Dosage Form Performance Research Articles

Advances in IgY antibody dosage form design and delivery strategies: Current status and future perspective.

Immunoglobulin Y (IgY), a unique type of antibody found in birds, is attracting increasing attention for a broad range of biomedical applications. Rational IgY protection, dosage form design, and delivery are highly essential to transform functional IgY antibodies into desired IgY products for therapeutic and prophylactic administration. Although progress has been made in this field, it remains in the early stages, highlighting the fundamental research and development needed in this aspect of IgY technology. Hence, this article reviews the conventional and innovative IgY dosage designs and delivery strategies, emphasizes the challenges faced in various IgY delivery systems, discusses the criteria for evaluating IgY dosage form performance, and provides a comprehensive analysis of the current research status and prospects of IgY delivery strategies.

In Vitro Simulation of the Fasted Gastric Conditions and Their Variability to Elucidate Contrasting Properties of the Marketed Dabigatran Etexilate Pellet-Filled Capsules and Loose Pellets.

Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro-in vivo extrapolation.

Development of Ternary Amorphous Solid Dispersions Manufactured by Hot-Melt Extrusion and Spray-Drying─Comparison of In Vitro and In Vivo Performance.

Producing amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is favorable from an economic and ecological perspective but also limited to thermostable active pharmaceutical ingredients (APIs). A potential technology shift from spray-drying to hot-melt extrusion at later stages of drug product development is a desirable goal, however bearing the risk of insufficient comparability of the in vitro and in vivo performance of the final dosage form. Hot-melt extrusion was performed using API/polymer/surfactant mixtures with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the polymer and evaluated regarding the extrudability of binary and ternary amorphous solid dispersions (ASDs). Additionally, spray-dried ASDs were produced, and solid-state properties were compared to the melt-extruded ASDs. Tablets were manufactured of a ternary ASD lead candidate comparing their in vitro dissolution and in vivo performance. The extrudability of HPMCAS was improved by adding a surfactant as plasticizer, thereby lowering the high melt-viscosity. d-α-Tocopheryl polyethylene glycol succinate (TPGS) as surfactant showed the most similar solid-state properties between spray-dried and extruded ASDs compared to those of poloxamer 188 and sodium dodecyl sulfate. The addition of TPGS, however, barely affected API/polymer interactions. The in vitro dissolution experiment and in vivo dog study revealed a higher drug release of tablets manufactured from the spray-dried ASD compared to the melt-extruded ASD; this was attributed to the different particle size. We could further demonstrate that the drug release can be controlled by adjusting the particle size of melt-extruded ASDs leading to a similar release profile compared to tablets containing the spray-dried dispersion, which confirmed the feasibility of a technology shift from spray-drying to HME upon drug product development.

Inhalation Dosage Forms: A Focus on Dry Powder Inhalers and Their Advancements.

In this review, an extensive analysis of dry powder inhalers (DPIs) is offered, focusing on their characteristics, formulation, stability, and manufacturing. The advantages of pulmonary delivery were investigated, as well as the significance of the particle size in drug deposition. The preparation of DPI formulations was also comprehensively explored, including physico-chemical characterization of powders, powder processing techniques, and formulation considerations. In addition to manufacturing procedures, testing methods were also discussed, providing insights into the development and evaluation of DPI formulations. This review also explores the design basics and critical attributes specific to DPIs, highlighting the significance of their optimization to achieve an effective inhalation therapy. Additionally, the morphology and stability of 3 DPI capsules (Spiriva, Braltus, and Onbrez) were investigated, offering valuable insights into the properties of these formulations. Altogether, these findings contribute to a deeper understanding of DPIs and their development, performance, and optimization of inhalation dosage forms.

In Vitro and In Vivo Evaluation of Dark Chocolate as Age-appropriate Oral Matrix

Swallowing difficulties encountered by geriatric patients who undergo polypharmacy represent a significant challenge that hampers patient compliance and therapeutic management. As an appealing and sensory-pleasing, chocolate-based formulations have emerged as a potential alternative oral dosage form suitable for both the elderly and paediatric populations. However, the extent to which the incorporation of drugs into a chocolate matrix affects their oral availability remains unclear. Therefore, the objective of this investigation was to explore the in vitro and in vivo performance of an ibuprofen-based chocolate dosage form. A matrix based on dark chocolate and the model drug was prepared at two distinct temperatures: 50 and 80 °C. In vitro release studies revealed that ibuprofen formulated through co-melting at 80 °C exhibited a statistically significant slower drug release (p < 0.05) compared to formulations prepared at 50 °C in both FaSSGF (fasted-state simulated gastric fluid) and lipolysis media. The enzymatic degradation of chocolate in the presence of lipase accelerated in vitro ibuprofen release from chocolate matrices. To delve deeper into the bioavailability of ibuprofen within the chocolate formulations, we conducted an in vivo assessment, comparing the pharmacokinetic profiles of ibuprofen in its conventional suspension form with our chocolate-based dosage forms. A notable drop (p < 0.05) in the maximum serum concentration of ibuprofen when incorporated into co-melted or solid-suspension chocolate matrices. However, no significant differences in plasma exposure were observed between the two formulations. These findings shed a light on the potential of chocolate to extend of ibuprofen when integrated into various chocolate matrices, showcasing the potential held by these innovative formulations.

Flurbiprofen cataplasms: Development and validation of in-vitro dissolution methods and evaluation of multimedia dissolution profiles

The investigation of the systemic release performance of dosage forms using in vitro tools is a crucial objective in the realm of pharmaceutical development. The dissolution methodology is an effective tool for monitoring batch-to-batch variabilities in quality control and gaining insight into the release mechanisms of pharmaceutical drugs. The majority of the dissolution techniques that have been approved are primarily intended for solid oral dosage forms. Nevertheless, these techniques have also been applied to various other dosage forms, including transdermal drug delivery systems. The administration of medication through cataplasm, a transdermal application, poses challenges in understanding the characteristics of drug release. Flurbiprofen is classified as a class II drug according to the Biopharmaceutics Classification System and is commonly administered in the form of a cataplasm for its analgesic properties. A dissolution method was developed to assess the in vitro release profile of the flurbiprofen transdermal delivery system. This method utilized a United States Pharmacopeia dissolution apparatus V, with a disc assembled over the paddle. Additionally, a method for quantification was developed using liquid chromatography. The discriminatory aspect of the developed method has faced criticism due to substantial alterations in excipient composition. Furthermore, we have developed clearly defined multimedia release profiles within the physiological pH range. The validation of the dissolution and chromatography systems was conducted.

Multiscale X-ray imaging and characterisation of pharmaceutical dosage forms

A correlative, multiscale imaging methodology for visualising and quantifying the morphology of solid dosage forms by combining ptychographic X-ray computed nanotomography (PXCT) and scanning small- and wide-angle X-ray scattering (S/WAXS) is presented. The methodology presents a workflow for multiscale analysis, where structures are characterised from the nanometre to millimetre regime. Here, the method is demonstrated by characterising a hot-melt extruded, partly crystalline, solid dispersion of carbamazepine in ethyl cellulose. Characterisation of the morphology and solid-state phase of the drug in solid dosage forms is central as this affects the performance of the final formulation. The 3D morphology was visualised at a resolution of 80 nm over an extended volume through PXCT, revealing an oriented structure of crystalline drug domains aligned in the direction of extrusion. Scanning S/WAXS showed that the nanostructure is similar over the cross section of the extruded filament, with minor radial changes in domain sizes and degree of orientation. The polymorphic forms of carbamazepine were qualified with WAXS, showing a heterogeneous distribution of the metastable forms I and II. This demonstrates the methodology for multiscale structural characterization and imaging to enable a better understanding of the relationships between morphology, performance, and processing conditions of solid dosage forms.

3D Printing Technology as a Promising Tool to Design Nanomedicine-Based Solid Dosage Forms: Contemporary Research and Future Scope.

3D printing technology in medicine is gaining great attention from researchers since the FDA approved the first 3D-printed tablet (Spritam®) on the market. This technique permits the fabrication of various types of dosage forms with different geometries and designs. Its feasibility in the design of different types of pharmaceutical dosage forms is very promising for making quick prototypes because it is flexible and does not require expensive equipment or molds. However, the development of multi-functional drug delivery systems, specifically as solid dosage forms loaded with nanopharmaceuticals, has received attention in recent years, although it is challenging for formulators to convert them into a successful solid dosage form. The combination of nanotechnology with the 3D printing technique in the field of medicine has provided a platform to overcome the challenges associated with the fabrication of nanomedicine-based solid dosage forms. Therefore, the major focus of the present manuscript is to review the recent research developments that involved the formulation design of nanomedicine-based solid dosage forms utilizing 3D printing technology. Utilization of 3D printing techniques in the field of nanopharmaceuticals achieved the successful transformation of liquid polymeric nanocapsules and liquid self-nanoemulsifying drug delivery systems (SNEDDS) to solid dosage forms such as tablets and suppositories easily with customized doses as per the needs of the individual patient (personalized medicine). Furthermore, the present review also highlights the utility of extrusion-based 3D printing techniques (Pressure-Assisted Microsyringe-PAM; Fused Deposition Modeling-FDM) to produce tablets and suppositories containing polymeric nanocapsule systems and SNEDDS for oral and rectal administration. The manuscript critically analyzes contemporary research related to the impact of various process parameters on the performance of 3D-printed solid dosage forms.

Experimental determination and computational prediction of blend time in the USP dissolution testing Apparatus 1

The USP Apparatus 1 (rotating basket) is a preferred testing tool to evaluate the in vitro dissolution performance of pharmaceutical oral solid dosage forms, both as a quality control tool and to determine optimal drug formulations. The test relies on taking samples from the dissolution vessel during the dissolution process to obtain drug dissolution-time profiles. Of significant importance is the determination of the blend time, i.e., the time needed for the drug substance released from the dosage form to become dispersed throughout the vessel, especially at the sampling point. How representative these samples are with respect to the amount of drug dissolved can vary depending on operating and geometrical parameters. Here, the blend time in the USP Apparatus 1 was obtained experimentally and computationally for different operating conditions (basket mesh size, liquid fill volume, and rotation intensity) using the discoloration method coupled with image processing and by conducting time-dependent simulations using the Lattice-Boltzmann Large-Eddy Simulation approach. The experimental and predicted blend times were found to be in agreement. Additionally, an empirical correlation for blend time was developed. These results will help practitioners determine the effect of operating parameters on how representative the samples taken during the test are.

Excipient Taxonomy for the 21st Century

The performance of pharmaceutical dosage forms relies heavily on the characteristics of the excipients that are incorporated into the drug product during the manufacturing process. Therefore, it is imperative that formulators are able to accurately and completely specify the key chemical and physical properties of those excipients. Current approaches to describing excipients are outdated and inadequate for the needs of the 21st century and in this article we highlight the benefits of a more systematic and comprehensive approach to specifying and controlling excipient properties. We hope that this will prompt the users, suppliers, and manufacturers of excipients to take a careful look at current approaches and develop tangible proposals for attaining an enhanced future state.

Dynamic Changes in Gastrointestinal Fluid Characteristics after Food Ingestion Are Important for Quantitatively Predicting the In Vivo Performance of Oral Solid Dosage Forms in Humans in the Fed State.

The aim of this study was to develop a simulation model to predict the in vivo performance of solid oral dosage forms in humans in the fed state. We focused on investigating the effect of dynamic changes in gastrointestinal (GI) fluid characteristics in the fed state on the in vivo performance of solid dosage forms. We used six solid dosage forms containing weak base drugs as model formulations, two with positive food effects in humans, two with negative food effects, and two which are not affected by food ingestion. These model drug formulations were used to perform biorelevant dissolution tests in the stomach and small intestine under both prandial states. The in vitro properties of the drug products obtained from these tests were then coupled with in silico models (fasted or fed) to predict food effects in humans. We successfully incorporated the dynamic changes in GI fluid characteristics and their effects on the in vivo dissolution of drugs into the prediction model for the fed state. This newly designed physiologically based biopharmaceutics modeling approach provided the precise and quantitative prediction of food effects (i.e., changes in Cmax and AUC after food ingestion) in humans while considering the dynamic changes in fluid characteristics in the fed state.

Development of a digital twin of a tablet that mimics a real solid dosage form: Differences in the dissolution profile in conventional mini-USP II and a biorelevant colon model

The performance of colon-targeted solid dosage forms is commonly assessed using standardised pharmacopeial dissolution apparatuses like the USP II or the miniaturised replica, the mini-USP II. However, these fail to replicate the hydrodynamics and shear stresses in the colonic environment, which is crucial for the tablet's drug release process. In this work, computer simulations are used to create a digital twin of a dissolution apparatus and to develop a method to create a digital twin of a tablet that behaves realistically. These models are used to investigate the drug release profiles and shear rates acting on a tablet at different paddle speeds in the mini-USP II and biorelevant colon models to understand how the mini-USP II can be operated to achieve more realistic (i.e., in vivo) hydrodynamic conditions.The behaviour of the tablet and the motility patterns used in the simulations are derived from experimental and in vivo data, respectively, to obtain profound insights into the tablet's disintegration/drug release processes. We recommend an “on-off” operating mode in the mini-USP II to generate shear rate peaks, which would better reflect the in vivo conditions of the human colon instead of constant paddle speed.

A brief overview of sustained released drug delivery system

The most popular and patient-friendly method of drug administration is often thought to be the oral route of administration. Compared to conventional release formulations, advancements in formulation technology, including modified release dosage forms or sustained release oral dosage forms, have been extensively accepted. A sustained release dosage form provides a prolonged release of the drug over an extended period, thereby giving better patient compliance and enhanced bioavailability. Sustain release systems are considered a wiser approach for drugs with short half-lives requiring repeated dosing. Sustained release drug delivery has a range of advantages over conventional dosage forms, including increased patient compliance due to less frequent drug administration, significantly reduced steady state drug level fluctuations, maximum drug utilization, the increased safety margin of potent drugs, lower healthcare costs due to improved therapy, and shorter treatment times. The present review focuses on design, fabrication, and various factors that influence the performance of sustained-release dosage forms.

A REVIEW ON QUANTUM DOTS (QDS)

Recently, the drugs in nanometer size range have found to increase the performance of various dosage forms. Quantum dots (QDs) have gained attention and interest of scientists due to their targeting and imaging potential in nano based drug delivery, in pharmaceutical and biomedical (cell biology) applications. They are artificial semiconductor nanocrystals that have tunable and efficient photo luminescence with narrow emission spectra and high light stability making them excellent probes for bioimaging applications. QDs absorb white light and can produce different colors determined by the size of the particles and band Gap. Nowadays, quantum dots are used for labeling live biological material in vitro and in vivo in animals (other than humans) for research purposes and also useful for immunoassay studies. In the present article, we have discussed various aspects of QDs, highlighting their pharmaceutical and biomedical applications and current challenges in introducing QDs into clinical practice.

Design and Evaluation of Two-Step Biorelevant Dissolution Methods for Docetaxel Oral Formulations.

Dissolution is a pivotal tool for oral formulations. Dissolution could be used to either reduce the risk of product failure through quality control or predict and understand in vivo performance of drug formulations. The latter is always challenging because multiple factors such as selection of media, gastrointestinal components, physiological factors, consideration of fasted and fed state are involved. Previously published dissolution methods such as one-step dissolution in individual simulated gastric fluid, simulated intestinal fluid, or phosphate buffer saline did not signify the realistic gastrointestinal transit effect. Docetaxel (DTX), a poorly water-soluble drug, is commercially available only as injectable dosage forms, and thus many publications studied the development of oral DTX formulations. In our previous report, we developed oral lipid-based DTX granules that showed higher oral absorption in rats compared to DTX powder. However, one-step dissolution in simulated gastric fluid showed no difference between DTX granules and DTX powder. Therefore, the present study aimed to develop new two-step biorelevant dissolution methods for DTX oral formulations. In the study, new two-step biorelevant dissolution methods in fasted or fed states with pancreatin were developed and compared with other previously reported dissolution methods. The new two-step biorelevant dissolution methods successfully discriminated the difference of dissolution between DTX granules and DTX powder, which reflected the in vivo difference of absorption of these two formulations. Moreover, food effects were confirmed for DTX. The new dissolution methods have the potential to be used to predict and understand in vivo performance of oral solid dosage forms.

Interaction and Compatibility Studies in the Development of Olmesartan Medoxomil and Hydrochlorothiazide Formulations under a Real Manufacturing Process.

A drug–drug and drug–excipient interactions and compatibilities study was conducted for two fixed-dose combination (FDC) products containing olmesartan medoxomil (OLM)/hydrochlorothiazide (HCT) 20/12.5 mg and OLM/HCT 40/12.5 mg during their development including storage. The study consisted of the evaluation of samples retrieved during all stages of a real manufacturing process. Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetry (TGA), Fourier transform infrared spectroscopy (FT-IR), and contact angle techniques were applied to the samples to determine interactions and incompatibilities. Dissolution tests and long-term stability studies were conducted to evaluate dosage form performance. Results showed weak solid–state interactions able to obtain a eutectic mixture of OLM and HCT while microcrystalline cellulose (MC) impacted the thermal stability of both drugs. Reliable dissolution and long-term stability tests confirmed that the interactions observed were not considered incompatibilities because they were not influenced by the performance of the final products.

Importance of Gastric Secretion and the Rapid Gastric Emptying of Ingested Water along the Lesser Curvature ("Magenstraße") in Predicting the In Vivo Performance of Liquid Oral Dosage Forms in the Fed State Using a Modeling and Simulation.

The objective of the present study was to develop an in silico model of the stomach for predicting oral drug absorption in fed humans. We focused on a model capable of simulating dynamic fluid volume changes and included a simulated Magenstraße "stomach road," a route along the lesser curvature that often carries fluids rapidly to assess the gastric emptying of drugs. Two types of model liquid drug formulations, liquid-filled soft gelatin capsules (enzalutamide, cyclosporine, and nifedipine) and oral solutions (levofloxacin and fenfluramine), were used. An in silico model was assembled, and simulations were performed using Stella Professional software. The secretion rate of the gastric juice induced by food ingestion was assessed along with the gastric emptying of the ingested water via the Magenstraße in the fed state. The model for the fed state successfully described the in vivo performance of the model drug formulations. These results clearly indicate the importance of including gastric secretion and the kinetics of Magenstraße when predicting the in vivo performance of dosage forms using an in silico modeling and simulation of fed humans. This simulation model should be further optimized to allow for the different physiological mechanisms following the ingestion of different types of meals, as well as modifications for interindividual and intraindividual variabilities in gastrointestinal physiology in the fed state in the future.

Analytical Challenges and Metrological Approaches to Ensuring Dietary Supplement Quality: International Perspectives.

The increased utilization of metrology resources and expanded application of its’ approaches in the development of internationally agreed upon measurements can lay the basis for regulatory harmonization, support reproducible research, and advance scientific understanding, especially of dietary supplements and herbal medicines. Yet, metrology is often underappreciated and underutilized in dealing with the many challenges presented by these chemically complex preparations. This article discusses the utility of applying rigorous analytical techniques and adopting metrological principles more widely in studying dietary supplement products and ingredients, particularly medicinal plants and other botanicals. An assessment of current and emerging dietary supplement characterization methods is provided, including targeted and non-targeted techniques, as well as data analysis and evaluation approaches, with a focus on chemometrics, toxicity, dosage form performance, and data management. Quality assessment, statistical methods, and optimized methods for data management are also discussed. Case studies provide examples of applying metrological principles in thorough analytical characterization of supplement composition to clarify their health effects. A new frontier for metrology in dietary supplement science is described, including opportunities to improve methods for analysis and data management, development of relevant standards and good practices, and communication of these developments to researchers and analysts, as well as to regulatory and policy decision makers in the public and private sectors. The promotion of closer interactions between analytical, clinical, and pharmaceutical scientists who are involved in research and product development with metrologists who develop standards and methodological guidelines is critical to advance research on dietary supplement characterization and health effects.

DESIGN OF DISSOLUTION STUDY PROTOCOL FOR PULMONARY DOSAGE FORMS: CRITERIA FOR SELECTION OF BIO-RELEVANT DISSOLUTION MEDIUM

Pulmonary dosage forms constitute an important route of drug delivery for systemic absorption of drugs in management of respiratory diseases as well as diseases such as diabetes, migraine, osteoporosis, and cancer. Performance of different pulmonary dosage forms is greatly influenced by aerodynamic particle size distribution of inhalable particles, spray pattern, fraction of dose actually deposited on pulmonary epithelium, dissolution of active pharmaceutical ingredient and ultimately absorption across pulmonary barriers. In vitro dissolution study should be designed to predict in vivo performance precisely, providing key information on bioavailability and establishing in vitro-in vivo correlation. To obtain meaningful data from dissolution study, focus should be on composition of dissolution medium, dissolution conditions and dissolution test apparatus. For pulmonary dosage forms, selection of physiologically relevant dissolution medium, mimicking lung fluid (LF) is a challenging task. Attempts are being made to develop bio-relevant dissolution medium to overcome the limitations associated with use of conventional media lacking lung surfactant proteins, or several salts normally present in pleural fluid. Use of simulated LFs can give a better understanding of the release mechanisms and possible in vivo behavior of pulmonary dosage forms thereby enhancing the predictive capability of the dissolution testing. In the review, efforts have been taken to provide comprehensive information on composition, physicochemical characteristics and functions of physiological LF, challenges associated with the design and development of dissolution study protocol for pulmonary dosage forms, criteria for selection of an appropriate bio-relevant dissolution medium, comparative study on various reported bio-relevant dissolution media and dissolution apparatuses employed for in vitro characterization of performance of pulmonary dosage forms.

Bootstrap analysis for dissolution similarity factor f2 - bringing confidence for borderline results – a case study

In vitro dissolution testing is one of the most important tools for characterizing the performance of oral solid dosage forms. In order to demonstrate similarity between test and reference product, comparative dissolution profiles are performed. Selection of a suitable method for comparison of the dissolution profile of the reference product and the test product is of great importance especially in the case of biowaivers when similarity assessment is based on the in vitro data only. Various approaches have been developed for the comparison of dissolution profiles, however the usage of the f2 similarity factor is widely accepted due to its simplicity. When the conditions for using f2 similarity factor are not fulfilled due to high variable dissolution profiles, f2 bootstrap method is then recommended. The focus of this study is to see whether it is benefitial f2 bootstrap analysis to replace the usage of simple f2 for comparison of dissolution profiles that fulfill the prerequisites for using the f2 method in cases when borderline f2 results are obtained. Keywords: Bootstrap analysis, comparative dissolution profiles, similarity factor f2