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1.  SNEDDS Containing Poorly Water Soluble Cinnarizine; Development and in Vitro Characterization of Dispersion, Digestion and Solubilization 
Pharmaceutics  2012;4(4):641-665.
Self-Nanoemulsifying Drug Delivery Systems (SNEDDSs) were developed using well-defined excipients with the objective of mimicking digested SNEDDSs without the use of enzymes and in vitro lipolysis models and thereby enabling studies of the morphology and size of nanoemulsions as well as digested nanoemulsions by Cryo-TEM imaging and Dynamic Light Scattering. Four SNEDDSs (I-IV) were developed. Going from SNEDDS I to IV lipid content and solubility of the model drug cinnarizine decreased, which was also the case for dispersion time and droplet size. Droplet size of all SNEDDS was evaluated at 1% (w/w) dispersion under different conditions. Cinnarizine incorporation increased the droplet size of SNEDDSs I and II whereas for SNEDDSs III and IV no difference was observed. At low pH cinnarizine had no effect on droplet size, probably due to increased aqueous solubility and partitioning into the aqueous phase. Dispersion of the SNEDDSs in Simulated Intestinal Media (SIM) containing bile salts and phospholipids resulted in a decrease in droplet size for all SNEDDS, as compared to dispersion in buffer. Increasing the bile salt/phospholipid content in the SIM decreased the droplet sizes further. Mimicked digested SNEDDS with highest lipid content (I and II) formed smaller nanoemulsion droplet sizes upon dispersion in SIM, whereas droplet size from III and IV were virtually unchanged by digestion. Increasing the bile acid/phosphatidylcholine content in the SIM generally decreased droplet size, due to the solubilizing power of the endogenous surfactants. Digestion of SNEDDSs II resulted in formation of vesicles or micelles in fasted and fed state SIM, respectively. The developed and characterized SNEDDS provide for a better knowledge of the colloid phases generated during digestion of SNEDDS and therefore will enable studies that may yield a more detailed understanding of SNEDDS performance.
PMCID: PMC3834928  PMID: 24300374
self-nanoemulsifying drug delivery system; cinnarizine; cryo-TEM; dynamic light scattering; droplet size
2.  Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report 
The AAPS Journal  2010;12(3):371-377.
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.
PMCID: PMC2895434  PMID: 20440588
bioequivalence; interchangeability; modified release; pharmaceutical equivalence; therapeutic equivalence
3.  Clinical Relevance of Dissolution Testing in Quality by Design 
The AAPS Journal  2008;10(2):380-390.
Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.
PMCID: PMC2751384  PMID: 18686045
bioequivalence; biopharmaceutics classification system (BCS); biowaiver; in vitro dissolution; in vitro in vivo correlation (IVIVC); quality by design (QbD)
4.  Summary Workshop Report: Bioequivalence, Biopharmaceutics Classification System, and Beyond 
The AAPS Journal  2008;10(2):373-379.
The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.
PMCID: PMC2751390  PMID: 18679807
bioavailability; bioequivalence; biopharmaceutics classification system (BCS); oral absorption; permeability; regulatory science; solubility
5.  Gastric flow and mixing studied using computer simulation. 
The fed human stomach displays regular peristaltic contraction waves that originate in the proximal antrum and propagate to the pylorus. High-resolution concurrent manometry and magnetic resonance imaging (MRI) studies of the stomach suggest a primary function of antral contraction wave (ACW) activity unrelated to gastric emptying. Detailed evaluation is difficult, however, in vivo. Here we analyse the role of ACW activity on intragastric fluid motions, pressure, and mixing with computer simulation. A two-dimensional computer model of the stomach was developed with the 'lattice-Boltzmann' numerical method from the laws of physics, and stomach geometry modelled from MRI. Time changes in gastric volume were specified to match global physiological rates of nutrient liquid emptying. The simulations predicted two basic fluid motions: retrograde 'jets' through ACWs, and circulatory flow between ACWs, both of which contribute to mixing. A well-defined 'zone of mixing', confined to the antrum, was created by the ACWs, with mixing motions enhanced by multiple and narrower ACWs. The simulations also predicted contraction-induced peristaltic pressure waves in the distal antrum consistent with manometric measurements, but with a much lower pressure amplitude than manometric data, indicating that manometric pressure amplitudes reflect direct contact of the catheter with the gastric wall. We conclude that the ACWs are central to gastric mixing, and may also play an indirect role in gastric emptying through local alterations in common cavity pressure.
PMCID: PMC1691895  PMID: 15615685

Results 1-5 (5)