Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2002-02-14
2003-03-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S484000, C424S497000, C264S041000, C264S046200, C427S099300, C427S213360
Reexamination Certificate
active
06534092
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 selected polymer molecular weight.
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 one or more solvents containing the wall forming material. Solvent is then removed from the microparticles and thereafter the microparticle product is obtained.
One variable that affects the in vitro and in vivo performance of the microparticle product is the molecular weight of the polymer or polymeric matrix material in the final microparticle product. Molecular weight affects drug release characteristics. The molecular weight of a polymer influences the biodegradation rate of the polymer. For a diffusional mechanism of active agent release, the polymer should remain intact until all of the active agent is released from the microparticles, and then degrade. The active agent can also be released from the microparticles as the polymeric matrix material bioerodes. By an appropriate selection of polymeric materials a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in affording multiphasic release patterns.
It has been reported that the molecular weight of the poly(D,L-lactide) (“DL-PL”) component of microcapsules containing up to 50% thioridazine free base decreased during fabrication, and in dissolution rate studies of the microcapsule (see Maulding, H. V. et al., Biodegradable Microcapsules: “Acceleration of Polymeric Excipient Hydrolytic Rate by Incorporation of a Basic Medicament”, Journal of Controlled Release, Volume 3, 1986, pages 103-117; hereinafter “the Maulding article”). The results reported in the Maulding article reveal that the degradation rate of DL-PL in ketotifen free base microcapsules was greater when the encapsulation process was carried out at 4° C. than it was when the encapsulation process was carried out at 25° C. In contrast, the degradation rate of DL-PL in thioridazine free base microcapsules was greater when the encapsulation process was carried out at 23° C. than it was when the encapsulation process is carried out at 4° C. Based on these results, the Maulding article suggests circumventing the polymer degradation by carrying out the preparation of microcapsules at 4° C. in the case of thioridazine base. The Maulding article does not provide a method by which the molecular weight of the polymer in the finished microparticle can be conveniently controlled. Nor does the Maulding article provide a method for preparing microparticles that have a selected polymer molecular weight in the finished microparticle product.
Thus, there is a need in the art for an improved method for preparing microparticles that controls the molecular weight of the polymer or polymeric matrix material in the finished microparticle product. There is a particular need in the art for an improved process that provides a method for preparing microparticles that have a selected polymer molecular weight. The present invention, the description of which is fully set forth below, solves the need in the art for such an improved method.
SUMMARY OF THE INVENTION
The present invention relates to a method for preparing microparticles. The present invention allows microparticle products of varying polymer molecular weights to be produced using the same molecular weight starting material. The present invention also allows microparticle products with substantially the same polymer molecular weight to be produced from starting materials of varying molecular weight. In one aspect of the invention, a method of preparing microparticles having a selected microparticle polymer molecular weight is provided. The method comprises:
(a) preparing a first phase, the first phase comprising a nucleophilic compound, a polymer having a starting molecular weight, and a solvent for the polymer;
(b) combining the first phase with a second phase under the influence of mixing means to form an emulsion;
(c) combining the emulsion and an extraction medium, thereby forming microparticles; and
(d) maintaining the first phase at a hold temperature for a hold period prior to step (b), the hold period of sufficient duration to allow the starting molecular weight of the polymer to reduce so that the selected microparticle polymer molecular weight is achieved.
In a further aspect of the present invention, another method for preparing microparticles is provided. The method comprises:
(a) providing a polymer having a starting molecular weight;
(b) dissolving the polymer and a nucleophilic compound in a solvent to form a first phase;
(c) combining the first phase with a second phase under the influence of mixing means to form an emulsion;
(d) combining the emulsion and an extraction medium, thereby forming microparticles; and
(e) maintaining the first phase at a hold temperature for a hold period prior to step (c), wherein the hold period is selected so that the starting molecular weight reduces so that a selected microparticle polymer molecular weight is achieved.
In other aspects of the present invention, the foregoing methods comprise adding an active agent to the first phase. In yet further aspects of the present invention, the foregoing methods comprise adding an inactive agent to the first phase.
In further aspects of the invention, the hold temperature is increased, thereby increasing the molecular weight decay of the polymer to reduce the duration of the hold period. The hold temperature can be decreased, thereby decreasing the molecular weight decay of the polymer to increase the duration of the hold period.
Other aspects of the present invention include a microencapsulated active agent and microparticles prepared by the methods of the present invention.
Features and Advantages
It is a feature of the present invention that it can be used to prepare microparticles, including microparticles containing an active agent.
It is a further feature of the present invention that it allows the hold time and temperature of a nucleophilic compound/polymer solution to be modified to achieve a selected polymer molecular weight in the microparticle product.
An advantage of the present invention is that a selected polymer molecular weight can be achieved in the microparticle product by using a variety of polymers, having varying starting molecular weights, by varying the hold time of the nucleophilic compound/polymer solution.
A further advantage of the present invention is that microparticle products of varying polymer molecular weights can be produced using the same starting polymer, or using a polymer having the same starting molecular weight.
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Hotz Joyce M.
Lyons Shawn L.
Ramstack J. Michael
Rickey Michael E.
Wright Steven G.
Alkermes Controlled Therapeutics Inc. II
Covington & Burling
Fubara Blessing
Page Thurman K.
Reister Andrea G.
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