Microencapsulation of lemongrass and mangosteen peel as phytogenic compounds to gas kinetics, fermentation, degradability, methane production, and microbial population using in vitro gas technique.

The purpose of the current study was to evaluate the impact of various doses of microencapsulated lemongrass and mangosteen peel (MELM) on gas dynamics, rumen fermentation, degradability, methane production, and microbial population in in vitro gas experiments. With five levels of microencapsulated-phytonutrient supplementation at 0, 1, 2, 3, and 4% of substrate, 0.5 g of roughage, and a concentrate ratio of 60:40, the trial was set up as a completely randomized design. Under investigation, the amount of final asymptotic gas volume was corresponding responded to completely digested substrate (b) increased cubically as a result of the addition of MELM (P < 0.01) and a cubic rise in cumulative gas output. The amount of MELM form did not change the pH and NH3-N concentration of the rumen after 12 and 24 h of incubation. However, methane production during 24 h of incubation, the levels were cubically decreased with further doses of MELM (P < 0.01) at 12 h of incubation. Increasing the dosage of MELM supplementation at 2% DM resulted in a significant increase in the digestibility of in vitro neutral detergent fiber (IVNDF) and in vitro true digestibility (IVTD) at various incubation times (P < 0.05), but decreased above 3% DM supplementations. Moreover, the concentration of propionic acid (C3) exhibited the variations across the different levels of MELM (P < 0.05), with the maximum concentration obtained at 2% DM. The populations of Fibrobacter succinogenes, Ruminococcus albus, Ruminococcus flavefaciens, and Megasphaera elsdenii revealed a significant increase (P < 0.05), while the quantity of Methanobacteriales decreased linearly with increasing doses of MELM. In conclusion, the inclusion of MELM at a concentration of 2% DM in the substrate which could enhance cumulative gas production, NDF and true digestibility, C3 production, and microbial population, while reducing methane concentration and Methanobacterial abundance.

Cell microencapsulation techniques for cancer modelling and drug discovery.

Cell encapsulation into spherical microparticles is a promising bioengineering tool in many fields, including 3D cancer modelling and pre-clinical drug discovery. Cancer microencapsulation models can more accurately reflect the complex solid tumour microenvironment than 2D cell culture and therefore would improve drug discovery efforts. However, these microcapsules, typically in the range of 1 - 5000 µm in diameter, must be carefully designed and amenable to high-throughput production. This review therefore aims to outline important considerations in the design of cancer cell microencapsulation models for drug discovery applications and examine current techniques to produce these. Extrusion (dripping) droplet generation and emulsion-based techniques are highlighted and their suitability to high-throughput drug screening in terms of tumour physiology and ease of scale up is evaluated.

3D microencapsulation models of cancer offer a customisable platform to mimic key aspects of solid tumour physiology in vitro. However, many 3D models do not recapitulate the hypoxic conditions and altered tissue stiffness established in many tumour types and stages. Furthermore, microparticles for cancer cell encapsulation are commonly produced using methods that are not necessarily suitable for scale up to high-throughput manufacturing. This review aims to evaluate current technologies for cancer cell-laden microparticle production with a focus on physiological relevance and scalability. Emerging techniques will then be touched on, for production of uniform microparticles suitable for high-throughput drug discovery applications.

Microcrystalline cellulose from soybean hull as an excipient in solid dosage forms: Preparation, powder characterization, and tableting properties.

Microcrystalline cellulose (MCC) is one of the essential functional excipients in the formulation of tablets. The need for cheaper MCC sources has drawn significant attention to exploring renewable sources. In this study, MCC was produced from soybean hull (SBH), the primary by-product of the soy industry, using a novel, simplified, and cost-effective approach. Various characterization techniques were used to study the physicochemical properties and micromeritics of the SBH-based MCC powders and compare them to those of the commercial Avicel PH-101. SBH MCCs had a larger particle size, a broader particle size distribution, a higher degree of polymerization, a higher degree of crystallinity, better thermal stability, and slightly superior flowability and compressibility than Avicel PH-101. The tableting blends (containing 60 % MCC) were prepared, and the post-compression out-of-die Heckel analysis showed that formulations with aggregated SBH MCCs were less ductile than those made with Avicel PH-101, resulting in a lower porosity (better compressibility) of the latter at higher compression pressures. The hardness values for all formulations were above 6 kg, with higher values for those made with Avicel PH-101. The lubricant sensitivity was lower for SBH MCCs. All tablets made using developed formulations showed very low friability (<0.1 %) and short disintegration times (<90 s), making them well-suited candidates for manufacturing orally disintegrating tablets (ODTs).

Impact on Quality during In-Use Preparation of an Antibody Drug Conjugate with Eight Different Closed System Transfer Device Brands.

The aim of this study was to investigate the in-use compatibility of eight commercially available closed system transfer device brands (CSTDs) with a formulated model antibody drug conjugate (ADC). Overall, in-use simulated dosing preparation applying the CSTD systems investigated raised concerns for several product quality attributes. The incompatibilities observed were mainly associated with increased visible and subvisible particles formation as well as significant changes in holdup volumes. Visible and subvisible particles contained heterogeneous mixtures of particle classes, with the majority of subvisible particles associated with silicone oil leaching from CSTD systems during simulated dose preparation upon contact with the ADC formulation. These observations demonstrate that CSTD use may adversely impact product quality and delivered dose which could potentially lead to safety and efficacy concerns during administration. Other product quality attributes measured including turbidity, color, ADC recovery, and purity by size exclusion HPLC, did not show relevant changes. It is therefore strongly recommended to test and screen the compatibility of CSTDs with the respective ADC, in a representative in-use simulated administration setting, during early CMC development, i.e., well before the start of clinical studies, to include information about compatibility and to ensure that the CSTD listed in the manuals of preparation for clinical handling has been thoroughly assessed before human use.

High internal phase double emulsions stabilized by modified pea protein-alginate complexes: Application for co-encapsulation of riboflavin and ß-carotene.

The application of many hydrophilic and hydrophobic nutraceuticals is limited by their poor solubility, chemical stability, and/or bioaccessibility. In this study, a novel Pickering high internal phase double emulsion co-stabilized by modified pea protein isolate (PPI) and sodium alginate (SA) was developed for the co-encapsulation of model hydrophilic (riboflavin) and hydrophobic (ß-carotene) nutraceuticals. Initially, the effect of emulsifier type in the external water phase on emulsion formation and stability was examined, including commercial PPI (C-PPI), C-PPI-SA complex, homogenized and ultrasonicated PPI (HU-PPI), and HU-PPI-SA complex. The encapsulation and protective effects of these double emulsions on hydrophilic riboflavin and hydrophobic ß-carotene were then evaluated. The results demonstrated that the thermal and storage stabilities of the double emulsion formulated from HU-PPI-SA were high, which was attributed to the formation of a thick biopolymer coating around the oil droplets, as well as thickening of the aqueous phase. Encapsulation significantly improved the photostability of the two nutraceuticals. The double emulsion formulated from HU-PPI-SA significantly improved the in vitro bioaccessibility of ß-carotene, which was mainly attributed to inhibition of its chemical degradation under simulated acidic gastric conditions. The novel delivery system may therefore be used for the development of functional foods containing multiple nutraceuticals.

Chitosan for improved encapsulation of thyme aqueous extract in alginate-based microparticles.

Ionotropic gelation is a low-cost, easy and green microencapsulation technique. However, the encapsulation of highly soluble compounds is challenging because of the wide loss of material into the external water phase by passive diffusion and the consequent low encapsulation efficiency. In this work an important increase of encapsulation efficiency for Thymus vulgaris L. aqueous extract in alginate-based microparticles has been obtained. A formulation with the proper thyme extract/alginate ratio (30:70) was used as reference and then optimized by adding different co-carrier excipients. Microparticles obtained by dropping a solution containing thyme extract and alginate into a chitosan/calcium-chloride/acid acetic solution lead to a high encapsulation efficiency (70.43 ± 5.28 %). After drying, microparticles had a particle size of 1096 ± 72 µm, 20.087 ± 1.487 % of extract content, 6.2 % of residual water, and showed a complete release of thyme extract within one hour. Combining alginate and chitosan as polymeric co-carrier was a valuable option for efficiently encapsulating an aqueous extract by ionotropic gelation.

Spray drying Eudragit® E-PO with acetaminophen using 2- and 3-fluid nozzles for taste masking.

Conventional spray drying using a 2-fluid nozzle forms matrix microparticles, where drug is distributed throughout the particle and may not effectively mask taste. In contrast, spray drying using a 3-fluid nozzle has been reported to encapsulate material. The objective of this study was to spray dry Eudragit® E-PO (EE) with acetaminophen (APAP), a water-soluble model drug with a bitter taste, using 2- and 3-fluid nozzles for taste masking. Spray drying EE with APAP, however, resulted in yields of ≤ 13 %, irrespective of nozzle configuration. Yields improved when Eudragit® L 100-55 (EL) or Methocel® E6 (HPMC) was used in the inner fluid stream of the 3-fluid nozzle or in place of EE for the 2-fluid nozzle. Drug release from microparticles prepared with the 2-fluid nozzle was relatively rapid. Using EE in the outer fluid stream of the 3-fluid nozzle resulted in comparatively slower drug release, although drug release was observed, indicating that encapsulation was incomplete. Results from these studies also show that miscible polymers used in the two fluid streams mix during the spray drying process. In addition, findings from this study indicate that the polymer used in the inner fluid stream can impact drug release.

Rationalizing Counterion Selection for the Development of Lipophilic Salts: A Case Study with Venetoclax.

The use of lipid-based formulations (LBFs) can be hindered by low dose loading due to solubility limitations of candidate drugs in lipid vehicles. Formation of lipophilic salts through pairing these drugs with a lipophilic counterion has been demonstrated as a potential means to enhance dose loading in LBFs. This study investigated the screening of appropriate counterions to form lipophilic salts of the BCS class IV drug venetoclax. The physical properties, lipid solubility, and in vitro performance of the salts were analyzed. This study illustrated the versatility of alkyl sulfates and sulfonates as suitable counterions in lipophilic salt synthesis with up to ∼9-fold higher solubility in medium- and long-chain LBFs when compared to that of the free base form of venetoclax. All salts formulated as LBFs displayed superior in vitro performance when compared to the free base form of the drug due to the higher initial drug loadings in LBFs and increased affinity for colloidal species. Further, in vitro studies confirmed that venetoclax lipophilic salt forms using alkyl chain counterions demonstrated comparable in vitro performance to venetoclax docusate, thus reducing the potential for laxative effects related to docusate administration. High levels of the initial dose loading of venetoclax lipophilic salts were retained in a molecularly dispersed state during dispersion and digestion of the formulation, while also demonstrating increased levels of saturation in biorelevant media. The findings of this study suggest that alkyl chain sulfates and sulfonates can act as a suitable alternative counterion to docusate, facilitating the selection of counterions that can unlock the potential to formulate venetoclax as an LBF.

Whey protein concentrate and skimmed milk powder as encapsulation agents for coffee silverskin extracts processed by spray drying.

We tested the hypothesis that milk proteins, through microencapsulation, guarantee protection against bioactive substances in coffee silverskin extracts. Therefore, the aim of this study was to carry out technological, nutritional and physicochemical characterisation of a coffee silverskin extract microencapsulated using instant skim milk powder and whey protein concentrate as wall materials. The aqueous extract of coffee silverskin was spray-dried using 10% (w/v) skim milk powder and whey protein concentrate. The samples were characterised by determining the water content, water activity, particle size distribution, colour analysis and total phenolic compound content as well as antioxidant activity using 2,2-diphenyl-radical 1-picrylhydrazyl scavenging methods, nitric oxide radical inhibition and morphological analysis. The product showed water activity within a range that ensured greater stability, and the reduced degradation of the dried coffee silverskin extract with whey protein concentrate resulted in better rehydration ability. The luminosity parameter was higher and the browning index was lower for the encapsulated samples than for the pure coffee silverskin extract. The phenolic compound content (29.23 ± 8.39 and 34.00 ± 8.38 mg gallic acid equivalents/g for the coffee silverskin extract using skimmed milk powder and whey protein concentrate, respectively) and the antioxidant activity of the new product confirmed its potential as a natural source of antioxidant phenolic compounds. We conclude that the dairy matrices associated with spray drying preserved the bioactive and antioxidant activities of coffee silverskin extracts.

The Influence of PVP Polymer Topology on the Liquid Crystalline Order of Itraconazole in Binary Systems.

This study presents a novel approach by utilizing poly(vinylpyrrolidone)s (PVPs) with various topologies as potential matrices for the liquid crystalline (LC) active pharmaceutical ingredient itraconazole (ITZ). We examined amorphous solid dispersions (ASDs) composed of ITZ and (i) self-synthesized linear PVP, (ii) self-synthesized star-shaped PVP, and (iii) commercial linear PVP K30. Differential scanning calorimetry, X-ray diffraction, and broad-band dielectric spectroscopy were employed to get a comprehensive insight into the thermal and structural properties, as well as global and local molecular dynamics of ITZ-PVP systems. The primary objective was to assess the influence of PVPs' topology and the composition of ASD on the LC ordering, changes in the temperature of transitions between mesophases, the rate of their restoration, and finally the solubility of ITZ in the prepared ASDs. Our research clearly showed that regardless of the PVP type, both LC transitions, from smectic (Sm) to nematic (N) and from N to isotropic (I) phases, are effectively suppressed. Moreover, a significant difference in the miscibility of different PVPs with the investigated API was found. This phenomenon also affected the solubility of API, which was the greatest, up to 100 µg/mL in the case of starPVP 85:15 w/w mixture in comparison to neat crystalline API (5 µg/mL). Obtained data emphasize the crucial role of the polymer's topology in designing new pharmaceutical formulations.

In vitro evaluation of the percutaneous absorption of progesterone in anhydrous permeation-enhancing base using the Franz skin finite dose model and mass spectrometry.

Progesterone is used for hormone replacement therapy through various routes of administration. This study was conducted to (a) evaluate the stability of progesterone in a proprietary anhydrous permeation-enhancing base (APEB) and the efficiency of its skin permeation, and (b) determine the appropriateness of mass spectrometry as a method of analysis for permeated progesterone. Using a proven stability-indicating ultra-performance liquid chromatographic method, the compounded hormone (100 mg progesterone/g APEB gel) was determined to be physically and chemically stable at room temperature for six months. Skin permeation analysis using the Franz skin finite dose model and mass spectrometry imaging showed an optical density of 1699 for the permeated progesterone compounded in APEB and 550 for the permeated progesterone in a water containing VBC, which is a statistically significant different (P = 0.029). The study suggests that APEB can be used as a compounding base for effective skin permeation of progesterone, and mass spectrometry is a reliable method for visualization and quantitative analysis of permeated progesterone.

Lyophilised protein formulations as a patient-centric dosage form: A contribution toward sustainability paradigm.

At present, society has embraced the fact apropos population aging and climate changes, that demand, amongst others, innovative pharmaceutical technologies, emphasising the development of patient-specific delivery systems and thus the provision of efficient and sustainable drugs. Protein drugs for subcutaneous administration, by allowing less frequent application, represent one of the most important parts of the pharmaceutical field, but their development is inevitably faced with obstacles in providing protein stability and suitable formulation viscosity. To gain further knowledge and fill the gaps in the already constructed data platform for the development of monoclonal antibody formulations, we designed a study that examines small model proteins, i.e., bovine serum albumin. The main aim of the presented work is to evaluate the effect of protein concentrations on critical quality attributes of both, pre-lyophilised liquid formulations, and lyophilised products. Through the study, the hypothesis that increasing protein concentration leads to higher viscosity and higher reconstitution time without affecting the stability of the protein was confirmed. The most important finding is that sucrose plays a key role in the lyophilisation of investigated protein, nevertheless, it can be predicted that, to ensure the beneficial effect of mannitol, its amount has to prevail over the amount of sucrose.

The potential of three-dimensional printing for pediatric oral solid dosage forms.

Pediatric patients often require individualized dosing of medicine due to their unique pharmacokinetic and developmental characteristics. Current methods for tailoring the dose of pediatric medications, such as tablet splitting or compounding liquid formulations, have limitations in terms of dosing accuracy and palatability. This paper explores the potential of 3D printing as a solution to address the challenges and provide tailored doses of medication for each pediatric patient. The technological overview of 3D printing is discussed, highlighting various 3D printing technologies and their suitability for pharmaceutical applications. Several individualization options with the potential to improve adherence are discussed, such as individualized dosage, custom release kinetics, tablet shape, and palatability. To integrate the preparation of 3D printed medication at the point of care, a decentralized manufacturing model is proposed. In this setup, pharmaceutical companies would routinely provide materials and instructions for 3D printing, while specialized compounding centers or hospital pharmacies perform the printing of medication. In addition, clinical opportunities of 3D printing for dose-finding trials are emphasized. On the other hand, current challenges in adequate dosing, regulatory compliance, adherence to quality standards, and maintenance of intellectual property need to be addressed for 3D printing to close the gap in personalized oral medication.

Taste-masking methods in multiparticulate dosage forms with a focus on poorly soluble drugs.

In the past, the administration of medicines for children mainly involved changes to adult dosage forms, such as crushing tablets or opening capsules. However, these methods often led to inconsistent dosing, resulting in under- or overdosing. To address this problem and promote adherence, numerous initiatives, and regulatory frameworks have been developed to develop more child-friendly dosage forms. In recent years, multiparticulate dosage forms such as mini-tablets, pellets, and granules have gained popularity. However, a major challenge that persists is effectively masking the bitter taste of drugs in such formulations. This review therefore provides a brief overview of the current state of the art in taste masking techniques, with a particular focus on taste masking by film coating. Methods for evaluating the effectiveness of taste masking are also discussed and commented on. Another important issue that arises frequently in this area is achieving sufficient dissolution of poorly water-soluble drugs. Since the simultaneous combination of sufficient dissolution and taste masking is particularly challenging, the second objective of this review is to provide a critical summary of studies dealing with multiparticulate formulations that are tackling both of these issues.

Lipid-based systems with precipitation inhibitors as formulation approach to improve the drug bioavailability and/or lower its dose: a review.

Lipid-based systems, such as self-microemulsifying systems (SMEDDS) are attracting strong attention as a formulation approach to improve the bioavailability of poorly water-soluble drugs. By applying the "spring and parachute" strategy in designing supersaturable SMEDDS, it is possible to maintain the drug in the supersaturated state long enough to allow absorption of the complete dose, thus improving the drug's bio-availability. As such an approach allows the incorporation of larger amounts of the drug in equal or even lower volumes of SMEDDS, it also enables the production of smaller final dosage forms as well as decreased gastrointestinal irritation, being of particular importance when formulating dosage forms for children or the elderly. In this review, the technological approaches used to prolong the drug supersaturation are discussed regarding the type and concentration of polymers used in liquid and solid SMEDDS formulation. The addition of hypromellose derivatives, vinyl polymers, polyethylene glycol, polyoxyethylene, or polymetacrylate copolymers proved to be effective in inhibiting drug precipitation. Regarding the available literature, hypromellose has been the most commonly used polymeric precipitation inhibitor, added in a concentration of 5 % (m/m). However, the inhibiting ability is mainly governed not only by the physicochemical properties of the polymer but also by the API, therefore the choice of optimal precipitation inhibitor is recommended to be evaluated on an individual basis.

Influence of design parameters on sustained drug release properties of 3D-printed theophylline tablets.

The application of three-dimensional printing (3DP) in the pharmaceutical industry brings a broad spectrum of benefits to patients by addressing individual needs and improve treatment success. This study investigates the sustained release properties of 3DP tablets containing Theophylline (TPH), which is commonly used to treat respiratory diseases and recently having a comeback due to its potential in the treatment of conditions like Covid-19. Since TPH is a narrow therapeutic window (NTW) drug with serious side effects in the event of overdose, the release properties must be observed particularly closely. We employed a state-of-the-art single screw extrusion 3D printer, which is fed with granules containing the drug. By employing a Taguchi orthogonal array design of experiments (DOE), tablet design parameters and factor related process stability were sought to be evaluated fundamentally. Following this, examinations regarding tailored TPH dosages were undertaken and a relationship between the real printed dose of selected tablet designs and their sustained drug release was established. The release profiles were analyzed using different mathematical model fits and compared in terms of mean dissolution times (MDT). Finally, in-vivo/in-vitro correlation (IVIVC) and physiologically based pharmacokinetic (PBPK) modeling showed that a paradigm patient group could be covered with the dosage forms produced.

Effect of basket mesh size on the hydrodynamics of a partially filled (500 mL) USP rotating basket dissolution testing Apparatus 1.

The USP Rotating Basket Dissolution Testing Apparatus 1 is listed in the USP as one of the tools to assess dissolution of oral solid dosage forms. Baskets of different mesh sizes can be used to differentiate between dissolution profiles of different formulations. Here, we used Particle Image Velocimetry (PIV) to study the hydrodynamics of the USP Apparatus 1 using baskets with different mesh openings (10-, 20- and 40-mesh) revolving at 100 rpm, when the vessel was filled with 500 mL. The velocity profiles throughout the liquid were found to vary significantly using baskets of different mesh sizes, typically increasing with increased size of the opening of the basket mesh, especially for axial and radial velocities. This, in turn, resulted in a significantly different flow rate through the basket, which can be expected to significantly impact the dissolution rate of the drug product. A comparison between the results of this work with those of a previous study with a 900-mL fill volume (Sirasitthichoke et al., Intern. J. Pharmaceutics, 2021, 607: 120976), shows that although the hydrodynamics in the USP Apparatus 1 changed with fill level in the vessel, the flow rate through the basket was not significantly affected. This implies that tablets dissolving in the two systems would experience similar tablet-liquid medium mass transfer coefficients, and therefore similar initial dissolution rates, but different dissolution profiles because of the difference in volume.

Advancements in liposomal formulations: A comprehensive exploration of industrial production techniques.

Liposomes are nanosized, spherical vesicles consisting of an aqueous core encircled by one or more phospholipid bilayer shells. Liposomes have found extensive use in numerous biomedicine and nanomedicine applications due to their excellent biocompatibility, adaptable chemical composition, ease of preparation, and diverse structural characteristics. These applications include nanocarriers for drug delivery, immunoassays, nutraceuticals, tissue engineering, clinical diagnostics, and theranostics formulations. These applications stimulated significant efforts toward scaling up formation processes in anticipation of appropriate industrial advancement. Despite the advancements in conventional methods and the emergence of new approaches for liposome production, their inherent susceptibility to chemical and mechanical influences contributes to critical challenges, including limited colloidal stability and decreased efficiency in encapsulating cargo molecules. With this context, the current review provides brief insights into liposomes conventional and novel industrial production techniques. With a special focus on the structural parameters, and pivotal elements influencing the synthesis of an appropriate and stable formulation, followed by the various regulatory aspects of industrial production.

Fabrication and evaluation of stable amorphous polymer-drug composite particles via a nozzle-free ultrasonic nebulizer.

We present a promising method for producing amorphous drug particles using a nozzle-free ultrasonic nebulizer with polymers, specifically polyvinylpyrrolidone (PVP), poly(acrylic acid) (PAA), and Eudragit® S 100 (EUD). Model crystalline phase drugs-Empagliflozin, Furosemide, and Ilaprazole-are selected. This technique efficiently produces spherical polymer-drug composite particles and demonstrates enhanced stability against humidity and thermal conditions, compared to the drug-only amorphous particles. The composite particles exhibit improved water dissolution compared to the original crystalline drugs, indicating potential bioavailability enhancements. While there are challenges, including the need for continuous water supply for ultrasonic component cooling, dependency on the solubility of polymers and drugs in volatile organic solvents, and mildly elevated temperatures for solvent evaporation, our method offers significant advantages over traditional approaches. It provides a straightforward, flexible process adaptable to various drug-polymer combinations and consistently yields spherical amorphous solid dispersion (ASD) particles with a narrow size distribution. These attributes make our method a valuable advancement in pharmaceutical drug formulation and delivery.