Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-04-10
2002-05-28
Acquah, Samuel A. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S001290, C424S489000, C424S490000, C264S004100, C264S004330, C264S004600, C428S402210, C427S213300, C427S213360
Reexamination Certificate
active
06395304
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to preparation of microparticles. More particularly, the present invention relates to a method and an apparatus for preparing microparticles having a more controlled and symmetrical particle size distribution.
2. Related Art
A variety of methods is known by which compounds can be encapsulated in the form of microparticles. It is particularly advantageous to encapsulate a biologically active or pharmaceutically active agent within a biocompatible, biodegradable wall forming material (e.g., a polymer) to provide sustained or delayed release of drugs or other active agents. In these methods, the material to be encapsulated (drugs or other active agents) is generally dissolved, dispersed, or emulsified, using stirrers, agitators, or other dynamic mixing techniques, in a solvent containing the wall forming material. Solvent is then removed from the microparticles and thereafter the microparticle product is obtained.
Development of a microencapsulation process suitable for commercial scale production typically requires scaling up, by multiple factors, a laboratory scale process and/or a pilot scale process. The scaled-up process will almost always require larger piping and higher flow rates, particularly when the scale factor is very large or if it is desired or necessary to keep process transfer times similar to the smaller scale processes. Scale-up into new, larger equipment is often unpredictable and achieved in large measure through trial and error. However, the economic costs of large-scale trial and error experiments can be prohibitive.
One approach to aiding the scale-up process is to use a static mixer to form an emulsion, as disclosed in U.S. Pat. No. 5,654,008. In the method disclosed in U.S. Pat. No. 5,654,008, a first phase, comprising the active agent and the polymer, and a second phase are pumped through a static mixer into a quench liquid to form microparticles containing the active agent. The use of a static mixer to form the emulsion tends to make the scale-up more predictable and reliable than the scale-up of other dynamic-mixing processes for making microparticles. However, numerous trials and experiments are still required to completely and accurately scale-up, such as to commercial scale or by a factor of 20 or more, a process such as the one disclosed in U.S. Pat. No. 5,654,008.
For a commercial scale process, it is particularly important to control the distribution of the size of the microparticles to minimize yield losses. For example, microparticles, particularly controlled release microparticles containing an active agent or other type of substance to be released, can range in size of from about 25 &mgr;m to about 250 &mgr;m in diameter. For a particular commercial product, the useful or desired microparticle size range can be in the range of, for example, 25-150 &mgr;m. Even in an efficient commercial production process, some percentage of the microparticles produced will be larger than the upper size limit, and some percentage of the microparticles produced will be smaller than the lower size limit, resulting in yield losses. Typically, the more narrow or tighter the desired microparticle size range, the larger the yield losses that result. These yield losses could be avoided or minimized if a more narrow microparticle size distribution could be achieved. Narrowing the microparticle size distribution eliminates or significantly reduces the losses resulting from microparticles that fall outside of the desired microparticle size range.
Thus, there is a need in the art for an improved method and apparatus for preparing microparticles. There is a particular need in the art for an improved process that can control particle size distribution, and achieve a more narrow particle size distribution. There is a further need in the art for an improved process that can be more quickly, reliably, and accurately scaled-up from a laboratory or pilot scale to a commercial scale. The present invention, the description of which is fully set forth below, solves the need in the art for such improved methods and apparatus.
SUMMARY OF THE INVENTION
The present invention relates to an apparatus and method for preparing microparticles. In one aspect of the invention, a method of preparing microparticles is provided. The method comprises:
preparing a first phase, the first phase comprising an active agent and a polymer;
preparing a second phase;
preparing a quench liquid;
pumping the first phase and the second phase through a first static mixer to form an emulsion; and
flowing the emulsion through a manifold that includes a plurality of static mixers into the quench liquid whereby droplets of the emulsion form microparticles.
In a further aspect of the present invention, another method for preparing microparticles is provided. The method comprises:
preparing a first phase, the first phase comprising an active agent and a polymer;
preparing a second phase;
preparing a quench liquid;
combining the first phase and the second phase in a first static mixer to form an emulsion, the emulsion forming an outflow of the first static mixer;
dividing the outflow of the first static mixer to form at least two flow streams;
flowing each of the at least two flow streams through a separate second static mixer; and
combining the at least two flow streams with the quench liquid whereby droplets of the emulsion form microparticles.
In a further aspect of the present invention, a method for controlling particle size distribution of microparticles is provided. The method comprises:
preparing a first phase, the first phase comprising an active agent and a polymer;
preparing a second phase;
preparing a quench liquid;
pumping the first phase and the second phase through a static mixing assembly to form an emulsion;
flowing the emulsion into the quench liquid whereby droplets of the emulsion form microparticles; and
adjusting a residence time of the emulsion in the static mixing assembly to obtain a predetermined particle size distribution of the resulting microparticles, wherein the residence time is equal to a length of the static mixing assembly divided by an average velocity of the emulsion through the static mixing assembly.
In yet a further aspect of the present invention, a microencapsulated active agent prepared by a method for preparing microparticles is provided. Such a method comprises:
preparing a first phase, the first phase comprising an active agent and a polymer;
preparing a second phase;
preparing a quench liquid;
pumping the first phase and the second phase through a first static mixer to form an emulsion; and
flowing the emulsion through a manifold that includes a plurality of static mixers into the quench liquid whereby droplets of the emulsion form microparticles.
In yet a further aspect of the present invention, a microencapsulated active agent prepared by another method for preparing microparticles is provided. Such a method comprises:
preparing a first phase, the first phase comprising an active agent and a polymer;
preparing a second phase;
preparing a quench liquid;
combining the first phase and the second phase in a first static mixer to form an emulsion, the emulsion forming an outflow of the first static mixer;
dividing the outflow of the first static mixer to form at least two substantially identical flow streams;
flowing each of the at least two substantially identical flow streams through a separate second static mixer; and
combining the least two substantially identical flow streams with the quench liquid whereby droplets of the emulsion form microparticles.
In still a further aspect of the present invention, a system for preparing microparticles is provided. The system includes a first and second pump, and a first static mixer in fluid communication with each of the pumps. One of the pumps is configured to pump an organic phase into the first static mixer. One of the pumps is configured to pump a continuous phase into the first static mixer. A manifold, comprising a plurality of static mi
Lyons Shawn L.
Wright Steven G.
Acquah Samuel A.
Alkermes Controlled Therapeutics Inc. II
Covington & Burling
Reister Andrea G.
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