Many drugs, proteins and peptides for use in medical therapy are susceptible to degradation at the site of administration. In addition, many of these therapeutic agents have very short in vivo half-lives. Consequently, multiple injections or multiple oral doses are required to achieve desirable therapy. It is desirable to increase the therapeutic efficacy of these therapeutic agents containing active ingredients by using parenterally administrable formulations that provide controlled release of the therapeutic agents.
A formulation intended for parenteral use must meet a number of requirements in order to be approved by the regulatory authorities for use in humans. It must be biocompatible and/or biodegradable and/or bioabsorbable and all substances used and their degradation products should be non-toxic. By biodegradable, it is meant that the materials are degraded or broken down under physiological conditions in the body such that the degradation products are excretable or absorbable by the body. In addition, particulate therapeutic agents intended for injection must be small enough to pass through the injection needle, which means that they preferably should be smaller than 200 microns. The agent should not be degraded to any large extent in the formulation during production or storage thereof, or after administration, and should be released in a biologically active form with reproducible kinetics.
Various dosage forms have been proposed for therapeutic agents that require parenteral administration. For example, an agent may be microencapsulated by a phase separation process using a coacervation agent such as mineral oil, vegetable oils or the like, resulting in the formation of a microparticle containing the agent.
Another microencapsulation method entails formation of a three-phase emulsion containing a therapeutic agent, a polymer and water. A drying step yields microparticles of the agent microencapsulated in the polymer.
Also reported is the formation of microparticles by spray drying, rotary disc or fluidized bed techniques combining biodegradable polymers and therapeutic agents.
As mentioned above, there is a need to control the release of the microencapsulated therapeutic agent from a parenterally administrable sustained release formulation of microparticles. Often, the initial release rate of agent is high. This is known as the initial burst of the agent from the microparticle. In many of the controlled release systems based on biodegradable polymers, the release rate and initial burst of the therapeutic agent is largely dependent on the amount of agent incorporated into the microparticle. This is due to the formation of channels in the microparticles at higher agent loadings.
A well-known way of controlling the release of a therapeutic agent from a solid core is to apply a synthetic, biodegradable polymer coating that produces a rate-controlling film on the surface of the core particles. The release rate and initial burst of the therapeutic agent is controlled by factors including the thickness of the coating, the diffusivity of agent through the synthetic polymer comprising the coating, and the rate of biodegradation of the polymer.
Often, the method of applying the coating to the therapeutic agent particle requires use of organic solvents to dissolve the polymer used in the coating prior to the coating process. This is done in cases where the melting temperature of the polymer is high enough to detrimentally affect in the performance of the agent. The coating process typically involves dissolving the synthetic, biodegradable polymer in an organic solvent to form a solution, spray coating or fluidized-bed coating the solutions onto the microparticles, and evaporating the solvent.
Synthetic polymers utilized in coatings may include aliphatic polyesters, alkyd-type polyesters, polyanhydrides and poly(orthoester)s. Synthetic absorbable polymers typically degrade by a hydrolytic mechanism. Such synthetic absorbable polymers may include homopolymers, such as poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly(trimethylene carbonate) and poly(para-dioxanone); and copolymers, such as poly(lactide-co-glycolide), poly(epsilon-caprolactone-co-glycolide), and poly(glycolide-co-trimethylene carbonate). The polymers may be statistically random copolymers, segmented copolymers, block copolymers or graft copolymers. Alkyd-type polyesters prepared by the polycondensation of a polyol, polyacid and fatty acid are also useful as coatings on the surface of the core particles.
Proteins, consisting of amino acids, are large molecules that typically are dependant on a well-defined three-dimensional structure for many of their properties, including biological activities and immunogenicity. Their three-dimensional structures can be destroyed relatively easily by exposure to organic solvents, which can affect their biological activity. Thus, a drawback in connection with the use of synthetic, biodegradable polymers for sustained-release of proteins is the requirement to utilize organic solvents to dissolve the biodegradable polymers, with the associated risk of compromising the stability of the protein.
There is a need to develop a microparticle that can reduce exposure of the therapeutic agent to organic solvents that are used to dissolve the coating polymers; can control the release rate of active agent; allow production to be carried out with standard pharmaceutical equipment; and that can be administered parenterally. The present invention satisfies that need.