United States Patent:  5,945,126

Assignee:  Oakwood Laboratories L.L.C. (Oakwood, OH)

Filed:  February 13, 1997

A continuous process for producing microspheres wherein small particle sizes can be obtained without the problem of foaming. A drug and polymer containing dispersed phase is continuously introduced into a high intensity emulsification vessel along with a continuous phase. An emulsion of the dispersed phase is formed in the continuous phase by high intensity mixing effective to quickly solidify the dispersed phase polymer without having to take steps to address foaming.

Disclosure of the Invention

The present invention is directed to a continuous process for producing active agent containing polymer bodies, and more particularly microspheres. The microspheres produced according to the inventive process are ideal for carrying drugs, diagnostic reagents, or various other active agents. Not only is the inventive process continuous, it also provides a simple, economic and efficient means of scaling up from a test batch to full production while maintaining a product having uniform characteristics throughout the production cycle. No successively larger batches are required to scale up. Once a desired formulation is achieved on a small scale, one need only run the process for a longer period of time in order to obtain any desired batch size. Advantageously, the microspheres produced throughout the process have excellent uniformity.

Moreover, foaming can be minimized or entirely eliminated in the practice of the inventive process, without having to increase the viscosity of the continuous phase. Small particle sizes having high drug loads and low residual solvent concentrations are easily obtained in the inventive process, even when it is necessary to employ a viscous dispersed phase. It is extremely difficult, if not impossible, to obtain useful small particles with a highly viscous dispersed phase using current processes. The inventive process advantageously provides a great deal of flexibility in adjusting various parameters such as size, without jeopardizing loading efficiency, yield or uniformity, which enables use of the microspheres of the invention in a wide variety of delivery methods. For example, one advantage of the preferred embodiment is that mixing intensity can be adjusted independently of the flow rates of either or both of the dispersed and continuous phases, which provides significant flexibility.

Accordingly, it is an aspect of the invention to provide a continuous method of making active agent containing polymer bodies comprising forming a dispersed phase comprising active agent and polymer; providing a continuous phase in which said dispersed phase will form an emulsion; continuously introducing dispersed phase into a reactor vessel at a dispersed phase feed rate, and continuous phase into said reactor vessel at a continuous phase feed rate, said reactor vessel including means for forming an emulsion, and forming an emulsion of said dispersed phase in said continuous phase; and finally, continuously transporting said emulsion from said reactor vessel to a solvent removal vessel to remove solvent.

In one aspect of the invention the dispersed phase is fed to said reaction vessel at a rate of from about 4 ml/min to about 400 ml/min, and said continuous phase is fed to said reactor vessel at a rate of from about 1000 ml/min. to about 20,000 ml/min. In a preferred embodiment, the dispersed phase includes a hydrophilic peptide active agent and a copolymer of lactide and glycolide, and the process comprises emulsifying the dispersed and continuous phases in a manner effective to provide an average particle size of from about 5 .mu.m to about 40 .mu.m, and an active agent load of at least about 9%. Still more preferably, the average particle size of from about 5 .mu.m to about 40 .mu.m, and the active agent load is at least about 15%.

In one embodiment the continuous phase and dispersed phase are introduced into the reactor in a ratio of from 5:1 to 500:1. More preferably, the continuous phase and dispersed phase are introduced into the reactor in a ratio of from 40:1 to 200:1 and, more preferably still about 80:1. Preferably, the method comprises emulsifying said dispersed and continuous phases in a manner adapted to cause solidification of said dispersed phase polymer within about 10 seconds. Still more preferably solidification occurs within about 5 seconds. In one aspect of the invention, the means for forming an emulsion produces a mixing zone effective to cause solidification of dispersed phase polymer within about 10 seconds, and said dispersed phase is introduced into said reaction vessel in said mixing zone.

In a preferred aspect of the method the means for forming an emulsion comprises an impeller. In one embodiment, the method comprises forming said emulsion by running said impeller in excess of about 5,000 revolutions per minute. In another embodiment, the impeller is run at from about 6,000 to about 10,000 revolutions per minute. It is another aspect of the invention that the diameter of said impeller define a diameter of a cylindrical zone extending axially from said impeller, and said dispersed phase is introduced into said axially extending zone.

In one embodiment the dispersed phase is a homogeneous solution. In another embodiment the dispersed phase is an emulsion. In a preferred embodiment the average residence time of said dispersed phase in said reactor is less than about 5 seconds.

It is another aspect of the invention that the method steps are carried out for a period sufficient to produce a desired population of microspheres, and wherein the microspheres produced at the beginning of said period have substantially the same size and agent load as microspheres produced at the end of said period.

It is yet another aspect of the invention to provide a method of scaling up the production of active agent containing polymer bodies from a first population having a desired average particle size and agent loading, to a second, larger population having substantially the same average particle size and agent loading. This embodiment comprises introducing a continuous phase and a dispersed phase containing said active agent and polymer into a reactor vessel, and mixing said phases to form an emulsion of said dispersed phase in said continuous phase in said vessel; continuously transferring the emulsion from said reactor vessel to a solvent removal vessel and removing solvent from said emulsion therein; obtaining said first population having said desired average particle size and agent loading; and, thereafter, selecting a suitable duration for continuously performing the first two steps to produce a desired second larger population of agent containing polymer bodies, and continuously performing the first two steps for a period sufficient to obtain said second population.

In a preferred aspect of this embodiment the desired average particle size and agent loading in said first population is obtained by performing the first two steps, and adjusting at least one parameter selected from the feed rate of said dispersed phase into said reactor vessel, the feed rate of said continuous phase into said reactor vessel, and the intensity by which said continuous and dispersed phases are mixed, to obtain said desired average particle size and agent loading.

It is yet another aspect of the invention to provide microspheres made by the method disclosed herein.

Claim 1 of 26 Claims

1. A continuous method of making active agent containing polymer bodies comprising:

a) forming a dispersed phase comprising active agent and polymer;

b) providing a continuous phase in which said dispersed phase will form an emulsion;

c) continuously introducing dispersed phase into a reactor vessel at a dispersed phase feed rate, and continuous phase into said reactor vessel at a continuous phase feed rate, said reactor vessel including means for forming an emulsion, and forming an emulsion of said dispersed phase in said continuous phase;

d) continuously transporting said emulsion from said reactor vessel to a solvent removal vessel to remove solvent.

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