
         76 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer carrier and is free of surfactant, and wherein the hydrophobic agent is a dye or an imaging agent.  
     
     
         77 . The composition of  claim 73 , wherein the anti-cancer agent is Paclitaxel.  
     
     
         78 . The composition of  claim 72 , wherein the wherein the preparation is free of polymer carrier.  
     
     
         79 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is free of polymer carrier and wherein the crystallinity of the micronized hydrophobic agent is at least 50% of the crystallinity of the non-micronized hydrophobic agent, and wherein the hydrophobic agent is selected from the group consisting of anticonvulsant, antidiabetic, antifungal, antihypertensive, anti-infective, antimicrobial, antimycotic, antineoplastic, anti-cancer, anti-epileptic, antiparasitic, antiproliferative, antiviral, blood glucose regulator, diuretic, hormone, hypoglycemic, hypotensive, immunomodulator, immunoregulator, immunosuppressant, mood regulator, psychotropic, dyes, and imaging agents.  
     
     
         80 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is free of polymer carrier and wherein the crystallinity of the micronized hydrophobic agent is at least 50% of the crystallinity of the non-micronized hydrophobic agent, and wherein the hydrophobic agent is an antineoplastic, anti-cancer, or antiproliferative agent.  
     
     
         81 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is free of polymer carrier and wherein the crystallinity of the micronized hydrophobic agent is at least 50% of the crystallinity of the non-micronized hydrophobic agent, and wherein the hydrophobic agent is an antifungal or antimycotic agent.  
     
     
         82 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is free of polymer carrier and wherein the crystallinity of the micronized hydrophobic agent is at least 50% of the crystallinity of the non-micronized hydrophobic agent, and wherein the hydrophobic agent is an anti-infective or antimicrobial agent.  
     
     
         83 . A composition, comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is free of polymer carrier and wherein the crystallinity of the micronized hydrophobic agent is at least 50% of the crystallinity of the non-micronized hydrophobic agent, and wherein the hydrophobic agent is a dye or an imaging agent.  
     
     
         84 . The composition of  claim 80 , wherein the anti-cancer agent is Paclitaxel.  
     
     
         85 . The composition of  claim 79 , wherein the crystallinity is at least 75%.  
     
     
         86 . The composition of  claim 79 , wherein the crystallinity is greater than 90%.  
     
     
         87 . A method for delivering an agent to a subject, comprising: 
 orally administering a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is selected from the group consisting of anticonvulsant, antidiabetic, antifungal, antihypertensive, anti-infective, antimicrobial, antimycotic, antineoplastic, anti-cancer, anti-epileptic, antiparasitic, antiproliferative, antiviral, blood glucose regulator, diuretic, hormone, hypoglycemic, hypotensive, immunomodulator, immunoregulator, immunosuppressant, mood regulator, psychotropic, dyes, and imaging agents.    
     
     
         88 . A method for delivering an agent to a subject, comprising: 
 orally administering a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is an antineoplastic, anti-cancer, or antiproliferative agent.    
     
     
         89 . A method for delivering an agent to a subject, comprising: 
 orally administering a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is an antifungal or antimycotic agent.    
     
     
         90 . A method for delivering an agent to a subject, comprising: 
 orally administering a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is an anti-infective or antimicrobial agent.    
     
     
         91 . A method for delivering an agent to a subject, comprising: 
 orally administering a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is a dye or an imaging agent.    
     
     
         92 . The method of  claim 88 , wherein the anti-cancer agent is Paclitaxel.  
     
     
         93 . The method of  claim 87 , wherein the bioactivity of the hydrophobic agent is retained.  
     
     
         94 . The method of  claim 87 , wherein there is at least a 5% increase in the relative bioavailability of the micronized hydrophobic agent as compared to the non-micronized hydrophobic agent.  
     
     
         95 . The method of  claim 87 , wherein the preparation is free of polymer.  
     
     
         96 . The method of  claim 87 , wherein the micronized hydrophobic agent is microencapsulated by phase inversion nanoencapsulation.  
     
     
         97 . A method for delivering an agent to a subject, comprising: 
 administering microparticles of a micronized hydrophobic agent encapsulated by phase inversion nanoencapsulation having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is selected from the group consisting of anticonvulsant, antidiabetic, antifungal, antihypertensive, anti-infective, antimicrobial, antimycotic, antineoplastic, anti-cancer, anti-epileptic, antiparasitic, antiproliferative, antiviral, blood glucose regulator, diuretic, hormone, hypoglycemic, hypotensive, immunomodulator, immunoregulator, immunosuppressant, mood regulator, psychotropic, dyes, and imaging agents.    
     
     
         98 . A method for delivering an agent to a subject, comprising: 
 administering microparticles of a micronized hydrophobic agent encapsulated by phase inversion nanoencapsulation having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is an antineoplastic, anti-cancer, or antiproliferative agent.    
     
     
         99 . A method for delivering an agent to a subject, comprising: 
 administering microparticles of a micronized hydrophobic agent encapsulated by phase inversion nanoencapsulation having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is an antifungal or antimycotic agent.    
     
     
         100 . A method for delivering an agent to a subject, comprising: 
 administering microparticles of a micronized hydrophobic agent encapsulated by phase inversion nanoencapsulation having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is an anti-infective or antimicrobial agent.    
     
     
         101 . A method for delivering an agent to a subject, comprising: 
 administering microparticles of a micronized hydrophobic agent encapsulated by phase inversion nanoencapsulation having an average particle size of less than 1 micron, wherein the preparation is composed of less than 5% polymer and is free of surfactant, and wherein the hydrophobic agent is a dye or an imaging agent.    
     
     
         102 . The method of  claim 98 , wherein the anti-cancer agent is Paclitaxel.  
     
     
         103 . The method of  claim 97 , wherein the microparticles are administered orally.  
     
     
         104 . The method of  claim 97 , wherein the bioactivity of the hydrophobic agent is retained.  
     
     
         105 . The method of  claim 97 , wherein there is at least a 5% increase in the relative bioavailability of the micronized hydrophobic agent as compared to the non-encapsulated micronized hydrophobic agent.  
     
     
         106 . The method of  claim 97 , wherein the preparation is free of polymer.  
     
     
         107 . A method for achieving 100% bioactivity comprising: 
 orally administering to the subject a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein 100% of the orally administered agent is bioactive, and wherein the hydrophobic agent is selected from the group consisting of anticonvulsant, antidiabetic, antifingal, antihypertensive, anti-infective, antimicrobial, antimycotic, antineoplastic, anti-cancer, anti-epileptic, antiparasitic, antiproliferative, antiviral, blood glucose regulator, diuretic, hormone, hypoglycemic, hypotensive, immunomodulator, immunoregulator, immunosuppressant, mood regulator, psychotropic, dyes, and imaging agents.    
     
     
         108 . A method for achieving 100% bioactivity comprising: 
 orally administering to the subject a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein 100% of the orally administered agent is bioactive, and wherein the hydrophobic agent is an antineoplastic, anti-cancer, or antiproliferative agent.    
     
     
         109 . A method for achieving 100% bioactivity comprising: 
 orally administering to the subject a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein 100% of the orally administered agent is bioactive, and wherein the hydrophobic agent is an antifungal or antimycotic agent.    
     
     
         110 . A method for achieving 100% bioactivity comprising: 
 orally administering to the subject a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein 100% of the orally administered agent is bioactive, and wherein the hydrophobic agent is an anti-infective or antimicrobial agent.    
     
     
         111 . A method for achieving 100% bioactivity comprising: 
 orally administering to the subject a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein 100% of the orally administered agent is bioactive, and wherein the hydrophobic agent is a dye or an imaging agent.    
     
     
         112 . The method of  claim 108 , wherein the anti-cancer agent is Paclitaxel.  
     
     
         113 . The method of  claim 107 , wherein the preparation is composed of less than 5% polymer and is free of surfactant.  
     
     
         114 . The method of  claim 107 , wherein the preparation is free of polymer.