Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Applied Pharmaceutical Sciences
Applied Pharmaceutical Sciences
Christopher T. Rhodes
A novel method for in situ preparation of injectable biodegradable microspheres from the copolymer poly(lactide-co-glycolide) (PLGA) without incorporating unacceptable organic solvents is described. The delivery system is a dispersion of PLGA microglobules ("premicrospheres" or "embryonic microspheres") in an acceptable vehicle mixture (continuous phase) and whose integrity is maintained by use of appropriate stabilizers. A solution of PLGA. triacetin, drug, PEG 400, and Tween 80 (Oil Phase 1) are added dropwise with continuous homogenization to miglyol 812-Span 80 solution (Oil Phase 2), thereby inducing phase separation (coacervation) of PLGA and forming PLGA microglobules (containing the drug) dispersed in the continuous phase. This novel drug delivery system (NDDS) is a dispersion and has a viscous consistency but is sufficiently syringeable. When injected, it comes in contact with water from aqueous buffer or physiological fluid and as a result, the microglobules harden to form solid matrix type microparticles entrapping the drug (in situ formed microspheres). The drug is then released from these microspheres in a controlled fashion.
This novel microencapsulation process overcomes some of the disadvantages associated with the existing methods by: (i) excluding the use of unacceptable organic solvents and using acceptable vehicle mixture instead to prepare biodegradable PLGA microspheres, (ii) forming drug containing PLGA microglobules ("premicrospheres" or "embryonic microspheres") which could be considered as precursors to the final microsphere product; these on coming in contact with water harden to form discreet PLGAmicrospheres which subsequently exhibit non-variable, predictable, and controlled drug release profile, and (iii) precluding the need for reconstitution of the PLGA microspheres before their administration.
The composition, rationale, and optimization of the NDDS is described here. The characteristics of this NDDS were affected by various formulation (varibles such as: (i) the PLGA concentration and type, (ii) the substitution of the continuous phase by a fresh Oil Phase 2, (iii) the concentration of PEG 400 and the encapsulated drug, (iv) the addition of an hydrophilic excipient (mannitol), and (v) the types of encapsulated drugs and the vehicles added to the system. The characteristics of the NDDS were reproducible and were not affected by a 15 days/4° C storage condition. Also, the formulation, process, and the storage (15 days/4° C) conditions did not adversely affect the physical stability of the encapsulated proteins.
Besides producing injectable in situ formed microspheres, this novel microencapsulation process can be modified to yield injectable in situ formed implant or isolated microspheres. Thus this novel microencapsulation process is versatile and it can produce various drug loaded injectable biodegradable PLGA devices having different characteristics.
Jain, Rajeev, "CONTROLLED DRUG DELIVERY FROM A NOVEL INJECTABLE IN SITU FORMED BIODEGRADABLE PLGA MICROSPHERE SYSTEM" (1998). Open Access Dissertations. Paper 177.