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      Design of Poly(lactic- co-glycolic Acid) (PLGA) Nanoparticles for Vaginal Co-Delivery of Griffithsin and Dapivirine and Their Synergistic Effect for HIV Prophylaxis

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          Abstract

          Long-acting topical products for pre-exposure prophylaxis (PrEP) that combine antiretrovirals (ARVs) inhibiting initial stages of infection are highly promising for prevention of HIV sexual transmission. We fabricated core-shell poly(lactide- co-glycolide) (PLGA) nanoparticles, loaded with two potent ARVs, griffithsin (GRFT) and dapivirine (DPV), having different physicochemical properties and specifically targeting the fusion and reverse transcription steps of HIV replication, as a potential long-acting microbicide product. The nanoparticles were evaluated for particle size and zeta potential, drug release, cytotoxicity, cellular uptake and in vitro bioactivity. PLGA nanoparticles, with diameter around 180–200 nm, successfully encapsulated GRFT (45% of initially added) and DPV (70%). Both drugs showed a biphasic release with initial burst phase followed by a sustained release phase. GRFT and DPV nanoparticles were non-toxic and maintained bioactivity (IC 50 values of 0.5 nM and 4.7 nM, respectively) in a cell-based assay. The combination of drugs in both unformulated and encapsulated in nanoparticles showed strong synergistic drug activity at 1:1 ratio of IC 50 values. This is the first study to co-deliver a protein (GRFT) and a hydrophobic small molecule (DPV) in PLGA nanoparticles as microbicides. Our findings demonstrate that the combination of GRFT and DPV in nanoparticles is highly potent and possess properties critical to the design of a sustained release microbicide.

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          DDSolver: an add-in program for modeling and comparison of drug dissolution profiles.

          In recent years, several mathematical models have been developed for analysis of drug dissolution data, and many different mathematical approaches have been proposed to assess the similarity between two drug dissolution profiles. However, until now, no computer program has been reported for simplifying the calculations involved in the modeling and comparison of dissolution profiles. The purposes of this article are: (1) to describe the development of a software program, called DDSolver, for facilitating the assessment of similarity between drug dissolution data; (2) to establish a model library for fitting dissolution data using a nonlinear optimization method; and (3) to provide a brief review of available approaches for comparing drug dissolution profiles. DDSolver is a freely available program which is capable of performing most existing techniques for comparing drug release data, including exploratory data analysis, univariate ANOVA, ratio test procedures, the difference factor f (1), the similarity factor f (2), the Rescigno indices, the 90% confidence interval (CI) of difference method, the multivariate statistical distance method, the model-dependent method, the bootstrap f (2) method, and Chow and Ki's time series method. Sample runs of the program demonstrated that the results were satisfactory, and DDSolver could be served as a useful tool for dissolution data analysis.
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            The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems--a review.

            Poly(D,L-lactic-co-glycolic acid) (PLGA) is the most frequently used biodegradable polymer in the controlled release of encapsulated drugs. Understanding the release mechanisms, as well as which factors that affect drug release, is important in order to be able to modify drug release. Drug release from PLGA-based drug delivery systems is however complex. This review focuses on release mechanisms, and provides a survey and analysis of the processes determining the release rate, which may be helpful in elucidating this complex picture. The term release mechanism and the various techniques that have been used to study release mechanisms are discussed. The physico-chemical processes that influence the rate of drug release and the various mechanisms of drug release that have been reported in the literature are analyzed in this review, and practical examples are given. The complexity of drug release from PLGA-based drug delivery systems can make the generalization of results and predictions of drug release difficult. However, this complexity also provides many possible ways of solving problems and modifying drug release. Basic, generally applicable and mechanistic research provides pieces of the puzzle, which is useful in the development of controlled-release pharmaceuticals. Copyright © 2011 Elsevier B.V. All rights reserved.
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              Simulated Biological Fluids with Possible Application in Dissolution Testing

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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                16 April 2019
                April 2019
                : 11
                : 4
                : 184
                Affiliations
                [1 ]Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; hyang96@ 123456its.jnj.com (H.Y.); jil132@ 123456pitt.edu (J.L.); patels10@ 123456mwri.magee.edu (S.K.P.)
                [2 ]Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
                [3 ]Center for Predictive Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA; kenneth.palmer@ 123456louisville.edu
                [4 ]International Partnership for Microbicides, Silver Spring, MD 20910, USA; bdevlin@ 123456ipmglobal.org
                [5 ]Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
                Author notes
                [* ]Correspondence: rohanlc@ 123456upmc.com ; Tel.: +1-412-641-6108
                Author information
                https://orcid.org/0000-0002-1235-3458
                Article
                pharmaceutics-11-00184
                10.3390/pharmaceutics11040184
                6523646
                30995761
                58b37351-0eb0-4deb-887b-b99e338b7949
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 February 2019
                : 11 April 2019
                Categories
                Article

                microbicides,hiv,combination arvs,sustained release,synergism,plga nanoparticles,co-delivery

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