Publications by authors named "Peter Langguth"

162 Publications

Evaluation of the Physicochemical Properties of the Iron Nanoparticle Drug Products: Brand and Generic Sodium Ferric Gluconate.

Mol Pharm 2021 Feb 23. Epub 2021 Feb 23.

Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), Fe Mössbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00922DOI Listing
February 2021

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Carbamazepine.

J Pharm Sci 2021 Feb 18. Epub 2021 Feb 18.

Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered "highly soluble" across the range of pH values usually encountered in the upper gastrointestinal tract. Furthermore, evidence in the open literature suggests that carbamazepine is a BCS Class 2 drug. Nevertheless, the oral absolute bioavailability of carbamazepine lies between 70 - 78% and both in vivo and in vitro data support the classification of carbamazepine as a highly permeable drug. Since the therapeutic and toxic plasma level ranges overlap, carbamazepine is considered to have a narrow therapeutic index. For these reasons, a BCS based biowaiver for IR tablets of carbamazepine cannot be recommended. Interestingly, in nine out of ten studies, USP dissolution conditions (900 mL water with 1% SLS, paddle, 75 rpm) appropriately discriminated among bioinequivalent products and this may be a way forward to predicting whether a given formulation will be bioequivalent to the comparator product.
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http://dx.doi.org/10.1016/j.xphs.2021.02.019DOI Listing
February 2021

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metformin Hydrochloride.

J Pharm Sci 2021 Jan 13. Epub 2021 Jan 13.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA. Electronic address:

Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin's Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transporter-mediated drug and is highly soluble, but only 50% of an orally administered dose is absorbed from the gut. Therefore, metformin is a BCS Class III substance. A BCS-based approval approach for major changes to marketed products and new generics is admissible if test and reference dosage forms have the identical active pharmaceutical ingredient and if in vitro dissolution from both are very rapid (i.e. at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Recent International Council for Harmonisation BCS guidance indicates all excipients for Class III biowaivers are recommended to be qualitatively the same and quantitatively similar (except for preservatives, flavor agents, colorant, or capsule shell or film coating excipients). However, despite metformin being a prototypical transporter-mediated drug, there is no evidence that commonly used excipients impact metformin absorption, such that this restriction on excipients for BCS III drugs merits regulatory relief. Commonly used excipients in usual amounts are not likely to impact metformin absorption.
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http://dx.doi.org/10.1016/j.xphs.2021.01.011DOI Listing
January 2021

Molecular hydrogen (H ) as a potential treatment for acute and chronic fatigue.

Arch Pharm (Weinheim) 2020 Dec 23:e2000378. Epub 2020 Dec 23.

Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.

Many diseases as well as acute conditions can lead to fatigue, which can be either temporary or chronic in nature. Acute fatigue develops frequently after physical exercise or after alcohol hangover, whereas microbial infections such as influenza or COVID-19 and chronic diseases like Parkinson's disease or multiple sclerosis are often associated with chronic fatigue. Oxidative stress and a resulting disturbance of mitochondrial function are likely to be common denominators for many forms of fatigue, and antioxidant treatments have been shown to be effective in alleviating the symptoms of fatigue. In this study, we review the role of reactive oxygen and nitrogen species in fatigue and the antioxidant effects of the intake of molecular hydrogen. We propose that molecular hydrogen is well suited for the treatment of temporary and chronic forms of oxidative stress-associated fatigue.
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http://dx.doi.org/10.1002/ardp.202000378DOI Listing
December 2020

Toward Mechanistic Design of Surrogate Buffers for Dissolution Testing of pH-Dependent Drug Delivery Systems.

Pharmaceutics 2020 Dec 10;12(12). Epub 2020 Dec 10.

Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, 55099 Mainz, Germany.

The in vivo dissolution of enteric-coated (EC) products is often overestimated by compendial in vitro dissolution experiments. It is of great interest to mimic the in vivo conditions as closely as possible in vitro in order to predict the in vivo behavior of EC dosage forms. The reason behind this is the overly high buffering capacity of the common compendial buffers compared to the intestinal bicarbonate buffer. However, a bicarbonate-based buffer is technically difficult to handle due to the need for continuous sparging of the media with CO to maintain the desired buffer pH. Therefore, bicarbonate buffers are not commonly used in routine practice and a non-volatile alternative is of interest. A mathematical mass transport modelling approach was previously found to enable accurate calculation of surrogate buffer molarities for small molecule compounds; however, the additional complexity of polymeric materials makes this difficult to achieve for an enteric coat. In this work, an approach was developed allowing relatively rapid screening of potential surrogate buffers for enteric coating. It was found that the effective buffering pKa of bicarbonate at the surface of a dissolving enteric polymer tended to be around 5.5, becoming higher when the dissolving enteric polymer formed a gel of greater firmness/viscosity and vice versa. Using succinate (pKa 5.2 under physiological ionic strength) and/or citrate (pKa 5.7 under physiological ionic strength) at conjugate base molarities corresponding to bicarbonate molarities in the intestinal segments of interest as an initial "guess" can minimize the number of experimental iterations necessary to design an appropriate surrogate.
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http://dx.doi.org/10.3390/pharmaceutics12121197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764239PMC
December 2020

Lung Deposition Using the Respimat Soft Mist™ Inhaler Mono and Fixed-Dose Combination Therapies: An / Analysis.

COPD 2021 Feb 11;18(1):91-100. Epub 2020 Dec 11.

Analytical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.

Tiotropium and olodaterol are mainstay treatments for chronic obstructive pulmonary disease (COPD) and yield important clinical improvements, especially when used in fixed-dose combination. Whilst previous studies have shown consistent delivery of tiotropium to the lungs with the Respimat inhaler, no such study has been carried out for olodaterol or the components of their fixed-dose combination (TIO/OLO). Combining and models, we measured the amount of drug retained in the mouth-throat area, entering the trachea and reaching the lung periphery. We applied a hybrid deposition model that considered the experimentally determined output of an Alberta throat model ( dose to lung) combined with a computational fluid dynamic model of the lungs (). Regardless of the COPD breathing pattern, ≥50% of the nominal dose of either tiotropium, olodaterol, or TIO and OLO in the fixed-dose combination reached the lung. Of the dose reaching the lungs, greater than 50% is deposited in the lung periphery (from generation 8 onwards). Our study demonstrated that aerosol delivery the Respimat inhaler achieved high deposition deep into the lung periphery with all formulations evaluated.
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http://dx.doi.org/10.1080/15412555.2020.1853091DOI Listing
February 2021

Investigation of pH-Responsiveness inside Lipid Nanoparticles for Parenteral mRNA Application Using Small-Angle X-ray Scattering.

Langmuir 2020 11 27;36(44):13331-13341. Epub 2020 Oct 27.

Department of Pharmaceutics and Biopharmaceutics, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D-55099 Mainz, Germany.

Messenger ribonucleic acid (mRNA)-based nanomedicines have shown to be a promising new lead in a broad field of potential applications such as tumor immunotherapy. Of these nanomedicines, lipid-based mRNA nanoparticles comprising ionizable lipids are gaining increasing attention as versatile technologies for fine-tuning toward a given application, with proven potential for successful development up to clinical practice. Still, several hurdles have to be overcome to obtain a drug product that shows adequate mRNA delivery and clinical efficacy. In this study, pH-induced changes in internal molecular organization and overall physicochemical characteristics of lipoplexes comprising ionizable lipids were investigated using small-angle X-ray scattering and supplementary techniques. These changes were determined for different types of ionizable lipids, present at various molar fractions and N/P ratios inside the phospholipid membranes. The investigated systems showed a lamellar organization, allowing an accurate determination of pH-dependent structural changes. The differences in the pH responsiveness of the systems comprising different ionizable lipids and mRNA fractions could be clearly revealed from their structural evolution. Measurements of the degree of ionization and pH-dependent mRNA loading into the systems by fluorescence assays supported the findings from the structural investigation. Our approach allows for direct in situ determination of the structural response of the lipoplex systems to changes of the environmental pH similar to that observed for endosomal uptake. These data therefore provide valuable complementary information for understanding and fine-tuning of tailored mRNA delivery systems toward improved cellular uptake and endosomal processing.
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http://dx.doi.org/10.1021/acs.langmuir.0c02446DOI Listing
November 2020

Hybrid Biopolymer and Lipid Nanoparticles with Improved Transfection Efficacy for mRNA.

Cells 2020 09 5;9(9). Epub 2020 Sep 5.

Department of Pharmaceutics and Biopharmaceutics, Johannes Gutenberg University Mainz, D-55131 Mainz, Germany.

Hybrid nanoparticles from lipidic and polymeric components were assembled to serve as vehicles for the transfection of messenger RNA (mRNA) using different portions of the cationic lipid DOTAP (1,2-Dioleoyl-3-trimethylammonium-propane) and the cationic biopolymer protamine as model systems. Two different sequential assembly approaches in comparison with a direct single-step protocol were applied, and molecular organization in correlation with biological activity of the resulting nanoparticle systems was investigated. Differences in the structure of the nanoparticles were revealed by thorough physicochemical characterization including small angle neutron scattering (SANS), small angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM). All hybrid systems, combining lipid and polymer, displayed significantly increased transfection in comparison to lipid/mRNA and polymer/mRNA particles alone. For the hybrid nanoparticles, characteristic differences regarding the internal organization, release characteristics, and activity were determined depending on the assembly route. The systems with the highest transfection efficacy were characterized by a heterogenous internal organization, accompanied by facilitated release. Such a system could be best obtained by the single step protocol, starting with a lipid and polymer mixture for nanoparticle formation.
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http://dx.doi.org/10.3390/cells9092034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563888PMC
September 2020

Unraveling the behavior of oral drug products inside the human gastrointestinal tract using the aspiration technique: History, methodology and applications.

Eur J Pharm Sci 2020 Dec 18;155:105517. Epub 2020 Aug 18.

Drug delivery & Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven Herestraat 49, box 921, 3000 Leuven, Belgium. Electronic address:

Fluid sampling from the gastrointestinal (GI) tract has been applied as a valuable tool to gain more insight into the fluids present in the human GI tract and to explore the dynamic interplay of drug release, dissolution, precipitation and absorption after drug product administration to healthy subjects. In the last twenty years, collaborative initiatives have led to a plethora of clinical aspiration studies that aimed to unravel the luminal drug behavior of an orally administered drug product. The obtained drug concentration-time profiles from different segments in the GI tract were a valuable source of information to optimize and/or validate predictive in vitro and in silico tools, frequently applied in the non-clinical stage of drug product development. Sampling techniques are presently not only being considered as a stand-alone technique but are also used in combination with other in vivo techniques (e.g., gastric motility recording, magnetic resonance imaging (MRI)). By doing so, various physiological variables can be mapped simultaneously and evaluated for their impact on luminal drug and formulation behavior. This comprehensive review aims to describe the history, challenges and opportunities of the aspiration technique with a specific focus on how this technique can unravel the luminal behavior of drug products inside the human GI tract by providing a summary of studies performed over the last 20 years. A section 'Best practices' on how to perform the studies and how to treat the aspirated samples is described. In the conclusion, we focus on future perspectives concerning this technique.
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http://dx.doi.org/10.1016/j.ejps.2020.105517DOI Listing
December 2020

In Vitro Evaluation of Enteric-Coated HPMC Capsules-Effect of Formulation Factors on Product Performance.

Pharmaceutics 2020 Jul 23;12(8). Epub 2020 Jul 23.

Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, D-55099 Mainz, Germany.

A comparative study on different enteric-coated hard capsules was performed. The influence of different formulation factors like choice of enteric polymer, triethyl citrate (TEC) concentration (plasticizer), talc concentrations (anti-tacking agent), and different coating process parameters on the sealing performance of the capsule and the disintegration time were investigated. Furthermore, the influence of different disintegration test methods (with disc vs. without disc and 50 mM U.S. Pharmacopoeia (USP) buffer pH 6.8 vs. biopredictive 15 mM phosphate buffer pH 6.5) was evaluated. All formulations showed sufficient but not equivalent acid resistance when tested. Polymer type was the main factor influencing the capsule sealing and disintegration time. In addition, TEC and talc could affect the performance of the formulation. Regarding the choice of the disintegration test method, the presence of a disc had for the most part only limited influence on the results. The choice of disintegration buffer was found to be important in identifying differences between the formulations.
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http://dx.doi.org/10.3390/pharmaceutics12080696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465055PMC
July 2020

Effect of thickener on disintegration, dissolution and permeability of common drug products for elderly patients.

Eur J Pharm Biopharm 2020 Aug 17;153:168-176. Epub 2020 Jun 17.

Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.

Dysphagia is a very common problem suffered by elderly patients. The use of thickeners during administration in these patients helps to prevent difficulties with swallowing larger solid dosage forms. However, there are several indications when the thickeners may influence disintegration and dissolution processes of solid dosage forms, potentially affecting therapeutic efficacy. In this paper the effects of a commonly used thickener on tablet disintegration, dissolution and subsequent absorption of 6 formulated drugs frequently used in elderly patients (Aspirin, Atenolol, Acenocumarol, Candesartan, Ramipril and Valsartan) in two different administration conditions (intact tablet and crushed tablet) are reported. Disintegration times were determined using a modified disintegration test device. The presence of thickener leads to a pseudoplastic behavior with clearly increased viscosity values. The thickener was also shown to significantly affect the release processes (dissolution and disintegration), but not the permeability of the studied drugs. When tablets are crushed the effect of the thickener on drug dissolution is avoided. Consequently, crushing the tablets would be a recommendation for these drugs if the use of a thickener is necessary in patients with dysphagia.
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http://dx.doi.org/10.1016/j.ejpb.2020.06.005DOI Listing
August 2020

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Moxifloxacin Hydrochloride.

J Pharm Sci 2020 09 12;109(9):2654-2675. Epub 2020 Jun 12.

Fraunhofer IME & Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. Electronic address:

In this monograph, literature data is reviewed to evaluate the feasibility of waiving in vivo bioequivalence testing and instead applying the Biopharmaceutics Classification System (BCS) based methods to the approval of immediate-release solid oral dosage forms containing moxifloxacin hydrochloride as the sole active pharmaceutical ingredient. To facilitate the feasibility decision, solubility and permeability and dissolution characteristics in the context of the BCS, therapeutic index, therapeutic use, pharmacokinetic parameters, bioequivalence/bioavailability issues, drug-excipient interactions and other relevant data were taken into consideration. Moxifloxacin is a BCS class I drug with a wide therapeutic index. Bioequivalence risks arising from the presence of different excipients in the formulation and due to manufacturing variables were deemed to be low. The risks can be further reduced if the choice of excipients is limited to those present in products already approved in International Conference on Harmonisation or associated countries and if the results of in vitro dissolution studies comply with the specifications stipulated in the appropriate biowaiver guidelines. Under these conditions, we conclude that a BCS-based biowaiver can be recommended for moxifloxacin immediate-release solid oral dosage forms.
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http://dx.doi.org/10.1016/j.xphs.2020.06.007DOI Listing
September 2020

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate.

J Pharm Sci 2020 06 30;109(6):1846-1862. Epub 2020 Mar 30.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany; Fraunhofer IME, Frankfurt, Germany. Electronic address:

Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the Food and Drug Administration, World Health Organization and European Medicines Agency, taking the degradation at some pH values into consideration. Together with solubility and permeability data for cephalexin monohydrate from the literature, it was demonstrated to be a Biopharmaceutics Classification System Class 1 drug. The pharmacokinetic behavior, results of bioequivalence studies published in the literature, as well as the therapeutic uses, potential toxicity and potential excipient effects on bioavailability were also assessed. Cephalexin has a wide therapeutic index and no bioequivalence problems have been reported. Dissolution studies were run under Biopharmaceutics Classification System-biowaiver conditions for the pure drug and 2 generic formulations available on the German market. Considering all relevant aspects, it was concluded that a biowaiver-based approval for products containing cephalexin monohydrate as the single active pharmaceutical ingredient is scientifically justified, provided that well-established excipients are used in usual amounts and that both test and reference dosage forms meet the guideline criteria of either "rapidly dissolving" or "very rapidly dissolving."
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http://dx.doi.org/10.1016/j.xphs.2020.03.025DOI Listing
June 2020

Current Progress in Particle-Based Systems for Transdermal Vaccine Delivery.

Front Immunol 2020 26;11:266. Epub 2020 Feb 26.

Third Department of Medicine - Hematology, Oncology, Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Transcutaneous immunization (TCI) via needle-free and non-invasive drug delivery systems is a promising approach for overcoming the current limitations of conventional parenteral vaccination methods. The targeted access to professional antigen-presenting cell (APC) populations within the skin, such as Langerhans cells (LCs), various dermal dendritic cells (dDCs), macrophages, and others makes the skin an ideal vaccination site to specifically shape immune responses as required. The stratum corneum (SC) of the skin is the main penetration barrier that needs to be overcome by the vaccine components in a coordinated way to achieve optimal access to dermal APC populations that induce priming of T-cell or B-cell responses for protective immunity. While there are numerous approaches to penetrating the SC, such as electroporation, sono- or iontophoresis, barrier and ablative methods, jet and powder injectors, and microneedle-mediated transport, we will focus this review on the recent progress made in particle-based systems for TCI. This particular approach delivers vaccine antigens together with adjuvants to perifollicular APCs by diffusion and deposition in hair follicles. Different delivery systems including nanoparticles and lipid-based systems, for example, solid nano-emulsions, and their impact on immune cells and generation of a memory effect are discussed. Moreover, challenges for TCI are addressed, including timely and targeted delivery of antigens and adjuvants to APCs within the skin as well as a deeper understanding of the ill-defined mechanisms leading to the induction of effective memory responses.
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http://dx.doi.org/10.3389/fimmu.2020.00266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055421PMC
February 2020

In vitro prediction of in vivo absorption of ibuprofen from suspensions through rational choice of dissolution conditions.

Eur J Pharm Biopharm 2020 Apr 26;149:229-237. Epub 2020 Feb 26.

Johannes Gutenberg-Universität, Staudingerweg 5, 55128 Mainz, Germany. Electronic address:

Two ibuprofen suspension formulations were investigated for their dissolution in various bicarbonate, phosphate and acetate buffers. Phosphate and acetate gave faster release than bicarbonate at comparable molarities. Nevertheless, mass transport modelling using the reversible non-equilibrium (RNE) approach enabled the calculation of phosphate molarities that gave good matches to physiological bicarbonate in terms of ibuprofen dissolution. This shows that developing surrogate buffers for bicarbonate that are devoid of the technical difficulties associated with the bicarbonate-CO systems is possible. In addition, the intestinal dissolution kinetics of the tested suspensions were determined by applying compartmental pharmacokinetic modelling to plasma profiles that were previously obtained for these suspensions in an in vivo study performed on healthy human volunteers. The in vitro dissolution profiles in bicarbonate compared reasonably well with the profiles representing the in vivo intestinal dissolution kinetics of the tested suspensions when applied to healthy human volunteers in a pharmacokinetic study. This shows the possible potential toward extending biowaivers so that they include BCS class IIa compounds.
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http://dx.doi.org/10.1016/j.ejpb.2020.02.009DOI Listing
April 2020

Enteric Hard Capsules for Targeting the Small Intestine: Positive Correlation between In Vitro Disintegration and Dissolution Times.

Pharmaceutics 2020 Feb 3;12(2). Epub 2020 Feb 3.

Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, D-55099 Mainz, Germany.

In this study, the potential for correlation between disintegration and dissolution performance of enteric-coated (EC) dosage forms was investigated. Different enteric hard shell capsule formulations containing caffeine as model drug were tested for disintegration (in a compendial disintegration tester) and for dissolution in both USP type I (basket) and type II (paddle) apparatuses using different media. Overall, good correlations were obtained. This was observed for both the basket and the paddle apparatus, indicating that the use of disintegration testing as a surrogate for dissolution testing (allowed by International Conference on Harmonization (ICH) for immediate release dosage forms in case, in addition to other conditions, a correlation between disintegration and dissolution is proven) could be extended to include delayed release dosage forms.
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http://dx.doi.org/10.3390/pharmaceutics12020123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076532PMC
February 2020

evaluation of poloxamer forming gels for bedaquiline fumarate salt and pharmacokinetics following intramuscular injection in rats.

Int J Pharm X 2019 Dec 24;1:100016. Epub 2019 May 24.

Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Saarstraße 21, 55122 Mainz, Germany.

The objective of this study was to evaluate and drug release from forming gels prepared with poloxamer 338 (P338) and/or 407 (P407) in N-methyl-2-pyrrolidone (NMP)/water mixtures for the model compound bedaquiline fumarate salt. The impact of total poloxamer concentration (20%-25% (w/w)), P338/P407 ratio (100/0%-0/100% (w/w)) and NMP/water ratio (0/100%-25/75% (v/v)) on gel point temperature (GPT) was investigated via a design of experiments (DoE), showing that GPT decreased mainly with increasing poloxamer concentration and decreasing P338/P407 ratio, while the relation with NMP/water ratio was more complex resulting in a flexion. Based on the DoE, four formulations with 10 mg/g bedaquiline fumarate salt, a fixed NMP/water ratio of 25/75% (v/v) and varying total poloxamer concentration and P338/P407 ratio were selected for evaluation of gel erosion . The fastest eroding formulation had the lowest total poloxamer concentration (20% (w/w)) and the lowest P338/P407 ratio (20.4/79.6% (w/w)), while the formulation with the highest total poloxamer concentration (23.5% (w/w)) and highest P338/P407 ratio (100/0% (w/w)) showed the lowest gel erosion rate. These fast and slow eroding formulations showed a similar trend for drug release and pharmacokinetics after intramuscular (IM) injection in rats. t of the IM administered poloxamer forming gels was about 6 h and a short-term sustained drug release was observed in rats up to 24 h after dosing, similar to a solution of bedaquiline fumarate salt in polyethylene glycol (PEG400)/water. In conclusion, IM administration of the evaluated poloxamer forming gels may be useful for drugs that require a short-term sustained release, but is not able to extend drug release rates up to weeks or months.
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http://dx.doi.org/10.1016/j.ijpx.2019.100016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733418PMC
December 2019

Transcutaneous immunization with CD40 ligation boosts cytotoxic T lymphocyte mediated antitumor immunity independent of CD4 helper cells in mice.

Eur J Immunol 2019 11 19;49(11):2083-2094. Epub 2019 Aug 19.

Third Department of Medicine - Hematology, Oncology, Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Transcutaneous immunization (TCI) is a novel vaccination strategy that utilizes skin-associated lymphatic tissue to induce immune responses. Employing T-cell epitopes and the TLR7 agonist imiquimod onto intact skin mounts strong primary, but limited memory CTL responses. To overcome this limitation, we developed a novel imiquimod-containing vaccination platform (IMI-Sol) rendering superior primary CD8 and CD4 T-cell responses. However, it has been unclear whether IMI-Sol per se is restricted in terms of memory formation and tumor protection. In our present work, we demonstrate that the combined administration of IMI-Sol and CD40 ligation unleashes fullblown specific T-cell responses in the priming and memory phase, strongly enhancing antitumor protection in mice. Interestingly, these effects were entirely CD4 T cell independent, bypassing the necessity of helper T cells. Moreover, blockade of CD70 in vivo abrogated the boosting effect of CD40 ligation, indicating that the adjuvant effect of CD40 in TCI is mediated via CD70 on professional APCs. Furthermore, this work highlights the so far underappreciated importance of the CD70/CD27 interaction as a promising adjuvant target in TCI. Summing up, we demonstrate that the novel formulation IMI-Sol represents a powerful vaccination platform when applied in combination with sufficient adjuvant thereby overcoming current limitations of TCI.
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http://dx.doi.org/10.1002/eji.201848039DOI Listing
November 2019

[Intravenous Iron Substitution in Chronic Disease - in Whom, When and How?]

Dtsch Med Wochenschr 2019 07 16;144(14):969-977. Epub 2019 Jul 16.

Klinik für Kardiologie und Nephrologie, Rhein-Maas Klinikum.

In recent years, considerable progress has been made in the detection and treatment of iron deficiency. The results are also relevant for many specialist areas and, in particular, for patients with chronic inflammatory diseases. In daily practice, iron deficiency is often neither identified nor consistently treated.An iron deficiency can - even before anaemia occurs - reduce the quality of life and influence the course of the underlying disease. In patients with chronic diseases , the iron status should be monitored regularly. Especially, the currently available oral iron preparations for these patients are inefficient, because of the limitated tolerability and, furthermore, because of restricted enteral iron uptake due to inflammation. For this reason, various guidelines recommend intravenous iron substitution.
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http://dx.doi.org/10.1055/a-0810-8596DOI Listing
July 2019

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron.

J Pharm Sci 2019 10 8;108(10):3157-3168. Epub 2019 Jun 8.

Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. Electronic address:

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of "high solubility" as well as "high permeability" and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran 8 mg) and multiples thereof (16 mg = Zofran 8 mg × 2 tablets and 24 mg = Zofran 8 mg × 3 tablets) meet the criteria of "rapidly dissolving" in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.
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http://dx.doi.org/10.1016/j.xphs.2019.05.033DOI Listing
October 2019

Mass Transport Analysis of Bicarbonate Buffer: Effect of the CO-HCO Hydration-Dehydration Kinetics in the Fluid Boundary Layer and the Apparent Effective p K Controlling Dissolution of Acids and Bases.

Mol Pharm 2019 06 13;16(6):2626-2635. Epub 2019 May 13.

Department of Pharmaceutical Sciences , University of Michigan , 428 Church Street , Ann Arbor , Michigan 48109 , United States.

The main buffering system influencing ionizable drug dissolution in the human intestinal fluid is bicarbonate-based; however, it is rarely used in routine pharmaceutical practice due to the volatility of dissolved CO. The typical pharmaceutical buffers used fail to capture the unique aspects of the hydration-dehydration kinetics of the bicarbonate-CO system. In particular, CO is involved in a reversible interconversion with carbonic acid (HCO), which is the actual conjugate acid of the system, as follows CO + HO ⇌ HCO. In contrast to ionization reactions, this interconversion does not equilibrate very rapidly compared to the diffusional processes through a typical fluid diffusion boundary layer at a solid-liquid interface. In this report, a mathematical mass transport analysis was developed for ionizable drug dissolution in bicarbonate using the rules of conservation of mass and electric charge in addition to accounting for the diffusional times and reaction rate constants of the CO-HCO interconversion. This model, which includes both the hydration reaction rate and dehydration reaction rate, we called the "reversible non-equilibrium" (RNE) model. The predictions made by this RNE approach for ionizable drug dissolution rates were compared to the experimental data generated by an intrinsic dissolution method for three ionizable drugs, indomethacin, ibuprofen, and haloperidol. The results demonstrate the superiority of predictions for the RNE approach compared to the predictions of a model assuming equilibrium between CO and HCO, as well as models ignoring reactions. The analysis also shows that bicarbonate buffer can be viewed as having an effective p K in the boundary layer that is different from that in bulk and is hydrodynamics-dependent.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00187DOI Listing
June 2019

Designing robust immediate release tablet formulations avoiding food effects for BCS class 3 drugs.

Eur J Pharm Biopharm 2019 Jun 19;139:177-185. Epub 2019 Mar 19.

Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, 55128 Mainz, Germany. Electronic address:

Food induced viscosity in the gastrointestinal tract is reported to reduce the bioavailability of tablets containing BCS class 3 drugs, mainly by retarding their disintegration and dissolution of the active pharmaceutical ingredient. The role of formulation factors in minimizing this negative food effect is largely unknown. Combinations of disintegrants were studied together with soluble and insoluble fillers and trospium chloride as model drug substance. Different batches of tablets were compressed at 10 kN and 30 kN, by incorporating different combinations of croscarmellose sodium (CSS), cross-linked (CPD) and sodium starch glycolate (SSG) at low level i.e, 2% + 2% and high level i.e, 4% + 4% of compressional weight, while taking lactose as a soluble filler and dibasic calcium phosphate (DCP) and microcrystalline cellulose (MCC) as insoluble fillers. Under low viscous conditions, disintegration of DCP based tablets was faster compared to lactose based tablets, but under high viscous conditions, simulating the effect of an ingested FDA meal, the disintegration behavior was reverted. Increased compressional force prolonged the disintegration of lactose and DCP based formulations under fasted conditions. However, when evaluated under food viscosity conditions, DCP based tablets compressed at higher force showed rapid disintegration while no effect of increased compressional force in lactose based tablets was observed. MCC based tablets in particular showed largely prolonged disintegration times in viscous media irrespective of the disintegrant type and levels investigated. Disintegrant combinations possessing wicking ability with minimum or no gelling were found to reduce disintegration times. The disintegrant combination of CPD + CCS was effective in reducing disintegration and enhancing dissolution besides not being affected by changes in compressional force and their total proportion in the tablet. In conclusion, it is recommended to evaluate formulations under increased viscosity conditions during the development phase of tablets with an objective to minimize the negative effect of food viscosity on disintegration and dissolution.
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http://dx.doi.org/10.1016/j.ejpb.2019.03.015DOI Listing
June 2019

Impact of uncharged and charged stabilizers on in vitro drug performances of clarithromycin nanocrystals.

Eur J Pharm Biopharm 2019 Apr 12;137:68-76. Epub 2019 Feb 12.

Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Sri-Ayutthaya Road, Rajathavee, Bangkok, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand. Electronic address:

The purpose of this study was to evaluate the effect of charge on the in vitro drug performances of clarithromycin nanocrystals. To prepare different charges of nanocrystals, media milling was employed with the use of different stabilizing systems. The uncharged nanocrystals were prepared from poloxamer 407. The negatively and positively charged nanocrystals were stabilized using a combination of poloxamer 407 with sodium lauryl sulfate (SLS) and cetyltrimethylammonium bromide (CTAB), respectively. After production, the particle size of the negatively and positively charged nanocrystals was smaller than that of the uncharged one. The similar particle size of variously charged clarithromycin nanocrystals was selected to determine the in vitro drug performances. Dissolution profiles of the variously charged nanocrystals were similar; however, kinetic saturation solubility profiles were different. The positively charged nanocrystals showed higher mucoadhesiveness than the uncharged and the negatively charged nanocrystals. For drug permeation through NCI-N87 and Caco-2 cell monolayers, both charged nanocrystals showed a higher drug transport than the uncharged nanocrystals. It could be concluded that incorporating charge into clarithromycin nanocrystal formulations affected the particle size reduction process as well as the nanocrystal performances. Therefore, the surface charge is one of the crucial factors for the development of nanocrystal formulations.
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http://dx.doi.org/10.1016/j.ejpb.2019.02.004DOI Listing
April 2019

Handling forces for the use of different inhaler devices.

Int J Pharm 2019 Apr 31;560:315-321. Epub 2019 Jan 31.

Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. Electronic address:

Age and comorbidities can impact on the success of handling an inhaler. In this pilot study, we assessed finger strength in 62 participants (aged 5-17 years [n = 20], 18-65 years [n = 22] and > 65 years [n = 20]) by using different types of inhalers with integrated sensors (Respimat®, Breezhaler®, Aerolizer®, Genuair®, Diskus®, Ellipta®, HandiHaler®, Turbohaler® and a pressurized metered-dose inhaler [Atrovent®]). Parameters under investigation included the spontaneous and maximum achievable force and torque required to operate devices. Satisfaction with individual inhalers, and the relationship between satisfaction and strength, were also assessed. There was a marked difference in the compressive force required to operate individual inhalers, with maximum values ranging between 0.7 N and 39 N. Finger strength differed considerably between age groups, and participants with rheumatic disease showed different preferences and experienced more difficulties compared with healthy subjects. Satisfaction between devices was highly variable, and influenced by comorbidities and the ability to understand user instructions. Our findings suggest that individual patients' circumstances need to be considered when prescribing an inhaler and may help in the development of future devices, leading to design options with increased ease of operation.
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http://dx.doi.org/10.1016/j.ijpharm.2019.01.053DOI Listing
April 2019

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir.

Eur J Pharm Biopharm 2019 Mar 22;136:147-155. Epub 2019 Jan 22.

Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed.
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http://dx.doi.org/10.1016/j.ejpb.2019.01.021DOI Listing
March 2019

A novel technique for intraduodenal administration of drug suspensions/solutions with concurrent pH monitoring applied to ibuprofen formulations.

Eur J Pharm Biopharm 2019 Mar 16;136:192-202. Epub 2019 Jan 16.

Johannes Gutenberg-Universität, Staudingerweg 5, 55099 Mainz, Germany. Electronic address:

Characterization of dissolution of solid suspended drug particles in vivo is important for developing biopredictive in vitro tests. Therefore, methods to gain deeper insights into particle dissolution in vivo are needed. The soft Bioperm intubation method, a well established tool for investigation of permeability, absorption, metabolism, and drug interactions at predefined locations in the gastroinstinal tract, was modified. The novel intubation method involved pump-controlled infusion of pharmaceutical suspensions as well as simultaneous pH monitoring. This technique was used in a proof of concept study in healthy humans. Plasma sampling and non-compartmental analysis allowed comparison of three different ibuprofen drug products, a solution and two suspensions with different particle size distribution, as well as two different infusion rates. Both a particle size effect and an effect of altering infusion rates on pharmacokinetic parameters were shown. Moreover, it was possible to monitor intestinal pH changes after intestinal infusion. Infusion of ibuprofen resulted in a pH drop that was quantified by the concept of Area Between Curves (ABC).
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http://dx.doi.org/10.1016/j.ejpb.2019.01.010DOI Listing
March 2019

In vitro models for the prediction of in vivo performance of oral dosage forms: Recent progress from partnership through the IMI OrBiTo collaboration.

Eur J Pharm Biopharm 2019 Mar 20;136:70-83. Epub 2018 Dec 20.

Drug Delivery and Disposition, KU Leuven, Herestraat 49, Gasthuisberg, O&N2, Box 921, 3000 Leuven, Belgium. Electronic address:

The availability of in vitro tools that are constructed on the basis of a detailed knowledge of key aspects of gastrointestinal (GI) physiology and their impact on formulation performance and subsequent drug release behaviour is fundamental to the success and efficiency of oral drug product development. Over the last six years, the development and optimization of improved, biorelevant in vitro tools has been a cornerstone of the IMI OrBiTo (Oral Biopharmaceutics Tools) project. By bringing together key industry and academic partners, and by linking tool development and optimization to human studies to understand behaviour at the formulation/GI tract interface, the collaboration has enabled innovation, optimization and implementation of the requisite biorelevant in vitro tools. In this paper, we present an overview of the in vitro tools investigated during the collaboration and offer a perspective on their future use in enhancing the development of new oral drug products.
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http://dx.doi.org/10.1016/j.ejpb.2018.12.010DOI Listing
March 2019

Mass Transport Analysis of the Enhanced Buffer Capacity of the Bicarbonate-CO Buffer in a Phase-Heterogenous System: Physiological and Pharmaceutical Significance.

Mol Pharm 2018 11 26;15(11):5291-5301. Epub 2018 Oct 26.

University of Michigan , College of Pharmacy, Department of Pharmaceutical Sciences , 428 Church Street, Room 4002 , Ann Arbor , Michigan 48109 , United States.

The bicarbonate buffer capacity is usually considered in a phase-homogeneous system, at equilibrium, with no CO transfer between the liquid buffer phase and another phase. However, typically, an in vitro bicarbonate buffer-based system is a phase-heterogeneous system, as it entails continuously sparging (bubbling) the dissolution medium with CO in a gas mixture, at constant ratio, to maintain a constant partial pressure of CO and CO molarity at a prescribed value, with CO diffusing freely between the gas and the aqueous phases. The human gastrointestinal tract is also a phase-heterogeneous system, with CO diffusing across the mucosal membrane into the mesenteric arterial blood, which serves as a sink for CO from the intestinal lumen. In this report, a mass transport analysis of the apparent buffer capacity of a phase-heterogeneous bicarbonate-CO system is developed. It is shown that, most significantly, a phase-heterogeneous bicarbonate-CO system can have a much higher buffer capacity than a phase-homogeneous system such that the buffer capacity is dependent on the bicarbonate concentration. It is double that of a phase-homogeneous system at the pH = p K for a monoprotic buffer at the same concentration. This buffer capacity enhancement increases hyperbolically with pH above the p K, thus providing a much stronger buffering to keep the pH in the physiologically neutral range. The buffer capacity will be dependent on the bicarbonate molarity (which in vivo will depend on the bicarbonate secretion rate) and not the pH of the luminal fluid. Further, there is no conjugate acid accumulation as a result of bicarbonate neutralization, since the resulting carbonic acid (HCO) rapidly dehydrates producing CO and HO. The mass transport analysis developed in this report is further supported by in vitro experimental results. This enhanced bicarbonate buffer capacity in a phase-heterogeneous system is of physiological significance as well as significant for the dissolution and absorption of ionizable drugs.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00783DOI Listing
November 2018

Effect of alpha-linolenic acid in combination with the flavonol quercetin on markers of cardiovascular disease risk in healthy, non-obese adults: A randomized, double-blinded placebo-controlled crossover trial.

Nutrition 2019 02 12;58:47-56. Epub 2018 Jul 12.

Department of Nutrition and Food Sciences, Nutritional Physiology, University of Bonn, Bonn, Germany. Electronic address:

Objectives: Alpha-linolenic acid (ALA) and quercetin are characteristic compounds in plant-based diets. Cardioprotective effects have been described for both substances, although a possible benefit of combining ALA and quercetin has not, to our knowledge, been evaluated yet. The aim of this study was to investigate the potential independent and additive effects of ALA and quercetin on blood pressure (BP) and lipid and glucose metabolism, as well as on biomarkers of inflammation, oxidative stress, and antioxidant status in healthy, non-obese men and women. Another aim was to examine whether chronic supplementation of supranutritional doses of quercetin would result in an accumulation of plasma quercetin concentration over time.

Methods: In a double-blinded, placebo-controlled crossover trial, healthy volunteers were randomized to receive 3.6 g/d ALA plus 190 mg/d quercetin or placebo for 8 wk. Data from 67 individuals (34 men, 33 women, mean age: 24.6 y) were assessed.

Results: Plasma quercetin, tamarixetin, isorhamnetin, and kaempferol increased significantly from baseline to study end with ALA + quercetin but not with ALA + placebo. No significant effect on office systolic BP, mean 24 h ambulatory BP (ABP), or mean daytime ABP was seen in either study group. Both interventions significantly decreased total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B to a similar extent. No effect on high-density lipoprotein cholesterol, apolipoprotein A1, glucose, uric acid, oxidized low-density lipoprotein, C-reactive protein, or lipid-adjusted retinol, α-tocopherol, or β-carotene was seen in either group.

Conclusion: Although dietary supplements of 3.6 g/d ALA over an 8-wk period improved lipid profiles in healthy adults, antioxidative and oxidative status, inflammation, and BP remained unchanged. No evidence was seen for an additive or synergistic effect of ALA plus quercetin on markers of cardiovascular disease risk.
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http://dx.doi.org/10.1016/j.nut.2018.06.012DOI Listing
February 2019

Formulation predictive dissolution (fPD) testing to advance oral drug product development: An introduction to the US FDA funded '21st Century BA/BE' project.

Int J Pharm 2018 Sep 23;548(1):120-127. Epub 2018 Jun 23.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA. Electronic address:

Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions.
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http://dx.doi.org/10.1016/j.ijpharm.2018.06.050DOI Listing
September 2018