Surface-modified microparticles and methods of forming and using the same

Abstract

Surface-modified microparticles and methods of making and using such particles are disclosed. The surface modified microparticles include a preformed or core microparticle that contains at least one active agent. The outer surface of the preformed or core microparticle carries a net surface charge. A monolayer is associated with the outer surface of the preformed or core microparticle. The monolayer includes at least one charged compound that has a charge that is different from the net surface charge of the preformed or core microparticle,

1 . A method for preparing a surface-modified microparticle, comprising: 
 providing a solid and amorphous preformed microparticle comprising at least one active agent, said microparticle having an outer surface carrying a net surface charge;    exposing at least said outer surface of said preformed microparticle to at least one charged compound having a net charge that is opposite in sign to said net surface charge; and    forming a monolayer comprising said at least one charged compound, whereby said formed monolayer is associated with said outer surface,    
   
   
       2 . The method of  claim 1 , wherein said formed monolayer has an outer surface carrying a net surface charge that is different from that of said preformed microparticle.  
   
   
       3 . The method of  claim 1 , wherein said outer surface of said preformed microparticle consists substantially of said at least one active agent.  
   
   
       4 . The method of  claim 2 , wherein said formed monolayer is a saturated monolayer and said net surface charge is opposite in sign to that of said preformed microparticle.  
   
   
       5 . The method of  claim 1 , wherein said preformed microparticle comprises, by weight, approximately 40% to less than 100% of said at least one active agent distributed substantially homogeneously throughout said preformed microparticle.  
   
   
       6 . The method of  claim 1  wherein said preformed microparticle comprises, by weight, 80% or greater of said at least one active agent distributed substantially homogenously throughout said preformed microparticle.  
   
   
       7 . The method of  claim 1 , wherein said exposing further comprises: 
 providing a solution comprising said at least one charged compound and one or more of water, a buffer, and a water-miscible organic solvent and one or more solubility reducing agents; and    contacting said preformed microparticle in said solution.    
   
   
       8 . The method of  claim 1 , wherein said net surface charge is contributed substantially by said at least one active agent.  
   
   
       9 . The method of  claim 7 , wherein said one or more solubility reducing agents comprise one or more of alcohols, carbohydrates, non-ionic aqueous-miscible polymers, and inorganic ionic compounds comprising polyvalent cations.  
   
   
       10 . The method of  claim 7 , wherein said solution comprises, in weight-to-volume percentage, 16% polyethylene glycol and 0.7% sodium chloride and has a pH of between 4and 10.  
   
   
       11 . The method of  claim 7 , wherein said solution has a pH that differs from a surface-neutral point of said preformed microparticle by 0 to less than 0.3.  
   
   
       12 . The method of  claim 7 , wherein said solution has a pH that differs from a surface-neutral point of said preformed microparticle by 0.3 or greater.  
   
   
       13 . The method of  claim 1 , wherein said exposing is carried out at a temperature between 2° C. and 5° C.  
   
   
       14 . The method of  claim 1 , further comprising carrying out one or more treatments to the surface-modified microparticle, the treatments comprising manipulations of temperature, pressure, pH or a combination thereof.  
   
   
       15 . The method of  claim 14 , wherein the treatment comprises heating a suspension including the microparticle at an elevated temperature.  
   
   
       16 . The method of  claim 15  further comprising allowing said suspension to arrive at a depressed temperature that is lower than said elevated temperature.  
   
   
       17 . The method of  claim 7 , further comprising separating said surface-modified microparticle from said solution.  
   
   
       18 . The method of  claim 1 , wherein said at least one charged compound comprises one or more of polyelectrolytes, charged polyaminoacids, charged polysaccharides, polyionic polymers, charged peptides, charged proteinaceous compounds, charged lipids optionally in combination with uncharged lipids, charged lipid structures, and derivatives thereof.  
   
   
       19 . The method of  claim 1 , further comprising: 
 exposing at least said outer surface of a formed monolayer to at least one different charged compound having a net charge that is opposite in sign to said net surface charge of said formed monolayer; and    forming a subsequent monolayer comprising said at least one different charged compound, wherein said subsequent monolayer is associated with said formed monolayer    
   
   
       20 . The method of  claim 19 , wherein said subsequent monolayer has an outer surface carrying a net surface charge that is opposite in sign to that of said formed monolayer.  
   
   
       21 . The method of  claim 20 , further comprising forming one to five additional alternatingly charged monolayers.  
   
   
       22 . The method of  claim 20 , further comprising forming an odd number of additional alternatingly charged monolayers.  
   
   
       23 . The method of  claim 1 , further comprising forming said surface-modified microparticle capable of controlled release of said at least one active agent.  
   
   
       24 . The method of  claim 23 , wherein said controlled release comprises an initial burst and a substantially linear release profile.  
   
   
       25 . The method of  claim 1 , wherein said preformed microparticle is spherical.  
   
   
       26 . The microparticle of  claim 1  wherein said at least one active agent is a proteinaceous compound.  
   
   
       27 . The method of  claim 1 , wherein said preformed microparticle is free of covalent crosslinking and free of hydrogel.  
   
   
       28 . The method of  claim 1 , wherein said preformed microparticle is free of lipids and free of encapsulation.  
   
   
       29 . A method for preparing a surface-modified microparticle, comprising: 
 providing a liquid continuous phase system comprising at least one solvent, at least one active agent, at least one phase-separation enhancing agent;    inducing a phase change at optionally a controlled rate in said system to cause a liquid-solid phase separation;    forming a solid phase that comprises an amorphous and solid microparticle comprising said at least one active agent and having an outer surface carrying a net surface charge, and a liquid phase that comprises said solvent and said at least one phase-separation enhancing agents;    exposing at least said outer surface of said formed microparticle to at least one charged compound having a net charge that is opposite in sign to said net surface charge; and    forming a monolayer comprising said at least one charged compound, wherein said formed monolayer is associated with said outer surface of said formed microparticle.    
   
   
       30 . The method of  claim 29 , wherein said method is free of washing said formed microparticle prior to said exposing.  
   
   
       31 . The method of  claim 29 , further comprising washing said formed microparticle in the presence of at least one phase-separation enhancing agents prior to said exposing.  
   
   
       32 . The method of  claim 29 , wherein said exposing is carried out in the presence of at least one phase separation enhancing agents.  
   
   
       33 . The method of  claim 29  wherein said preformed microparticle comprises, by weight, 80% or greater of said at least one active agent distributed substantially homogenously throughout said preformed microparticle.  
   
   
       34 . The method of  claim 34 , wherein said exposing comprises: 
 providing a solution that comprises said at least one charged compound, optionally a polyvalent cation, and, in weight-to-volume percentage, 16% polyethylene glycol and 0.7% sodium chloride, and    incubating said formed microparticle in said solution at a temperature of 2° C. to 5° C. over a period of 1 second to 10 hours.    
   
   
       35 . The method of  claim 29 , wherein said at least one charged compound is provided in a solution having a pH that differs from a surface-neutral point of said formed microparticle by 0 to less than 0.3.  
   
   
       36 . The method of  claim 29 , wherein said at least one charged compound is provided in a solution having a pH that differs from a surface-neutral point of said formed microparticle by 0.3 or greater.  
   
   
       37 . The method of  claim 29 , further comprising forming said surface-modified microparticle having a monodisperse or polydisperse size distribution.  
   
   
       38 . A method for preparing a surface-modified microparticle, comprising: 
 providing an amorphous and solid preformed microparticle comprising at least one active agent, said preformed microparticle having an outer surface carrying a net surface charge;    exposing at least said outer surface of said preformed microparticle to at least one charged compound having a net charge that is opposite in sign to said net surface charge of said preformed microparticle;    forming an intermediate microparticle that comprises said preformed microparticle and a formed monolayer comprising said at least one charged compound, wherein said formed monolayer is associated with said outer surface of said preformed microparticle;    exposing at least said formed monolayer to at least one different charged compound;    forming said surface-modified microparticle that comprises said intermediate microparticle and a subsequent monolayer comprising said at least one different charged compound, wherein said surface-modified microparticle has a release profile for release of said at least one active agent that is different from the release profile of said intermediate microparticle.    
   
   
       39 . The method of  claim 38  further comprising carrying out one or more treatments to said intermediate microparticle, the treatment comprising manipulation of temperature, pressure, pH or a combination thereof.  
   
   
       40 . A method of  claim 39  wherein the treating comprises heating a suspension including the microparticle at an elevated temperature.  
   
   
       41 . A microparticle comprising: 
 a solid, amorphous core microparticle comprising 80% or greater, by weight, of at least one active agent, said core microparticle comprising an outer surface carrying a net surface charge; and    a monolayer comprising at least one charged compound associated at least by electrostatic interaction with said outer surface of said core microparticle, said charged compound having a net charge that is sufficiently different from said net surface charge of said core microparticle,    
   
   
       42 . The microparticle of  claim 41  wherein said at least one active agent is homogeneously distributed across said core microparticle.  
   
   
       43 . The microparticle of  claim 41  wherein said core microparticle is spherical.  
   
   
       44 . The microparticle of  claim 41  wherein said monolayer has a thickness of less than 50 nm.  
   
   
       45 . The microparticle of  claim 41  wherein said charge of said charged compound is opposite in sign to said net surface charge of said microparticle outer surface.  
   
   
       46 . The microparticle of  claim 41  further comprising another monolayer comprising at least one different charged compound, said other monolayer carrying a net charge that is different from said net charge of said monolayer associated with said core microparticle.  
   
   
       47 . The microparticle of  claim 46  wherein said net surface charge of said other monolayer is opposite in sign to that of said monolayer associated with said core microparticle.  
   
   
       48 . The microparticle of  claim 41  wherein said active agent is insulin or human growth hormone.  
   
   
       49 . A microparticle comprising at least 80% by weight of at least one active agent, the microparticle being solid, and an outer surface of the microparticle comprising at least one charged polymer associated with the active agent, wherein the microparticle is capable of displaying a 1-hour percentage of cumulative release of the active agent of 50% or less when subjected to in vitro release in a release buffer at pH 7.4 and 37° C., the release buffer consisting 10 mM Tris, 005% (w/v) Brij 35, and 0.9% (w/v) NaCl in water.  
   
   
       50 . A microparticle for in vivo administration comprising a solid, microparticle having at least 80%, by weight, of at least one proteinaceous compound homogeneously distributed across said microparticle, wherein the outer surface of said microparticle comprises at least one charged compound associated with said outer surface, 
 wherein upon administration, said microparticle provides a C max  and t max  that is than the C max  and t max  of said core microparticle.    
   
   
       51 . The microparticle of  claim 50  wherein said monolayer associated with said microparticle outer surface comprises a positively charged compound selected from the group consisting essentially of positively charged polyelectrolytes, positively charged polyaminoacids and positively charged polysaccharides.  
   
   
       52 . The microparticle of  claim 50  wherein said monolayer associated with said core comprises a negatively charged compound selected from the group consisting essentially of negatively charged polyelectrolytes, negatively charged polyaminoacids and negatively charged polysaccharides.  
   
   
       53 . The microparticle of  claim 51  wherein said another monolayer comprises a negatively charged compound selected from the group consisting essentially of negatively charged polyelectrolytes, negatively charged polyaminoacids and negatively charged polysaccharides.  
   
   
       54 . The microparticle of  claim 52  wherein said another monolayer comprises a positively charged compound selected from the group consisting essentially of positively charged polyelectrolytes, positively charged polyaminoacids and positively charged polysaccharides.  
   
   
       55 . The microparticle of  claim 50  wherein said proteinaceous compound is insulin or human growth hormone.