The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by employing standard differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and intrinsic dissolution rate studies. Quantum mechanical calculations were performed to obtain information regarding intermolecular interactions in the studied co-amorphous ATR-IRB system. The co-amorphous formulation showed a significant improvement in the intrinsic dissolution rate (IDR) of IRB over pure crystalline as well as its amorphous counterpart. An unusual behavior was observed for ATR, as the IDR of ATR in the co-amorphous formulation was slightly lower than that of amorphous ATR alone. Short-term physical aging studies of up to 8 h proved that the ATR-IRB co-amorphous system remained in the amorphous form. Furthermore, no physical aging occurred in the co-amorphous system. FT-IR, density functional theory calculations, and analysis of Tg value of co-amorphous system using the Couchman–Karasz equation revealed the presence of molecular interactions between APIs, which may contribute to the increased physical stability.
The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR–TER cocrystal formation was ball milling. The stoichiometry of the ITR–TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR–TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR–oxalic acid > ITR–succinic acid > ITR–TER. Additionally, the ITR–TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations.
Purpose: In 2010 the European Medicines Agency allowed a two-stage design in bioequivalence studies. However, in the public domain there are mainly articles describing the theoretical and statistical base for the application of the two-stage design. One of the reasons seems to be the lack of practical guidance for the Sponsors on when and how the two-stage design can be beneficial in bioequivalence studies. Methods: Different variants with positive and negative outcomes have been evaluated, including a pivotal study, pilot + pivotal study and two-stage study. The scientific perspective on the two-stage bioequivalence study has been confronted with the industrial one. Results: Key information needed to conduct a bioequivalence study – such as in vitro data and pharmacokinetics – have been listed and organized into a decision scheme. Advantages and disadvantages of the two-stage design have been summarized. Conclusion: The use of the two-stage design in bioequivalence studies seems to be a beneficial alternative to the 2 × 2 crossover study. Basic information on the properties of the active substance and the characteristics of the drug form are needed to make an initial decision to carry out the two-stage study.
Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [μg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [μg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [μg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80–125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.
ELISA has become a standard analytical tool in the numerous branches of science and industry. Processing of the ELISA results may be a multistep process, often requiring a prior adaptation, using proprietary software, or exporting the results into external internet platforms. It may be problematic in the light of good documentation practices and maintaining good data integrity. In this paper, we present the development and application of the ELISA Tool software. The program is based on a Python scripting programming language and is available under an open-source license. The ELISA Tool allows users to fully control and validate the calculation procedure through a user-friendly graphical user interface. The modular architecture of the software allows its application in other information technology (IT) projects used for data processing in research laboratories. We successfully applied the ELISA Tool for the analysis of real-life samples. The ELISA Tool allowed import of the measurement data, an approximation of the calibration curves with two different algorithms, exploration and diagnostics of the model fit, and generation of the final report with the calculations while maintaining the raw data file unchanged. We report here for the first time the implementation of the idea of full control over data processing, from measured raw data to the final report. We obtained a transparent, open, registered system of data processing control, independent of third parties. The modular and flexible architecture of the created software encourages its further development following the individual demands of the users.
Since 2010, the European Medicines Agency has allowed conducting a bioequivalence study in two steps. This approach is called two-stage design. The approach allows to select a large enough group in the second step to finish the study in accordance with the requirements (i.e. statistical power), but also to stop the study if there is no chance of bioequivalence. Such a possibility may be beneficial for pharmaceutical companies, despite more restrictive statistical assumptions. However, it seems that it is not often used. The cause may be non-standard approach and too laconic description in the guideline. Due to limited implementation of 2-stage design in bioequivalence, we can still treat it as a novelty. In our work, we try to explain opportunities and risks of 2-stage design for the Sponsors.
Open Research Biopharmaceutical Internships Support (ORBIS) is an international, Horizon 2020 project funded by Maria Skłodowska-Curie Actions, Research and Innovation Staff Exchange (RISE) programme. Six academic institutions and four pharmaceutical companies from seven countries cooperate with the aim to improve the preclinical pathway of medicine development through increased Research and Development (R&D) productivity, especially focusing on processes and technologies which address the challenge of poor drug bioavailability. The RISE scheme supports secondments, meaning that early stage and experienced researchers are sent to consortium partner institutions to advance studies on pharmaceutical preformulation, dosage forms and drug delivery systems and methods of biopharmaceutical evaluation. The ORBIS project enables secondees to gain news skills and develop their competences in an international and intersectoral environment, strengthening the human capital and knowledge synergy in the European pharmaceutical R&D sector.
Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and treatment-resistant sequela of many chemotherapeutic medications. Ligands of α2δ subunits of voltage-gated Ca channels, such as pregabalin, have shown efficacy in reducing mechanical sensitivity in animal models of neuropathic pain. In addition, some data suggest that pregabalin may be more efficacious in relieving neuropathic pain in subjects with increased sensitivity to pinprick. We hypothesized that greater mechanical sensitivity, as quantified by decreased mechanical pain threshold at the feet, would be predictive of a greater reduction in average daily pain in response to pregabalin vs placebo. In a prospective, randomized, double-blinded study, 26 patients with painful CIPN from oxaliplatin, docetaxel, or paclitaxel received 28-day treatment with pregabalin (titrated to maximum dose 600 mg per day) and placebo in crossover design. Twenty-three participants were eligible for efficacy analysis. Mechanical pain threshold was not significantly correlated with reduction in average pain (P = 0.97) or worst pain (P = 0.60) in response to pregabalin. There was no significant difference between pregabalin and placebo in reducing average daily pain (22.5% vs 10.7%, P = 0.23) or worst pain (29.2% vs 16.0%, P = 0.13) from baseline. Post hoc analysis of patients with CIPN caused by oxaliplatin (n = 18) demonstrated a larger reduction in worst pain with pregabalin than with placebo (35.4% vs 14.6%, P = 0.04). In summary, baseline mechanical pain threshold tested on dorsal feet did not meaningfully predict the analgesic response to pregabalin in painful CIPN.
Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development. Thus, ensuring high quality of bioanalytical methods is of critical importance. Incurred sample reanalysis (ISR)—one of the tools used to validate a method—is included in the bioanalytical regulatory recommendations. The methodology of this test is well established, but the estimation of the sample size is still commented on and contested. We have applied the hypergeometric distribution to evaluate ISR test passing rates in different clinical study sizes. We have tested both fixed rates of the clinical samples—as currently recommended by FDA and EMA—and a fixed number of ISRs. Our study revealed that the passing rate using the current sample size calculation is related to the clinical study size. However, the passing rate is much less dependent on the clinical study size when a fixed number of ISRs is used. Thus, we suggest using a fixed number of ISRs, e.g., 30 samples, for all studies. We found the hypergeometric distribution to be an adequate model for the assessment of similarities in original and repeated data. This model may be further used to optimize the sample size needed for the ISR test as well as to bridge data from different methods. This paper provides a basis to re-consider current ISR recommendations and implement a more statistically rationalized and risk-controlled approach.
Bioanalysis concerns the identification and quantification of analytes in various biological matrices. Validation of any analytical method helps to achieve reliable results that are necessary for proper decisions on drug dosing and patient safety. In the case of bioanalytical methods, validation additionally covers steps of pharmacokinetic and toxicological studies – such as sample collection, handling, shipment, storage, and preparation. We drew our attention to the difference of both the newest FDA Guidance and the EMA Guideline on bioanalytical method validation. We aimed to point out advantages of both documents from the laboratory perspective. The FDA and the EMA documents are similar, but not identical. The EMA describes the practical conduct of experiments more precisely, while the FDA presents reporting recommendations more comprehensively. There are also differences in recommended validation parameters. We hope that the International Council for Harmonisation will combine advantages of both documents to avoid confusing differences in terminology as well as the unnecessary effort of being compliant with two or more guidelines. https://www.sciencedirect.com/science/article/abs/pii/S0731708518320077
The Open Research Biopharmaceutical Interships Support (ORBIS) research Project aims at increasing the effectiveness of drug development. International and intersectoral integration of academic and industrial research will contribiute to pharmaceutical and chemical knowledge-sharing. Researchers will engage general public to broaden understanding of drug development process. Ultimately, the project contributes to making the drugs more affordable and accessable to the patients. ORBIS Project research objectives are focused on: • improving drug substance development by innovative synthesis and evaluation of active compounds and their physicochemical forms, • advancing pharmaceutical preformulation studies by developing new industry-relevant methods for evaluation of drug substances and their polymorphic forms, • enhancing the oral drug delivered by advanced drug delivery systems and optimized manufacturing, • enhancing the topical and transdermal drug delivery by devising new systems based on better understanding of drug transport across the skin, • improving biopharmaceutical evaluation of dosage forms and delivery systems by challenging the current testing approaches and methods of bioanalysis. ORBIS Project has received funding from the Horizon 2020 Framework Program, Marie Skłodowska Curie Actions, Research and Innovation Staff Exchange (H2020-MSCA-RISE-2017).The project brings together four European and one American academic center and four European pharmaceutical companies. Prof. Janina Lulek, from Poznan University of Medical Sciences (PUMS), is the project Coordinator and Chair and Prof. Andrzej Kutner, from Pharmaceutical Research Institute (PRI), is the Co-chair. Key contribiutors include: Prof. Lidia Tajber (Trinity College Dublin, Ireland), Prof. Bożena Michnik-Kohn (Rutgers, The State University of New Jersey, USA, RUTG), Prof. Anne Juppo (University of Helsinki, Finland), Dr. Oleg Syarkevych (Farmak JSC, Kiev, Ukraine), Dr. Aleksandra Dumicic (Zentiva k.s., Prague, Czech Republic, ZNT), Dr. Sharon Davin (Applied Process Company Ltd., Dublin, Ireland, APC) and Dr. Grzegorz Garbacz (Physiolution GmbH, Greifswald, Germany). ORBIS Project is carried out through exchange of early stage and experienced academic and industrial researchers within dedicated research and training work packages. ORBIS Project training is focused on extending the staff skills in drug development processes by participating in inter-sectoral research projects and activities. Initial results of short-term visits of researchers from the Pharmaceutical Research Institute will be presented. References:  ORBIS website: http://orbisproject.eu/  ORBIS Facebook: https://www.facebook.com/ORBISproject  ORBIS Twitter: https://twitter.com/ORBIS_project  ORBIS Researchgate: https://www.researchgate.net/project/ORBIS-Open-Research-Biopharmaceutical-Internships-Support-MSCA-RISE-2017-No-778051  P. J. Rudzki, B. Milanowski, L. Tajber, G. Garbacz, E. Jakubowska, M. Rychter, A. Kutner, J. Lulek, International and intersectoral ORBIS project launched under Horizon 2020, Farm. Pol. 2018.
Bioequivalence (BE) of orally administered drugs is a well-established field of regulatory science. It is based on comparing time-related changes of drug concentrations measured in human plasma for test and reference products. BE of topically administered drugs is not as straightforward issue [1,2]. Clinical endpoint BE studies may involve hundreds of patients - more than clinical evaluation of original drug . Thus, implementation of ethical and cost-effective methodology for studying bioequivalence of topical drugs is critical for assuring patients’ access to generic medicines. Since over 25 years the dermal microdialysis enables measurement of drug concentrations in the dermis and subcutaneous tissue . The test and reference products may be studied simultaneously in the same subject. This decreases intrasubject variability and the sample size needed to draw statistically sound conclusions. Thus, it suits well for the BE evaluation. So why dermal microdialysis marriage has not yet become a golden standard for bioequivalence of topical drugs? In our study we try to figure out the current obstacles and future perspectives of this marriage. References  A. Yacobi, V.P. Shah, E.D. Bashaw, E. Benfeldt et al., Pharm Res., 31(4) (2014) 837-846  M. Lu, H. Xing, X. Chen, L. Xian, J. Jiang et al., Asian J Pharm Sci., 11(6) (2016) 700-707  R.A. Lionberger, AAPS J., 10(1) (2008) 103-109  R. Holmgaard, J.B. Nielsen, E. Benfeldt, Skin Pharmacol Physiol., 23(5) (2010) 225-243
Research and Innovation Solubility improvement of poorly water soluble drug genistein (GI) by forming of cocrystals with amino acids-initial experiments: • determination of solubility of GI and amino acids: L-proline (L-Pro), L-aspartic acid (L-Asp) and L-glutamic acid (L-Glu) in 1-propanol and 2-propanol (IPA), with the use of Crystal 16; • preliminary studies for cocrystallisation of GI with L-Pro, L-Glu and L-Asp. Solubility of GI 0,000 0,005 0,010 0,015 0,020 0,025 0,030 0,035 20,0 30,0 40,0 50,0 60,0 70,0 80,0 Concentration [g/g of solvent]
Bioequivalence (BE) of orally administered drugs is a well-established field of regulatory science. It is based on comparing time-related changes of drug concentrations measured in human plasma for test and reference products. BE of topically administered drugs is not as straightforward issue [1,2]. Clinical endpoint BE studies may involve hundreds of patients - more than clinical evaluation of original drug . Thus, implementation of ethical and cost-effective methodology for studying bioequivalence of topical drugs is critical for assuring patients’ access to generic medicines. Since over 25 years the dermal microdialysis enables measurement of drug concentrations in the dermis and subcutaneous tissue . The test and reference products may be studied simultaneously in the same subject. This decreases intrasubject variability and the sample size needed to draw statistically sound conclusions. Thus, it suits well for the BE evaluation. So why dermal microdialysis marriage has not yet become a golden standard for bioequivalence of topical drugs? In our study we try to figure out the current obstacles and future perspectives of this marriage. References:  Yacobi A, Shah VP, Bashaw ED, Benfeldt E et al. Pharm Res. 2014;31(4):837-846.  Lu M, Xing H, Chen X, Xian L, Jiang J eta al. Asian J Pharm Sci. 2016;11(6):700-707.  Lionberger RA. AAPS J. 2008;10(1):103-109.  Holmgaard R, Nielsen JB, Benfeldt E. Skin Pharmacol Physiol. 2010;23(5):225-243. The ORBIS Project received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 778051.
The ORBIS project (Open Research Biopharmaceutical Internships Support) is dedicated to pharmaceutical development studies and is based on staff exchange. The lead institution on this project is Poznań University of Medical Sciences (PUMS) with Prof. Janina Lulek the grant coordinator. The ORBIS consortium comprises academic institutions and pharmaceutical companies from the European Union and associated countries. Rutgers University, the State University of New Jersey, USA is the project partner. The ORBIS project was launched at PUMS in April 2018. It is expected that cooperation with world-leading scientific institutions and pharmaceutical companies from Europe and the US will contribute to dynamic development of industrial pharmacy in Poland. KEYWORDS: pharmaceutical development pharmaceutical industry, exchange of scientists, European Union, Horizon 2020 [Projekt ORBIS (Open Research Biopharmaceutical Internships Support) dotyczy badań w procesie rozwoju produktów leczniczych i polega na wymianie pracowników badawczych. Liderem projektu jest Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu (UMP), a koordynatorem prof. Janina Lulek (UMP). Konsorcjum tworzą ośrodki naukowe i przedsiębiorstwa z krajów członkowskich i stowarzyszonych z Unią Europejską, a partnerem projektu jest Rutgers, The State University of New Jersey, USA. Uroczyste otwarcie projektu miało miejsce w Centrum Biblioteczno-Konferencyjnym UMP w kwietniu 2018 r. Oczekujemy, że współpraca z wiodącymi ośrodkami naukowymi oraz przedsiębiorstwami z Europy i USA przyczynią się do dynamicznego rozwoju farmacji przemysłowej w Polsce. SŁOWA KLUCZOWE: badania i rozwój, przemysł farmaceutyczny, wymiana naukowców, Unia Europejska, Horyzont 2020