Methods for microsphere production

Details Methods for microsphere production Methods for microsphere production

1999-05-05

2001-05-01

Nutter, Nathan M. (Department: 1711)

Plastic and nonmetallic article shaping or treating: processes

Encapsulating normally liquid material

Liquid encapsulation utilizing an emulsion or dispersion to...

C264S004300, C264S004330, C264S004600, C427S213300, C427S213310, C427S213350, C427S213360, C428S402200, C428S402210

Reexamination Certificate

active

06224794

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to a process for the preparation of polymeric microspheres. In particular, the present invention relates to a process for preparing microspheres in a manner that provides control over the average particle size, and particle size distribution, of the polymeric microspheres.
BACKGROUND OF THE INVENTION
Polymeric microspheres, i.e., microspheres formed (at least in part) from polymer, have found a variety of uses in the medical and industrial areas. Furthermore, biodegradable polymers have been the subject of numerous studies in controlled drug delivery (Conti et al.,
J. Microencapsulation
9:153 (1992); Cohen and Bernstein,
Microparticulate Systems for the Delivery of Proteins and Vaccines
(Marcel Dekker Inc. 1996)). As drug carriers, microspheres formed from biodegradable polymer(s) have the advantages of providing a large surface area, being easily injected, and not requiring removal after completion of drug release. When used as an injectable drug delivery device, it has been found that drug release rate and microsphere interaction with cells is strongly dependent on the size distribution of the microspheres (Amsden and Goosen,
J. Contr. Rel.
43:183 (1997); Baker,
Controlled Release of Biologically Active Agents
(John Wiley 1987); Ishikawa. et al., J. Biomater. Sci., Polymer Ed. 2:53 (1991)).
Accordingly, there are numerous publications disclosing studies directed towards developing methods to prepare polymeric microspheres under conditions that allow for controlling the average particle size, and particle size distribution, of the microspheres. These methods include dispersion polymerization of the monomer, potentiometric dispersion of dissolved polymer within an emulsifying solution followed by solvent evaporation, electrostatically controlled extrusion, injection of dissolved polymer into an emulsifying solution through a porous membrane followed by solvent evaporation (see, e.g., Kuriyama et al.,
J. Appl. Poly. Sci.
50:107 (1993); Rembaum et al., U.S. Pat. No. 4,138,383; O'Donnell et al.,
J. Microencaps.
12:155 (1995); Hommel et al., U.S. Pat. No. 4,956,128; Amsden and Goosen,
J. Contr. Rel.
43:183 (1997); Reyderman and Stavchansky,
Pharm. Dev. Technol.
1:223 (1996); Ipponmatsu et al., U.S. Pat. No. 5,376,347; Shiga et al.,
J. Pharm. Pharmacol.
48:891 (1996
Additional methods include vibratory excitation of a laminar jet of monomeric material flowing in a continuous liquid medium containing a suitable suspending agent, irradiation of slowly thawing frozen monomer drops, emulsification and evaporation, emulsification and evaporation using a high shear apparatus and a high hydrophobic phase to hydrophilic phase ratio, controlled polymerization in a solvent, non-solvent mixture, extrusion into a high shear air flow, and continuous injection of dissolved polymer into a flowing non-solvent through a needle oriented in parallel to the direction of flow of the non-solvent (see also, e.g., Timm and Coleman, U.S. Pat. No. 4,444,961; Rhim et al. U.S. Pat. No. 4,981,625; Sansdrap and Moes,
Int. J. Pharm.
98:157 (1993); Rourke, U.S. Pat. No. 5,643,506; Sosnowski et al.,
J. Bioact. Compat. Polym.
9:345 (1994); Wang, U.S. Pat. No. 5,260,002; Leelarasamee et al.,
J. Microencaps.
5:147 (1988)).
As set forth below, each of these published methods has shortcomings that curtails the utility of the formed-microspheres in various applications, and particularly when the methods are applied to the continuous production of uniformly sized biocompatible, biodegradable, drug-loaded microspheres.
The monomer polymerization processes does not allow the easy inclusion of a bioactive agent within the formed polymeric microsphere (Kuriyama et al.,
J. Appl. Poly. Sci.
50:107 (1993); Rembaum et al., U.S. Pat. No. 4,138,383; Timm and Coleman, U.S. Pat. No. 4,444,961; Rhim et al. U.S. Pat. No. 4,981,625; Sosnowski et al.,
J. Bioact. Compat. Polym.
9:345 (1994)). Furthermore, the polymerization conditions may result in the deactivation of the drug, or the drug may become included in the polymer backbone.
The electrostatic extrusion process does not produce uniformly sized microspheres of a comparatively small diameter (Hommel et al., U.S. Pat. No. 4,956,128; Amsden and Goosen,
J. Contr. Rel.
43:183 (1997); Reyderman and Stavchansky,
Pharm. Dev. Technol.
1:223 (1996)).
The emulsification process of Sansdrap and Moes,
Int. J. Pharm.
98:157 (1993), produces relatively narrow size distributions but is performed in batch mode and in a very small scale (500 milliliters).
Injecting a polymer dissolved in a volatile solvent through a porous membrane produced microspheres of a narrow size distribution but the size of the microspheres is controlled virtually completely by the size of the pores in the glass membrane used, and only low viscosity polymer solutions were possible (Ipponmatsu et al., U.S. Pat. 5,376,347; Shiga et al.,
J. Pharm. Pharmacol.
48:891 (1996)).
The high shear emulsification process of Rourke, U.S. Pat. No. 5,643,506, cannot produce a wide range of microsphere average sizes having a narrow size distribution.
Finally, the injection method of Leelarasamee et al.,
J. Microencaps.
5:147 (1988), involves the use of a non-solvent which requires additional, and difficult removal steps which would decrease the incorporation efficiency of a lipophilic agent, and could not produce narrow microsphere size distributions. Furthermore, Leelarasamee et al. does not demonstrate the ability to control the microsphere average diameter through manipulation of the process parameters.
Thus, a need exists for a simple and reliable method for producing uniformly-sized microspheres. Furthermore, it is desirable to be able to produce uniformly sized microspheres in a continuous fashion in such a manner that the size of the microspheres is easily controllable, that the process is scaleable to large production, and that allows the use of volatile solvents. The present invention provides methods suitable for preparing microspheres. These methods address the problems associated with the existing procedures, offer significant advantages when compared to existing procedures, and in addition, provide other, related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides a process for forming microspheres. The process includes passing a first composition containing polymer and solvent through an orifice and directly into a second composition containing water and a microsphere-stabilizing agent, under at least one of conditions (a) and (b), wherein (a) the first composition flows through a first conduit along a first path and exits the first conduit at the orifice, the second composition flows through a second conduit along a second path in an upstream to downstream direction, the first conduit is connected to the second conduit and terminates at the orifice, the first and second paths being orientated at an angle &thgr; relative to each other, wherein 0°<&thgr;<180°; (b) the first composition being at a first temperature and including a solvent having a boiling point, the second composition being at a second temperature, the boiling point of the solvent being less than the second temperature.
This method forms a composition that includes water and microspheres, the microspheres being formed, at least in part, by the polymer. Such microspheres are suitable for use in the delivery of bioactive agents for animal, aquarian and human use, as a means of radio-imaging tissue, as well as for the controlled release of agro-chemicals.
The first conduit may extend into the second conduit to position the orifice within the second conduit, such that the orifice faces 45°≦&thgr;≦90°, where the orifice is facing downstream when &thgr;<90°.
In one aspect, the first fluid composition is injected through a needle and into the second fluid composition, the first composition including a polymer to be formed into a microsphere, the second composition flowing past a tip of the needle. In this way, a composition

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