scholarly journals Leveraging Oral Drug Development to a Next Level: Impact of the IMI-Funded OrBiTo Project on Patient Healthcare

2021 ◽  
Vol 8 ◽  
Author(s):  
Bart Hens ◽  
Patrick Augustijns ◽  
Hans Lennernäs ◽  
Mark McAllister ◽  
Bertil Abrahamsson
Keyword(s):  
Drug Development ◽  
In Silico ◽  
Oral Drug Delivery ◽  
Drug Product ◽  
Real Life ◽  
Drug Formulation ◽  
Oral Drug ◽  
Formulation Development ◽  
Drug Products

A thorough understanding of the behavior of drug formulations in the human gastrointestinal (GI) tract is essential when working in the field of oral drug development in a pharmaceutical company. For orally administered drug products, various GI processes, including disintegration of the drug formulation, drugrelease, dissolution, precipitation, degradation, dosage form transit and permeation, dictate absorption into the systemic circulation. These processes are not always fully captured in predictive in vitro and in silico tools, as commonly applied in the pre-clinical stage of formulation drug development. A collaborative initiative focused on the science of oral biopharmaceutics was established in 2012 between academic institutions and industrial companies to innovate, optimize and validate these in vitro and in silico biopharmaceutical tools. From that perspective, the predictive power of these models can be revised and, if necessary, optimized to improve the accuracy toward predictions of the in vivo performance of orally administered drug products in patients. The IMI/EFPIA-funded “Oral Bioavailability Tools (OrBiTo)” project aimed to improve our fundamental understanding of the GI absorption process. The gathered information was integrated into the development of new (or already existing) laboratory tests and computer-based methods in order to deliver more accurate predictions of drug product behavior in a real-life setting. These methods were validated with the use of industrial data. Crucially, the ultimate goal of the project was to set up a scientific framework (i.e., decision trees) to guide the use of these new tools in drug development. The project aimed to facilitate and accelerate the formulation development process and to significantly reduce the need for animal experiments in this area as well as for human clinical studies in the future. With respect to the positive outcome for patients, high-quality oral medicines will be developed where the required dose is well-calculated and consistently provides an optimal clinical effect. In a first step, this manuscript summarizes the setup of the project and how data were collected across the different work packages. In a second step, case studies of how this project contributed to improved knowledge of oral drug delivery which can be used to develop improved products for patients will be illustrated.

scholarly journals Measuring dissolution profiles of single controlled-release drug pellets

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Heran C. Bhakta ◽  
Jessica M. Lin ◽  
William H. Grover
Keyword(s):  
Controlled Release ◽  
Resonance Frequency ◽  
Drug Product ◽  
The Body ◽  
Sensor Data ◽  
Drug Dissolution ◽  
Oral Drug ◽  
High Temporal Resolution ◽  
Drug Products

AbstractMany solid-dose oral drug products are engineered to release their active ingredients into the body at a certain rate. Techniques for measuring the dissolution or degradation of a drug product in vitro play a crucial role in predicting how a drug product will perform in vivo. However, existing techniques are often labor-intensive, time-consuming, irreproducible, require specialized analytical equipment, and provide only “snapshots” of drug dissolution every few minutes. These limitations make it difficult for pharmaceutical companies to obtain full dissolution profiles for drug products in a variety of different conditions, as recommended by the US Food and Drug Administration. Additionally, for drug dosage forms containing multiple controlled-release pellets, particles, beads, granules, etc. in a single capsule or tablet, measurements of the dissolution of the entire multi-particle capsule or tablet are incapable of detecting pellet-to-pellet variations in controlled release behavior. In this work, we demonstrate a simple and fully-automated technique for obtaining dissolution profiles from single controlled-release pellets. We accomplished this by inverting the drug dissolution problem: instead of measuring the increase in the concentration of drug compounds in the solution during dissolution (as is commonly done), we monitor the decrease in the buoyant mass of the solid controlled-release pellet as it dissolves. We weigh single controlled-release pellets in fluid using a vibrating tube sensor, a piece of glass tubing bent into a tuning-fork shape and filled with any desired fluid. An electronic circuit keeps the glass tube vibrating at its resonance frequency, which is inversely proportional to the mass of the tube and its contents. When a pellet flows through the tube, the resonance frequency briefly changes by an amount that is inversely proportional to the buoyant mass of the pellet. By passing the pellet back-and-forth through the vibrating tube sensor, we can monitor its mass as it degrades or dissolves, with high temporal resolution (measurements every few seconds) and mass resolution (700 nanogram resolution). As a proof-of-concept, we used this technique to measure the single-pellet dissolution profiles of several commercial controlled-release proton pump inhibitors in simulated stomach and intestinal contents, as well as comparing name-brand and generic formulations of the same drug. In each case, vibrating tube sensor data revealed significantly different dissolution profiles for the different drugs, and in some cases our method also revealed differences between different pellets from the same drug product. By measuring any controlled-release pellets, particles, beads, or granules in any physiologically-relevant environment in a fully-automated fashion, this method can augment and potentially replace current dissolution tests and support product development and quality assurance in the pharmaceutical industry.

scholarly journals Evaluation of Excipient Risk in BCS Class I and III Biowaivers

2022 ◽  
Vol 24 (1) ◽  
Author(s):  
Melissa Metry ◽  
James E. Polli
Keyword(s):  
Drug Product ◽  
Scale Up ◽  
Drug Formulation ◽  
Product Regulatory ◽  
Drug Bioavailability ◽  
Drug Products ◽  
Fda Guidance ◽  
Regulatory Guidance

AbstractThe objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

scholarly journals A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery

Pharmaceutics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 625 ◽  
Author(s):  
Georgia Tsakiridou ◽  
Christos Reppas ◽  
Martin Kuentz ◽  
Lida Kalantzi
Keyword(s):  
In Silico ◽  
Oral Drug Delivery ◽  
Solid Dispersions ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Oral Drug ◽  
Main Task ◽  
Formulation Development ◽  
Scanning Calorimetry ◽  
Polymer Interactions

Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus®, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit® S100 were used as excipients. Solvent-based evaporation methods were used to prepare binary solid dispersions of drug and polymer. Data of the dilute solution viscosimetry were compared with in silico calculations of the Hansen solubility parameter (HSP), as well as phase separation/crystallization data obtained from X-ray diffraction and differential scanning calorimetry. HSP calculations in some cases led to false positive predictions of tacrolimus miscibility with the tested polymers. The novel rheology-based method provided valuable insights into drug-polymer interactions and likely miscibility with polymer. It is a rather fast, inexpensive, and robust analytical approach, which could be used complementary to in silico-based evaluation of polymers in early formulation development, especially in cases of rather large active pharmaceutical ingredients.

Integration of in vitro biorelevant dissolution and in silico PBPK model of carvedilol to predict bioequivalence of oral drug products

2018 ◽  
Vol 118 ◽  
pp. 176-182 ◽  
Author(s):  
Manuel Ibarra ◽  
Cristian Valiante ◽  
Patricia Sopeña ◽  
Alejandra Schiavo ◽  
Marianela Lorier ◽  
...  
Keyword(s):  
In Silico ◽  
Pbpk Model ◽  
Oral Drug ◽  
Drug Products ◽  
Biorelevant Dissolution

scholarly journals Biodegradable microcontainers – towards real life applications of microfabricated systems for oral drug delivery

Lab on a Chip ◽  
2019 ◽  
Vol 19 (17) ◽  
pp. 2905-2914 ◽  
Author(s):  
Zarmeena Abid ◽  
Sophie Strindberg ◽  
Madeeha M. Javed ◽  
Chiara Mazzoni ◽  
Lukas Vaut ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Oral Drug Delivery ◽  
Real Life ◽  
Oral Drug ◽  
Complete Study

We demonstrate the first complete study on fabrication of biodegradable microcontainers including their evaluation in vitro and in vivo.

scholarly journals Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 889
Author(s):  
Kaijie Qian ◽  
Lorenzo Stella ◽  
David S. Jones ◽  
Gavin P. Andrews ◽  
Huachuan Du ◽  
...  
Keyword(s):  
Solid Dispersion ◽  
Oral Drug Delivery ◽  
Drug Product ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Nucleation Theory ◽  
Product Development Process ◽  
Classical Nucleation Theory ◽  
Oral Drug ◽  
Amorphous Solid Dispersion

Among many methods to mitigate the solubility limitations of drug compounds, amorphous solid dispersion (ASD) is considered to be one of the most promising strategies to enhance the dissolution and bioavailability of poorly water-soluble drugs. The enhancement of ASD in the oral absorption of drugs has been mainly attributed to the high apparent drug solubility during the dissolution. In the last decade, with the implementations of new knowledge and advanced analytical techniques, a drug-rich transient metastable phase was frequently highlighted within the supersaturation stage of the ASD dissolution. The extended drug absorption and bioavailability enhancement may be attributed to the metastability of such drug-rich phases. In this paper, we have reviewed (i) the possible theory behind the formation and stabilization of such metastable drug-rich phases, with a focus on non-classical nucleation; (ii) the additional benefits of the ASD-induced drug-rich phases for bioavailability enhancements. It is envisaged that a greater understanding of the non-classical nucleation theory and its application on the ASD design might accelerate the drug product development process in the future.

scholarly journals In vitro evaluation of the genotoxicity of poly(anhydride) nanoparticles designed for oral drug delivery

2017 ◽  
Vol 523 (1) ◽  
pp. 418-426 ◽  
Author(s):  
T. Iglesias ◽  
M. Dusinska ◽  
N. El Yamani ◽  
J.M. Irache ◽  
A. Azqueta ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Oral Drug Delivery ◽  
Oral Drug ◽  
In Vitro Evaluation

Preparation, characterization and in-vitro evaluation of bacterial cellulose matrices for oral drug delivery

Cellulose ◽  
2017 ◽  
Vol 24 (11) ◽  
pp. 5041-5052 ◽  
Author(s):  
Munair Badshah ◽  
Hanif Ullah ◽  
Shujaat Ali Khan ◽  
Joong Kon Park ◽  
Taous Khan
Keyword(s):  
Drug Delivery ◽  
Bacterial Cellulose ◽  
Oral Drug Delivery ◽  
Oral Drug ◽  
In Vitro Evaluation

scholarly journals FORMULATION AND EVALUATION OF PERINDOPRIL MICROENCAPSULES BY USING DIFFERENT POLYMER

2017 ◽  
Vol 10 (2) ◽  
pp. 153
Author(s):  
Leena Jacob ◽  
Abhilash Tv ◽  
Shajan Abraham
Keyword(s):  
Drug Delivery ◽  
Particle Size ◽  
Release Rate ◽  
Oral Drug Delivery ◽  
Entrapment Efficiency ◽  
Water Soluble ◽  
Oral Drug ◽  
Percentage Yield ◽  
Drug Entrapment Efficiency

Objective: The study was carried out with an objective to achieve a potential sustained release oral drug delivery system of an antihypertensive drug, Perindopril which is a ACE inhibitor having half life of 2 hours. Perindopril is water soluble drug, so we can control or delay the release rate of drug by using release retarding polymers. This may also decrease the toxic side effects by preventing the high initial concentration in the blood.Method: Microcapsules were prepared by solvent evaporation technique using Eudragit L100 and Ethyl cellulose as a retarding agent to control the release rate and magnesium stearate as an inert dispersing carrier to decrease the interfacial tension between lipophilic and hydrophilic phase. Results: Prepared microcapsules were evaluated for the particle size, percentage yield, drug entrapment efficiency, flow property and in vitro drug release for 12 h. Results indicated that the percentage yield, mean particle size, drug entrapment efficiency and the micrometric properties of the microcapsules was influenced by various drug: polymer ratio. The release rate of microcapsules could be controlled as desired by adjusting the combination ratio of dispersing agents to retarding agents.Conclusion:Perindopril microcapsules can be successfully designed to develop sustained drug delivery, that reduces the dosing frequency and their by one can increase the patient compliance.

scholarly journals EFFECT OF NATURAL AND SYNTHETIC POLYMERS ON THE PROPERTIES OF CANDESARTAN CILEXETIL MATRIX TABLET PREPARED BY DRY GRANULATION

2016 ◽  
Vol 9 (9) ◽  
pp. 161
Author(s):  
Omar Saeb Salih ◽  
Roaa Abdalhameed Nief
Keyword(s):  
Drug Delivery ◽  
Candesartan Cilexetil ◽  
Oral Drug Delivery ◽  
In Vitro Release ◽  
Oral Drug ◽  
Matrix Tablet ◽  
Sustained Release Formulation ◽  
Weight Variation ◽  
Vitro Release

ABSTRACTObjective: The objective of this study is to develop a controlled release matrix tablet of candesartan cilexetil to reduce the frequency of administration,enhance bioavailability and improve patient compliance; a once daily sustained release formulation of candesartan cilexetil is desirable.Methods: The prepared tablets from F1 to F24 were evaluated with different evaluation parameters like weight variation, drug content, friability,hardness, thickness and swelling ability. In vitro release for all formulas were studied depends on the type and amount of each polymer, i.e. (16 mg,32 mg and 48 mg) respectively beside to the combination effect of polymers on the release of the drug from the tablet.Results: In vitro release showed that formula 13 had the faster release (100% after 4 h) which contained acacia (1:1) and the lowest sustain releasewas showed for F7 (73% after 8 h) which contained HPMC K100M (1:1). Formula 1 was an 89 % release after 8 h which contain eudragit RS100; F4was a 100 % release after 5 h which contain Na CMC, F10 was a 100% after 8 h which contain xanthan gum and F16 was a 100 % release after 5 hwhich contain tragacanth polymer. Formula 9 had a lower release than F7 and F8 respectively. Formula 7 can be used for sustain oral drug delivery ofcandesartan cilexetil while Formula 13 can be used in contrary as fast release tablets for faster response.Conclusion: Controlled drug delivery system is promising for less dosing and higher patient compliance.Keywords: Angiotensin II receptor antagonist, Hypertension, Matrix system, Control release.

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