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PLGA Microparticles Encapsulating Prostaglandin E1-Hydroxypropyl-β-cyclodextrin (PGE1-HPβCD) Complex for the Treatment of Pulmonary Arterial Hypertension (PAH)

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ABSTRACT

Purpose

To test the efficacy and viability of poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating an inclusion complex of prostaglandin E1 (PGE1) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) for pulmonary delivery of PGE1 for treatment of pulmonary arterial hypertension (PAH), a disease of pulmonary circulation.

Methods

PLGA-based microparticulate formulations of PGE1-HPβCD inclusion complex or plain PGE1 were prepared by a double-emulsion solvent evaporation method. HPβCD was used as a complexing agent to increase the aqueous solubility of PGE1, act as a porosigen to produce large porous particles, and promote absorption of PGE1. Particles were characterized for micromeritic properties, in vivo absorption, metabolic degradation, and acute safety.

Results

Incorporation of HPβCD in the microparticles resulted in development of large particles with internal pores, which, despite large mean diameters, had aerodynamic diameters in the inhalable range of 1 to 5 μm. HPβCD incorporation also resulted in a significant increase in the amount of drug released in vitro in simulated interstitial lung fluid, showing a desirable burst release profile required for immediate hemodynamic effects. Compared to plain PLGA microparticles, entrapment efficiency was decreased upon complexation with HPβCD. In vivo absorption profile indicated prolonged availability of PGE1 in circulation following pulmonary administration of the optimized microparticulate formulations, with an extended half-life of almost 4 hours. Metabolic degradation and acute toxicity studies suggested that microparticulate formulations were stable under physiological conditions and safe for the lungs and respiratory epithelium.

Conclusions

This study demonstrates the feasibility of PGE1-HPβCD complex encapsulated in PLGA microparticles as a potential delivery system for controlled release of inhaled PGE1.

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ACKNOWLEDGMENTS

The authors sincerely thank Mr. Charles Linch at the Department of Medical Photography and Electron Microscopy Texas Tech University Health Sciences Center, Lubbock, TX, for his help with the scanning electron microscopy experiments. This work was supported by an American Recovery and Reinvestment Act Fund, NIH 1R15HL103431 (FA).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, Texas, 79106, USA

    Vivek Gupta & Fakhrul Ahsan

  2. Department of Chemistry and Biochemistry, Texas Tech University, Memorial Circle and Boston, Lubbock, Texas, 79409, USA

    Marauo Davis & Louisa J. Hope-Weeks

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  1. Vivek Gupta
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  2. Marauo Davis
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Correspondence to Fakhrul Ahsan.

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Gupta, V., Davis, M., Hope-Weeks, L.J. et al. PLGA Microparticles Encapsulating Prostaglandin E1-Hydroxypropyl-β-cyclodextrin (PGE1-HPβCD) Complex for the Treatment of Pulmonary Arterial Hypertension (PAH). Pharm Res 28, 1733–1749 (2011). https://doi.org/10.1007/s11095-011-0409-6

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