Office of Research and Standards

Boston, MA, United States

Office of Research and Standards

Boston, MA, United States
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Andhariya J.V.,University of Connecticut | Shen J.,University of Connecticut | Choi S.,Office of Research and Standards | Wang Y.,Office of Research and Standards | And 2 more authors.
Journal of Controlled Release | Year: 2017

Establishment of in vitro-in vivo correlations (IVIVCs) for parenteral polymeric microspheres has been very challenging, due to their complex multiphase release characteristics (which is affected by the nature of the drug) as well as the lack of compendial in vitro release testing methods. Previously, a Level A correlation has been established and validated for polymeric microspheres containing risperidone (a practically water insoluble small molecule drug). The objectives of the present study were: 1) to investigate whether a Level A IVIVC can be established for polymeric microspheres containing another small molecule drug with different solubility profiles compared to risperidone; and 2) to determine whether release characteristic differences (bi-phasic vs tri-phasic) between microspheres can affect the development and predictability of IVIVCs. Naltrexone was chosen as the model drug. Three compositionally equivalent formulations of naltrexone microspheres with different release characteristics were prepared using different manufacturing processes. The critical physicochemical properties (such as drug loading, particle size, porosity, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microspheres and the reference-listed drug (Vivitrol®) were determined. The pharmacokinetics of the naltrexone microspheres were investigated using a rabbit model. The obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method, and compared with the in vitro release profiles of the naltrexone microspheres obtained using USP apparatus 4. Level A IVIVCs were established and validated for predictability. The results demonstrated that the developed USP 4 method was capable of detecting manufacturing process related performance changes, and most importantly, predicting the in vivo performance of naltrexone microspheres in the investigated animal model. A critical difference between naltrexone and risperidone loaded microspheres is their respective bi-phasic and tri-phasic release profiles with varying burst release and lag phase. These variations in release profiles affect the development of IVIVCs. Nevertheless, IVIVCs have been established and validated for polymeric microspheres with different release characteristics. © 2017


Andhariya J.V.,University of Connecticut | Choi S.,Office of Research and Standards | Wang Y.,Office of Research and Standards | Zou Y.,Office of Research and Standards | And 2 more authors.
International Journal of Pharmaceutics | Year: 2017

The objective of the present study was to develop a discriminatory and reproducible accelerated release testing method for naltrexone loaded parenteral polymeric microspheres. The commercially available naltrexone microsphere product (Vivitrol®) was used as the testing formulation in the in vitro release method development, and both sample-and-separate and USP apparatus 4 methods were investigated. Following an in vitro drug stability study, frequent media replacement and addition of anti-oxidant in the release medium were used to prevent degradation of naltrexone during release testing at “real-time” (37 °C) and “accelerated” (45 °C), respectively. The USP apparatus 4 method was more reproducible than the sample-and-separate method. In addition, the accelerated release profile obtained using USP apparatus 4 had a shortened release duration (within seven days), and good correlation with the “real-time” release profile. Lastly, the discriminatory ability of the developed accelerated release method was assessed using compositionally equivalent naltrexone microspheres with different release characteristics. The developed accelerated USP apparatus 4 release method was able to detect differences in the release characteristics of the prepared naltrexone microspheres. Moreover, a linear correlation was observed between the “real-time” and accelerated release profiles of all the formulations investigated, suggesting that the release mechanism(s) may be similar under both conditions. These results indicate that the developed accelerated USP apparatus 4 method has the potential to be an appropriate fast quality control tool for long-acting naltrexone PLGA microspheres. © 2017 Elsevier B.V.


Gu B.,University of Connecticut | Wang Y.,University of Connecticut | Wang Y.,Office of Research and Standards | Burgess D.J.,University of Connecticut
International Journal of Pharmaceutics | Year: 2015

The foreign body reaction is the major cause of the dysfunction and relatively short lifetime associated with implanted glucose biosensors. An effective strategy to maintain sensor functionality is to apply biocompatible coatings that elute drug to counter the negative tissue reactions. This has been achieved using dexamethasone releasing poly(lactic-co-glycolic acid) (PLGA) microspheres embedded in a polyvinyl alcohol (PVA) hydrogel coating. Accordingly, the biosensor lifetime relies on the duration and dose of drug release from the coating. To achieve long-term drug release mixed populations of microspheres have been used. In the current study, microspheres were prepared by blending low (25 KDa) and high (113 KDa) molecular weight PLGA at different mass ratios to overcome problems associated with mixing multiple populations of microspheres. "Real-time" in vitro studies demonstrated dexamethasone release for approximately 5 months. An accelerated method with discriminatory ability was developed to shorten drug release to less than 2 weeks. An in vivo pharmacodynamics study demonstrated efficacy against the foreign body reaction for 4.5 months. Such composite coatings composed of PLGA microspheres prepared using polymer blends could potentially be used to ensure long-term performance of glucose sensors. © 2015 Elsevier B.V. All rights reserved.


Strasinger C.,U.S. Food and Drug Administration | Raney S.G.,Office of Research and Standards | Tran D.C.,Office of Clinical Pharmacology | Ghosh P.,Office of Research and Standards | And 4 more authors.
Journal of Controlled Release | Year: 2016

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al., 2004 Prausnitz et al. (2004) [1]; Hadgraft and Lane, 2006 Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form.


Shen J.,University of Connecticut | Choi S.,Office of Research and Standards | Qu W.,Office of Research and Standards | Wang Y.,Office of Research and Standards | Burgess D.J.,University of Connecticut
Journal of Controlled Release | Year: 2015

The objective of the present study was to determine whether an in vitro-in vivo correlation (IVIVC) can be established for polymeric microspheres that are equivalent in formulation composition but prepared with different manufacturing processes. Risperidone was chosen as a model therapeutic and poly(lactic-co-glycolic acid) (PLGA) with similar molecular weight as that used in the commercial product Risperdal® Consta® was used to prepare risperidone microspheres. Various manufacturing processes were investigated to produce the risperidone microspheres with similar drug loading (approx. 37%) but distinctly different physicochemical properties (e.g. porosity, particle size and particle size distribution). In vitro release of the risperidone microspheres was investigated using different release testing methods (such as sample-and-separate and USP apparatus 4). In vivo pharmacokinetic profiles of the risperidone microsphere formulations following intramuscular administration were determined using a rabbit model. Furthermore, the obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method and the calculated in vivo release was compared with the in vitro release of these microspheres. Level A IVIVCs were established and validated for the compositionally equivalent risperidone microspheres based on the in vitro release data obtained using USP apparatus 4. The developed IVIVCs demonstrated good predictability and were robust. These results showed that the developed USP apparatus 4 method was capable of discriminating PLGA microspheres that are equivalent in formulation composition but with manufacturing differences and predicting their in vivo performance in the investigated animal model. © 2015 Elsevier B.V.


PubMed | U.S. Food and Drug Administration, Office of Research and Standards and Office of Clinical Pharmacology
Type: | Journal: Journal of controlled release : official journal of the Controlled Release Society | Year: 2016

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industrys conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industrys best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form.


PubMed | Office of Research and Standards and University of Connecticut
Type: | Journal: Journal of controlled release : official journal of the Controlled Release Society | Year: 2015

The objective of the present study was to determine whether an in vitro-in vivo correlation (IVIVC) can be established for polymeric microspheres that are equivalent in formulation composition but prepared with different manufacturing processes. Risperidone was chosen as a model therapeutic and poly(lactic-co-glycolic acid) (PLGA) with similar molecular weight as that used in the commercial product Risperdal Consta was used to prepare risperidone microspheres. Various manufacturing processes were investigated to produce the risperidone microspheres with similar drug loading (approx. 37%) but distinctly different physicochemical properties (e.g. porosity, particle size and particle size distribution). In vitro release of the risperidone microspheres was investigated using different release testing methods (such as sample-and-separate and USP apparatus 4). In vivo pharmacokinetic profiles of the risperidone microsphere formulations following intramuscular administration were determined using a rabbit model. Furthermore, the obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method and the calculated in vivo release was compared with the in vitro release of these microspheres. Level A IVIVCs were established and validated for the compositionally equivalent risperidone microspheres based on the in vitro release data obtained using USP apparatus 4. The developed IVIVCs demonstrated good predictability and were robust. These results showed that the developed USP apparatus 4 method was capable of discriminating PLGA microspheres that are equivalent in formulation composition but with manufacturing differences and predicting their in vivo performance in the investigated animal model.


PubMed | Office of Research and Standards and University of Connecticut
Type: Journal Article | Journal: International journal of pharmaceutics | Year: 2016

The objective of the present study was to develop a discriminatory and reproducible accelerated in vitro release method for long-acting PLGA microspheres with inner structure/porosity differences. Risperidone was chosen as a model drug. Qualitatively and quantitatively equivalent PLGA microspheres with different inner structure/porosity were obtained using different manufacturing processes. Physicochemical properties as well as degradation profiles of the prepared microspheres were investigated. Furthermore, in vitro release testing of the prepared risperidone microspheres was performed using the most common in vitro release methods (i.e., sample-and-separate and flow through) for this type of product. The obtained compositionally equivalent risperidone microspheres had similar drug loading but different inner structure/porosity. When microsphere particle size appeared similar, porous risperidone microspheres showed faster microsphere degradation and drug release compared with less porous microspheres. Both in vitro release methods investigated were able to differentiate risperidone microsphere formulations with differences in porosity under real-time (37 C) and accelerated (45 C) testing conditions. Notably, only the accelerated USP apparatus 4 method showed good reproducibility for highly porous risperidone microspheres. These results indicated that the accelerated USP apparatus 4 method is an appropriate fast quality control tool for long-acting PLGA microspheres (even with porous structures).


Zewdie T.,Office of Research and Standards | Smith C.M.,Office of Research and Standards | Hutcheson M.,Office of Research and Standards | West C.R.,Office of Research and Standards
Environmental Health Perspectives | Year: 2010

Objective: Perchlorate inhibits the uptake of iodide in the thyroid. Iodide is required to synthesize hormones critical to fetal and neonatal development. Many water supplies and foods are contaminated with perchlorate. Exposure standards are needed but controversial. Here we summarize the basis of the Massachusetts (MA) perchlorate reference dose (RfD) and drinking water standard (DWS), which are considerably lower and more health protective than related values derived by several other agencies. We also review information regarding perchlorate risk assessment and policy. Data sOurces: MA Department of Environmental Protection (DEP) scientists, with input from a science advisory committee, assessed a wide range of perchlorate risk and exposure information. Health outcomes associated with iodine insufficiency were considered, as were data on perchlorate in drinking water disinfectants. Data synthesis: We used a weight-of-the-evidence approach to evaluate perchlorate risks, paying particular attention to sensitive life stages. A health protective RfD (0.07 μg/kg/day) was derived using an uncertainty factor approach with perchlorate-induced iodide uptake inhibition as the point of departure. The MA DWS (2 μg/L) was based on risk management decisions weighing information on perchlorate health risks and its presence in certain disinfectant solutions used to treat drinking water for pathogens. cOnclusiOns: Current data indicate that perchlorate exposures attributable to drinking water in individuals at sensitive life stages should be minimized and support the MA DEP perchlorate RfD and DWS. Widespread exposure to perchlorate and other thyroid toxicants in drinking water and foods suggests that more comprehensive policies to reduce overall exposures and enhance iodine nutrition are needed.


PubMed | Office of Research and Standards
Type: Journal Article | Journal: Environmental science & technology | Year: 2014

Mercury (Hg) concentrations were monitored from 1999 to 2011 in largemouth bass (LMB) and yellow perch (YP) in 23 lakes in Massachusetts USA during a period of significant local and regional Hg emissions reductions. Average LMB tissue Hg concentration decreases of 44% were seen in 13 of 16 lakes in a regional Hg hotspot area. YP in all lakes sampled in this area decreased 43% after the major emissions reductions. Comparative decreases throughout the remainder of the state were 13% and 19% for LMB and YP respectively. Annual tissue mercury concentration rate decreases were 0.029 (LMB) and 0.016 mg Hg/kg/yr (YP) in the hotspot. In lakes around the rest of the state, LMB showed no trend and YP Hg decreased 0.0068 mg Hg/kg/yr. Mercury emissions from major point sources in the hotspot area decreased 98%, and 93% in the rest of the state from the early 1990s to 2008. The significant declines in fish Hg concentrations in many lakes occurred over the second half of a two decade decrease in Hg emissions primarily from municipal solid waste combustors and, secondarily, from other combustion point sources. In addition to the substantial Hg emissions reductions achieved in Massachusetts, further regional, national and global emissions reductions are needed for fish Hg levels to decrease below fish consumption advisory levels.

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