United States Patent:  6,087,003

Assignee:  Centre de Microencapsulation (Angers, FR)

Filed:  May 2, 1997

A microparticle comprising an active substance which is a central core made of liquid, gaseous or solid particle of regular or irregular shape, and the method for entrapping said active substance in a coating material which is conformationally distributed on said active substance and has a thickness ranging from the thickness of a monomolecular layer to about 100 .mu.m. These compositions are useful for applications that require protection, prolonged release, taste masking, improved stability, altered handling behavior, altered surface properties including particle wettability, and other desirably altered properties.

SUMMARY OF THE INVENTION

The invention relates to microparticles comprising an active substance, preferably an active substance in the form of a solid particle or an inert porous solid particle having absorbed therein an active substance in the liquid state or dissolved in a suitable solvent, the active substance or the inert solid being entrapped within a coating including a layer of a coating material. The microparticles are characterized in that the layer of coating material is conformationally distributed on the active substance and has a thickness ranging from the thickness of a mono-molecular layer to about 100 .mu.m, preferably to about 40 .mu.m. Preferably, the active substance found in the microparticles of the present invention is a central core comprising a liquid, gaseous or solid particle of regular or irregular shape. In the case of a solid particle of irregular shape, the coating of the microparticles of the present invention follows the surface of the particles being coated, including internal pores and crevices. The particle size of the microparticles of the present invention ranges in diameter from 1 nm to about 1 cm, preferably from 20 nm to 100 .mu.m.

In another embodiment of the present invention, the coating of the microparticles of the present invention comprises a plurality of layers of identical or different coating materials. The thickness of each layer may be identical or different.

Also within the scope of the present invention is a composition comprising a plurality of microparticles of even or uneven size distribution. The microparticles comprise an active substance conformationally entrapped within a layer of a coating substance having a thickness ranging from the thickness of a monomolecular layer to about 100 .mu.m. Preferably, the active substance of the microparticles forming the composition of the present invention is a central core comprising a solid particle.

The invention also relates to a process for entrapping an active substance, preferably a solid particle or an inert porous solid particle having the active substance absorbed therein, in a coating material. The process comprises suspending an active substance in a supercritical fluid containing a coating material dissolved therein under conditions which cause substantially no swelling and/or dissolution effect on the inert porous solide particle or the active substance if the active substance is in the solid state. The temperature and/or pressure of the supercritical fluid is then gradually reduced under controlled conditions to reduce the solubility of the coating material in the supercritical fluid to cause the coating material to be deposited onto the active substance. Particularly, the process is characterized in that the active substance is in the form of liquid droplets, gas, preferably in the form of solid particles or in the form of a liquid in which the solid substance is being dissolved, the liquid absorbed in a porous solid substrate. The liquid droplets, gas or preferably the solid particles are constantly agitated or stirred during their exposure to the supercritical fluid containing the coating material dissolved therein. More particularly, the active substance is a solid particle and the conditions under which the solid particle is coated by the coating material are chosen to maintain the physical integrity of the solid particle in other words to avoid solubilization of the solid particle throughout its contact with the SCF.

The process of the invention can also comprise further step in which the coating material deposited onto the active substrate is cured in a controlled manner.

In practising the process of the present invention, the active substance and the coating material can be placed in an autoclave which is then filled with a supercritical fluid under conditions of temperature and pressure required to dissolve the coating material in the supercritical fluid. Alternatively, the active substance can be placed in a autoclave which is then filled with a supercritical fluid containing the coating material already dissolved therein.

The present invention also relates to an apparatus for depositing a coating material dissolved in a supercritical fluid onto an active substance. The apparatus comprises a reservoir/reaction chamber capable of receiving and maintaining a gas under supercritical conditions, and a pressurizable reaction chamber in fluid communication with the reservoir/reaction chamber. The reaction chamber comprises stirring means to suspend the active substance when the supercritical fluid is introduced in the reaction chamber. The apparatus also comprises means for controlling the temperature and/or the pressure in the reaction chamber. Preferably, the stirring means is an agitator including a magnetic transmissions stirrer.

Particularly, the apparatus of the present invention can further comprise reservoir means in fluid communication with the supercritical gas condenser for dissolving the coating material in the supercritical fluid.

The final result is coated active substances in tire form of solids, liquids, gases, particles or articles with desireable properties obtained without the use of usual organic solvent(s). The coated active substances have a controlled thickness and/or geometry of coating material and are isolated after the coating system is depressurized to atmospheric pressure and returned to room temperature if the coating was done at some temperature other than room temperature.

Particularly, the invention relates to the coating of preformed solid particles or articles by controlled changes in a system that initially contains a mixture of a SCF and a coating material dissolved thereon. The mixture is maintained at temperature and pressure conditions under which the solid particles or articles are insoluble in the SCF. The temperature and/or pressure of the system is subsequently altered in such a manner as to cause controlled precipitation and/or crystallization of the coating material from the SCF phase onto the surface of the exposed solid particles or articles thereby forming coated solid particles or articles. The solid particles can be porous inert particles in which is absorbed an active substance dissolved in a solvent not miscible or having a substantially weak affinity for the SCF in which the coating substance is dissolved.

One of the important advantages of the process of the present invention resides in the fact that the resulting microparticles are substantially free of pores exposing the active material either in liquid, gaseous or solid form, to external conditions. The reason for this is that since the active substance is not dissolved in the SCF, upon return to normal pression conditions, the SCF does not escape from the central core to create important channels in the coating material and if the active substance is a solid particle. The SCF only escapes from the thin layer of coating material and temperature and pression conditions can be varied to promote a gradual escaping of the SCF from the coating material, thereby avoiding substantial pore formation. Also, because the process of the present invention does not require spraying of the active substance under which coating must be performed very quickly, and because the active substance is not solubilized in the SCF, it is possible to successively apply multiple layers of either identical or different coating materials onto the active substance. In order to do so, the temperature and pressure parameters of the SCF can be varied in a controlled manner to achieve desired dissolution and subsequent solidifying of the coating material.

Claim 1 of 17 Claims

1. A microparticle comprising a solid particle entrapped within a coating including a layer of coating material, wherein

the layer of said coating material is conformationally distributed on said solid particle and has a thickness ranging from the thickness of a mono-molecular layer to about 100 .mu.m; and

the coated microparticle has a diameter ranging from 20 nm to 100 .mu.m when the solid particle has a spherical shape.

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