Sustained release hydrophobic bioactive PLGA microspheres

#This invention relates to providing novel pharmaceutical compositions for local delivery and burst-free programmable, sustained release of hydrophobic drugs from biocompatible, biodegradable poly (DL-lactide-co-glycolide) (PLGA) microspheres. The resulting product is administered locally into soft tissues by sub-cutaneous or intra-muscular injection where it will locally sustain release the drug.

#This invention relates generally to providing novel blend of end-capped and uncapped providing novel biocompatible and biodegradable PLGA microspheres for burst-free programmable sustained release of hydrophobic biologically active agents which degrade over a period of up to 100 days in an aqueous physiological environment. The active agents contemplated within the scope of this invention includes the delivery of poly-peptide antibiotics, antimalarials, antituberculosis drugs, anesthetics, analgesics, anticancer agents, antiparasitic agents, antibacterial agents, antifungal agents, antiinflammatory agents, immunosuppressive agents, immunostimulatory agents, dentinal desensitizers, odor masking agents, nutritional agents, antioxidants, and insulins.

#The invention also relates especially to providing novel pharmaceutical compositions for sustained release of compounds for treating cancer, inflammatory and/or autoimmune disorders from PLGA microspheres.

#FIG. 1 shows the microsphere morphology of taxol PLGA: 10% core load formulation; Background Count Specifics: 426 particles; mean=5.05 um; median=2.74 um Taxol/PLGA Microspheres Counted: 230,046; Mean=7.75 um; Median=6.15 um;

#FIG. 2 shows the in vitro release kinetics of taxol/PLGA: 10% core load formation; Summary of Taxol Release; (1) Amount of taxol released over 10 days (based on supernatant data)=7.06% (749.13 ug). (2) Amount of taxol released over 10 days (based on residual data); Residual Taxol at 10 days=59.81% (6350.5 ug); 100%−59.81%=40.19% released over 10 days. (3) Time for complete PLGA degradation=approximately 20 days.

#FIG. 3 shows the microsphere morphology of taxol/PLGA: 20% core load formulation; Background Count Specifics; 103 particles; mean=3.39 um; median=1.78 um; Taxol/PLGA Microspheres Counted: 84,768; Mean=6.43 um; Median=4.69 um;

#The novel compositions described herein are formulated of chemotherapeutic agent, such as paclitaxel (taxol), doxorubicin, 5-fluorouracil, campthothecin, cisplatin, metronidazole campthothecin and combinations, derivatives, or functional equivalents thereof, which are not water soluble and has poor bioavailability in vivo encapsulated into a biocompatible/biodegradable polymeric matrix or in combination with hydrophillic agents for use especially in the treatment of breast cancer.

#The polymer bound taxol formulations of this invention represent another strategy to achieve prolonged exposure to taxol which appears to be more advantageous than infusion regiments. Of greatest utility are the biodegradable polymers, which include the poly(lactide-co-glycolide)(PLGA) copolymer. A variety of biodegradable polymer bound taxol formulations have been developed and have been shown to inhibit tumor growth and angiogenesis in animal models with minimal systemic toxicity; however, the release kinetics of taxol in these systems, which range from 10-25% of the drug released in approximately 50 days, are, most likely, not optimal for clinical use (18,17,11,12,19,20,21,22). The advantages of biodegradable polymers as a carrier for taxol include: (1) complete biodegradation, requiring no follow-up surgery to remove the drug carrier when the drug supply is exhausted (23,24); (2) tissue biocompatibility (25); 3) ease of administration via s.c. ir u,n, ubhectuib (23,26,27); (4) controlled, sustained release of the encapsulated drug upon hydrolysis of the polymer(27,23,28,24);(5) minimization or elimination of systemic toxicity, such as neutropenia 23,24,26,27); and (6) the convenience of the biodegradable polymer system itself, in terms of versatility (23,29,24,26).

#Surprisingly, our data indicates that we have developed a series of taxol/PLGA formulations which exhibit different and highly desirable rates of sustained, controlled release of taxol. Due to the sustained release characteristics of these microspheres, taxol/PLGA microsphere formulations are intended as a one-time treatment which sustain releases taxol from a subcutaneous (s.c) or intramuscular (i.m.) depot. Taxol/PLGA microspheres having a core load of 10%, 20%, 40%, and 50% were prepared via solvent evaporation and were characterized via scanning electron microscopy (SEM), particle sizing, and high performance liquid chromatography (HPLC). Microsphere morphology of these formulations showed intact spheres with an average diameter range of 5.69-7.75 um (FIGS. 1,3,5,7). Taxol core loading efficiency of all formulations ranged form 91.9%-95.48%. In vitro release of taxol into 37 degrees C PMS/albumin (pH 7.4; 0.4% albumin) over time was calculated based on the residual amount of taxol in the microsphere pellet. Results showed: (1)40.19% taxol release in 10 days using a 10% core load formulation; (2) 71.58% taxol release in 6 days using a 20% core load formulation (FIG. 4); (3) 48.09% taxol release in 6 days using a 40% core load formulation (FIG. 6); and (4) 39.84% taxol release in 6 days using a 50% core load formulation (FIG. 8).