Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-03-07
2002-11-12
Foelak, Morton (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S078050, C424S426000, C424S486000, C424S491000, C514S964000, C514S965000, C521S054000, C521S064000
Reexamination Certificate
active
06479065
ABSTRACT:
BACKGROUND OF THE INVENTION
Many illnesses or conditions require administration of a constant or sustained level of a medicament or biologically active agent to provide the most effective prophylactic or therapeutic effect. This may be accomplished through a multiple dosing regimen or by employing a system that releases the medicament in a sustained fashion.
Systems for delivering sustained levels of medication have employed biodegradable materials, such as polymers, encapsulating the medicament. The use of biodegradable polymers, for example, in the form of microparticles or microcarriers, provides a sustained release of medicaments, by utilizing the inherent biodegradability of the polymer to sustain the release of the medicament. The ability to provide a sustained level of medication can result in improved patient compliance.
Certain methods of fabricating polymer-based sustained release devices comprise the steps of dissolving a polymer in a solvent, adding to the polymer solution the active agent to be incorporated and removing the solvent from the mixture thereby forming a matrix of the polymer with the active agent distributed throughout the matrix.
However, many of these sustained release compositions can exhibit an increased release of biologically active agent over the first twenty-four hours after administration, commonly referred to as a burst. In some instances, this burst can result in an undesirable increase in the levels of biologically active agent and/or minimal release of agent thereafter. Therefore a need exists to exert additional control over release kinetics by, for example, reducing the burst of agent and/or providing an improved release profile.
SUMMARY OF THE INVENTION
The invention is based upon the discovery that the burst of biologically active agent from a sustained release composition can be decreased by annealing a substantial portion of the exterior surface of the sustained release composition. Annealing can be accomplished, for example, by the application of heat or of an annealing solvent, wherein the annealing solvent is a solvent for the polymer of the sustained release composition. The application of heat or annealing solvent can be accomplished, for example, using a fluidized bed system such as the Wurster process.
The invention relates to a sustained release composition and methods of forming and using said composition for the sustained release of biologically active agent. The sustained release composition of the invention comprises a biocompatible polymer and a biologically active agent characterized by a porous center and a less porous outer layer, wherein the outer layer and the center consist of essentially the same materials. The variance in porosity can be achieved by annealing at least a substantial portion of the exterior surface of a solid polymer/active agent matrix.
The sustained release composition exhibits a more favorable release profile than that observed with compositions of the same material but which do not have a center and outer layer of varying porosity as can be achieved through annealing. For example, the sustained release compositions which have been annealed exhibit a decrease in the release of agent over the first 24 hours following administration (i.e., reduced burst) which can in some instances lead to an increase in the duration of sustained release thereby providing increased therapeutic benefits.
An additional advantage of the present invention is that the annealed exterior surface of the sustained release composition, serves as a coating for the composition without the need for an additional coating component in the composition. As a result, the surface can be modified without a reduction in effective drug load or an increase in particle size. In addition, the surface can be rendered smoother and/or more spherical which can in some instances provide for better flowability and injectability of the sustained release composition.
The method of the invention for preparing a composition for the sustained release of a biologically active agent, comprises the steps of:
a) forming a mixture comprising a biologically active agent, a biocompatible polymer, and a polymer solvent;
b) removing the polymer solvent thereby forming a solid polymer/active agent matrix; and
c) annealing at least a substantial portion of the exterior surface of the polymer/active agent matrix.
Annealing can be accomplished for example by the application of heat or an annealing solvent to at least a substantial portion of the exterior surface of the polymer/active agent matrix. The application of heat or annealing solvent can preferably be conducted using a fluidized bed system.
The method can further comprise the step of forming droplets of the mixture prior to removal of the solvent. Further, the method can comprise freezing the droplets prior to removal of the solvent. According to the method of the invention, the droplets can be microdroplets. In a specific embodiment wherein droplets are formed of the mixture and then frozen, the solvent can be removed by an evaporation and/or extraction process. Phase separation is also a suitable method for removing the solvent.
The sustained release composition of the invention comprises a biocompatible polymer and a biologically active agent characterized by a porous center and a less porous outer layer, wherein the outer layer and the center consist of essentially the same materials. In a preferred embodiment, the sustained release composition is in the form of a microparticle. By “essentially the same materials” is meant that the biologically active agent and the biocompatible polymer of the center and outer layer can be the same, and that other components can also be present either in the center or outer layer provided that the component does not function as a coating material. For example, the outer layer may contain a component, such as a solvent, which is an artifact of the process.
The difference in porosity between the porous center and the less porous outer layer can be assessed, for example, by scanning electron microscopy. For example, freeze fracture scanning electron micrographs can be used in identifying the difference in porosity between the less porous outer layer and porous center. In addition, Helium Pycnometery can be used to determine solid density of the annealed and non-annealed composition. The specific surface area of the annealed and non-annealed compositions can also be determined using nitrogen sorption and a comparison made to indicate a less porous annealed composition as noted in the SEMs.
It is understood that the difference in porosity between the center and the outer layer can be in gradient form and that a marked differentiation of where the porous center ends and the less porous outer layer begins may not be present. However, it should be evident that the porosity of the outer layer as a whole is less than the porosity of the center portion as a whole.
In a preferred embodiment, the composition for sustained release of a biologically active agent is prepared according to the method of the invention as described above. In other words, in a preferred embodiment, the composition for the sustained release of biologically active agent is a composition prepared by the method comprising the steps of:
a) forming a mixture comprising a biologically active agent, a biocompatible polymer, and a polymer solvent;
b) removing the polymer solvent thereby forming a solid polymer/active agent matrix; and
c) annealing a substantial portion of the exterior surface of the polymer/active agent matrix.
The sustained release composition of the present invention can be used in a method for providing a therapeutically, prophylactically, or diagnostically effective amount of a biologically active agent to a subject for a sustained period having a reduced burst, as compared to the same composition which does not have layers of varying porosity of essentially the same materials, as can be achieved by annealing a substantial portion of the exterior surface. The invention therefore also relate
Jaworowicz Warren E.
Wright James I.
Alkermes Controlled Therapeutics Inc.
Foelak Morton
Hamilton Brook Smith & Reynolds P.C.
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