Feature Papers in Physical Pharmacy and Formulation

The mathematical models available in DDSolver were applied to experimental dissolution data obtained by analysing carvedilol release from hypromellose (HPMC)-based matrix tablets. Different carvedilol release profiles were generated by varying a comprehensive selection of fillers and carvedilol release modifiers in the formulation. Model fitting was conducted for the entire relevant dissolution data, as determined by using a paired t-test, and independently for dissolution data up to approximately 60% of carvedilol released. The best models were selected based on the residual sum of squares (RSS) results used as a general measure of goodness of fit, along with the utilization of various criteria for visual assessment of model fit and determination of the acceptability of estimated model parameters indicating burst release or lag time concerning experimental dissolution results and previous research. In addition, a model-dependent analysis of carvedilol release mechanisms was carried out. Full article

The efficacy of topical antifungal therapy in onychomycosis has been hindered by the failure of the antimycotic to permeate the nail plate. This research aims to design and develop a transungual system for the effective delivery of efinaconazole utilizing constant voltage iontophoresis. Seven prototype drug-loaded hydrogel formulations (E1–E7) were prepared to assess the influence of solvent (ethanol) and cosolvent (Labrasol^®) on transungual delivery. Optimization was performed to evaluate the effect of three independent variables; voltage, solvent-to-cosolvent ratio, and penetration enhancer (PEG 400) concentration on critical quality attributes (CQAs), such as drug permeation and loading into the nail. The selected hydrogel product was characterized for pharmaceutical properties, efinaconazole release from the nail, and antifungal activity. Preliminary data indicates ethanol, Labrasol^®, and voltage influence the transungual delivery of efinaconazole. Optimization design indicates a significant impact by applied voltage (p-0.0001) and enhancer concentration (p-0.0004) on the CQAs. Excellent correlation between selected independent variables and CQAs was confirmed by the high desirability value (0.9427). A significant (p < 0.0001) enhancement in the permeation (~78.59 µg/cm²) and drug loading (3.24 µg/mg) was noticed in the optimized transungual delivery with 10.5 V. FTIR spectral data indicates no interaction between the drug and excipients, while the DSC thermograms confirmed the amorphous state of the drug in the formulation. Iontophoresis produces a drug depot in the nail that releases above the minimum inhibitory concentration level for an extended period, potentially reducing the need for frequent topical treatment. Antifungal studies further substantiate the release data and have shown remarkable inhibition of Trichophyton mentagrophyte. Overall, the promising results obtained here demonstrate the prospective of this non-invasive method for the effective transungual delivery of efinaconazole, which could improve the treatment of onychomycosis. Full article

In vitro non-cellular permeability models such as the parallel artificial membrane permeability assay (PAMPA) are widely applied tools for early-phase drug candidate screening. In addition to the commonly used porcine brain polar lipid extract for modeling the blood–brain barrier’s permeability, the total and polar fractions of bovine heart and liver lipid extracts were investigated in the PAMPA model by measuring the permeability of 32 diverse drugs. The zeta potential of the lipid extracts and the net charge of their glycerophospholipid components were also determined. Physicochemical parameters of the 32 compounds were calculated using three independent forms of software (Marvin Sketch, RDKit, and ACD/Percepta). The relationship between the lipid-specific permeabilities and the physicochemical descriptors of the compounds was investigated using linear correlation, Spearman correlation, and PCA analysis. While the results showed only subtle differences between total and polar lipids, permeability through liver lipids highly differed from that of the heart or brain lipid-based models. Correlations between the in silico descriptors (e.g., number of amide bonds, heteroatoms, and aromatic heterocycles, accessible surface area, and H-bond acceptor–donor balance) of drug molecules and permeability values were also found, which provides support for understanding tissue-specific permeability. Full article

Amorphization is widely used as an effective method of increasing the solubility of insoluble drugs. However, some amorphous drugs exhibit a much lower dissolution rate than their corresponding crystalline form due to their gelation. In this study, we reported the gels formed from amorphous acemetacin (ACM) for the first time. Gelation was promoted at conditions of lower pH, higher temperature and lower ionic strength. Solid-state characterizations suggested that ACM gels may be formed by recrystallization. This mechanism provides a new direction in facilitating the elimination of gelation for amorphous drugs. Moreover, it also provides the basis for the development of sustained-release formulations using the gelation properties. Full article

Numerous obstacles challenge the treatment of fungal infections, including the uprising resistance and the low penetration of available drugs. One of the main active agents against fungal infections is itraconazole (ITZ), with activity against a broad spectrum of fungi while having few side effects. The aim of this study was to design ufasomes, oleic acid-based colloidal carriers, that could encapsulate ITZ to improve its penetration power. Employing a 2²3¹ factorial design, the effect of three independent factors (oleic acid amount, cholesterol concentration, and ITZ amount) was investigated and evaluated for the percentage encapsulation efficiency (%EE), particle size (PS), and zeta potential (ZP). Optimization was performed using Design^® expert software and the optimized ITZ-loaded ufasomes obtained had %EE of 99.4 ± 0.7%, PS of 190 ± 1 nm, and ZP of −81.6 ± 0.4 mV, with spherical unilamellar morphology and no aggregation. An in vitro microbiological study was conducted to identify the minimum inhibitory concentration of the selected formula against Candida albicans, which was found to be 0.0625 μg/mL. Moreover, the optimized formula reduced the expression of toll-like receptors-4 and pro-inflammatory cytokine IL-1β secretion in the C. albicans-infected fibroblasts, indicating that the proposed ITZ-loaded ufasomes are a promising drug delivery system for ITZ. Full article

Oily excipients are vital components of dermatological products. In this study, the in vitro and in vivo characteristics of Wild Olive Oil (WOO) were compared with two other types of olive oils: Extra Virgin Olive Oil (EVOO) and Virgin Olive Oil (VOO). This work has also included Liquid Paraffin (LP) and Rosehip Oil (RO) as reference oils. Melatonin was used in the study as a model drug to demonstrate the antioxidant capacity of the oils. The melatonin carrier capacity and antioxidant performance was related to the degree of unsaturation of the oils and was highest for RO and WOO and lowest for LP. However, the most stable oil to oxidation was LP. The in vivo performance of the oils in the skin of eight healthy volunteers was investigated with a dermoanalyser. The highest increment of oil and hydration in the skin was obtained with RO. The lowest perception of oiliness was described for WOO, which produced the highest increase in elasticity of the skin area where it was applied. An in vitro-in vivo correlation was therefore performed through multivariable analysis (MVA). Full article

Surfactants and cosolvents are often combined to solubilize insoluble drugs in commercially available intravenous formulations to achieve better solubilization. In this study, six marketed parenteral formulations with surfactants and cosolvents were investigated on the aggregation processes of micelles, the structural characterization of micelles, and the properties of solvent using molecular dynamics simulations. The addition of cosolvents resulted in better hydration of the core and palisade regions of micelles and an increase in both radius of gyration (R_g) and the solvent accessible surface area (SASA), causing a rise in critical micelle concentration (CMC), which hindered the phase separation of micelles. At the same time, the presence of cosolvents disrupted the hydrogen bonding structure of water in solution, increasing the solubility of insoluble medicines. Therefore, the solubilization mechanism of the cosolvent and surfactant mixtures was successfully analyzed by molecular dynamics simulation, which will benefit future formulation development for drug delivery. Full article

Enterococcus faecalis is an opportunistic microbial pathogen frequently associated with diverse infections, including those of the skin and teeth, as well as those from surgical wounds. It forms robust biofilms that are highly tolerant to most antimicrobials and first-line antibiotics. Therefore, investigating alternative strategies to eradicate its biofilms is a critical need. We recently demonstrated that trans-cinnamaldehyde (TC) potently kills E. faecalis biofilm cells and prevents biofilm recovery, and yet, the extreme hydrophobicity of TC hampers clinical translation. Here, we report that a complex of TC with an FDA-approved biosurfactant (acidic sophorolipid/ASL) significantly reduces the bacterial viability and biomass of E. faecalis biofilms, compared to TC alone. A confocal laser-scanning microscopic analysis demonstrated that the TC–ASL treatment significantly decreased the biofilm thickness and volume. In conclusion, our study highlights the anti-biofilm potential of the newly developed TC–ASL. Full article

Phytantriol-based lyotropic liquid crystals (LLCs) have emerged as a new nanodrug delivery system. However, the understanding of phytantriol-based LLCs is lacking. In this study, we use NMR technology to characterize LLC formation over two months. Three samples in different phases were prepared with different hydration states. NMR data, including 1D-¹H, ¹³C-{¹H}, 2D-HSQC, HMBC, COSY, NOESY, etc., were collected. A comprehensive analysis of these NMR data was performed on the three phases of phytantriol-based LLCs. The following results were achieved from the study. First, the ¹H and ¹³C-{¹H} spectra of phytantriol were assigned. Second, the change of NMR spectra during the formation of the phases was observed, and the change of hydration was calculated for the time-dependent phase formation. Third, the correlation peaks of 2D-NOESY were used to describe the spatial relationship of lipids–water interaction and lipid–lipid interaction. Full article

Colonic drug delivery of drugs is an area of great interest due to the need to treat high prevalence colonic local diseases as well as systemic conditions that may benefit from the advantages associated to this route of drug administration. In the last decade, the use of 3D printing technologies has expanded, offering the possibility of preparing personalized medicines in small batches directly at the point of care. The aim of this work is to design a high drug loaded 3D printed system prepared by a combination of Fused Deposition Modelling (FDM) and Injection Volume Filling (IVF) techniques intended for zero-order colonic drug release. For this purpose, different batches of binary and ternary filaments based on the thermoplastic polyurethane Tecoflex EG-72D (TPU), theophylline anhydrous (AT) as model drug, and magnesium stearate as lubricant have been developed and characterized. Filaments with the highest drug load and the best rheological properties were selected for the manufacture of a printed fractal-like structure based on multiple toroids. This design was proposed to provide high surface area, leading to increased drug release and water uptake in the colonic region. This structure was 3D printed by FDM and then coated in a unique step by IVF technology using the enteric polymer DrugCoat S 12.5. This way, an additional coating process is avoided, reducing costs and production time. Studies of drug release confirmed the ability of the structures to provide a five-hour period of constant drug delivery in the colonic region. Full article

Wound control in patients on anticoagulants is challenging and often leads to poor hemostasis. They have a higher tendency to develop alveolar osteitis after tooth extraction. The application of a hemostatic dressing that has a high absorbing capacity and is loaded with an antifibrinolytic drug could help in controlling the bleeding. Alginate/nano-hydroxyapatite (SA/Nano-HA) composite aerogels loaded with tranexamic acid (TXA) were prepared. Nano-HA served as a reinforcing material for the alginate matrix and a source of calcium ions that helps in blood clotting. It influenced the porosity and the water uptake capacity. TXA release from SA/Nano-HA aerogels showed a biphasic profile for up to 4 h. Blood coagulation studies were performed on human whole blood. The TXA-loaded aerogel significantly reduced the clotting time by 69% compared to the control (p < 0.0001). Recalcification time was significantly reduced by 80% (p < 0.0001). Scanning electron microscopy analysis revealed the porous nature of the aerogels and the ability of the optimum aerogel to activate and adhere platelets to its porous surface. The cell migration assay showed that there was a delay in wound healing caused by the TXA aerogel compared to the control sample after treating human fibroblasts. Results suggest that the developed aerogel is a promising dressing that will help in hemostasis after tooth extraction. Full article

Docetaxel (DTX)-based formulation development is still confronted with significant challenges, due to its refractory solubility and side effects on normal tissues. Inspired by the application of the transdermal drug delivery model to topical treatment, we developed a biocompatible and slow-release DTX-containing emulsion via self-assembly prepared by a high-speed electric stirring method and optimized the formulation. The results of accelerated the emulsion stability experiment showed that the emulsion prepared at 10,000 rpm/min had a stability of 89.15 ± 2.05%. The ADME, skin irritation, skin toxicity and molecular interaction between DTX and excipients were predicted via Discovery Studio 2016 software. In addition, DTX addition in oil or water phases of the emulsion showed different release rates in vitro and ex vivo. The DTX release ex vivo of the DTX/O-containing emulsion and the DTX/W-containing emulsion were 45.07 ± 5.41% and 96.48 ± 4.54%, respectively. In vitro antioxidant assays and anti-lipid peroxidation models revealed the antioxidant potential of DTX. However, DTX-containing emulsions could maintain and even enhance the antioxidant effect, both scavenging free radicals in vitro and inhibiting the process of lipid peroxidation. Full article

Curcuma longa L. is a traditional medicinal and spice plant containing a variety of lipophilic active substances with promising therapeutic properties. In this work, the solvent properties of supercritical carbon dioxide in a pressure and temperature range of 75–425 bar and 35–75 °C were investigated when Curcuma longa rhizomes were extracted. The three main curcuminoids, namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin, together with the three main constituents of the essential oil, i.e., ar-turmerone, α-turmerone, and β-turmerone, were analyzed in the resulting extracts. For statistical evaluation, experiments were performed employing a full factorial design, in which flow rate, extraction time, and drug load were kept constant. Within the given conditions, the experimental design revealed an optimum yield of all aforementioned substances, when supercritical carbon dioxide extraction was performed at 425 bar and 75 °C. For comparison, solvent extracts using methanol and n-hexane were prepared and their main components were characterized using LC-MS. The stability of the extracts was monitored upon storage for 6 months at 22 and 40 °C under protection from light. The decomposition of individual compounds was mainly observed in the presence of residual water in the extracts. Full article

As regulatory and technical landscapes for pharmaceutical formulation development are rapidly evolving, a risk-management approach using multivariate analysis is highly essential for designing a product with requisite critical quality attributes (CQA). Efinaconazole, a newly approved poorly water-soluble antifungal triazole drug has poor permeability. Spanlastics, new-generation surfactant nanovesicles, being fluidic, help improve the permeability of drugs. Therefore, we optimized efinaconazole spanlastics using the concepts of Formulation-by-Design (FbD) and explored the feasibility of transungual delivery for the management of onychomycosis. Using the Ishikawa fishbone diagram, the risk factors that may have an impact on the CQA of efinaconazole spanlastic vesicles were identified. Application of the Plackett–Burman experimental design facilitated the screening of eight different formulation and process parameters influencing particle size, transmittance, relative deformability, zeta potential, entrapment efficiency, and dissolution efficiency. With the help of Pareto charts, the three most significant factors were identified, viz., vesicle builder (Span), edge activator (Tween), and mixing time. The levels of these three critical variables were optimized by FbD to reduce the particle size and maximize the transparency, relative deformability, encapsulation efficiency, and dissolution efficiency of efinaconazole spanlastic nanovesicles. Bayesian and Lenth’s analysis and mathematical modeling of the experimental data helped to quantify the critical formulation attributes required for getting the formulation with optimum quality features. The optimized efinaconazole-loaded spanlastic vesicles had a particle size of 197 nm, transparency of 91%, relative deformability of 12.5 min, and dissolution efficiency of 81.23%. The spanlastic formulation was incorporated into a gel and explored ex vivo for transungual delivery. This explorative study provides an example of the application of principles of risk management, statistical multivariate analysis, and the FbD approach in developing efinaconazole spanlastic nanovesicles. Full article

This research aimed to boost granisetron (GS) delivery to the brain via the intranasal route to better manage chemotherapy-induced emesis. Glycerol monooleate (GMO), Poloxamer 407 (P 407) and Tween 80 (T 80) were used to formulate GS-loaded cubosomes (GS-CBS) utilizing a melt dispersion-emulsification technique. GS-CBS were characterized by testing particle diameter, surface charge and entrapment efficiency. The formulations were optimized using a Box–Behnken statistical design, and the optimum formula (including GMO with a concentration of 4.9%, P 407 with a concentration of 10%, and T 80 with a concentration of 1%) was investigated for morphology, release behavior, ex vivo permeation through the nasal mucosa, and physical stability. Moreover, the optimal formula was incorporated into a thermosensitive gel and subjected to histopathological and in vivo biodistribution experiments. It demonstrated sustained release characteristics, increased ex vivo permeability and improved physical stability. Moreover, the cubosomal in situ gel was safe and biocompatible when applied to the nasal mucosa. Furthermore, compared to a drug solution, the nose-to-brain pathway enhanced bioavailability and brain distribution. Finally, the cubosomal in situ gel may be a potential nanocarrier for GS delivery to the brain through nose-to-brain pathway. Full article

Hydrogel patches are some of the most effective dressings for wound healing. In this study, the Gantrez^® S-97 (Gan)/xyloglucan (XG) hydrogel patches were formulated by using a full central composite design (CCD). The optimized hydrogel patches consisted of 17.78% w/w of Gan and 0.1% w/w of XG. Honey and D. bulbifera extract were loaded in the Gan/XG hydrogel patches. The physical properties of the hydrogel patches, including water content, water absorption, rate of water vapor transmission, and mechanical properties, were examined. The D. bulbifera extract/honey-loaded patch exhibited a higher value of water absorption, tensile strength, and elongation than the honey-loaded patch and the unloaded patch, respectively. The biological activities of the patches were also investigated. All hydrogel patches protected wounds from external bacterial infection. The D. bulbifera extract/honey-loaded patch exhibited stronger antioxidant activity than the honey-loaded patch and the unloaded patch. Besides, all the hydrogel patches with concentrations of 0.5–2.5 mg/mL showed that they were nontoxic to fibroblast cells. The combination of D. bulbifera extract and honey in the patch affected fibroblast proliferation. In addition, all Gan/XG hydrogel patches significantly induced recovery of the scratch area. Therefore, the Gan/XG hydrogel patches could be candidates as wound dressings. Full article

The aim of this study was to improve the saturation solubility, dissolution profile and oral bioavailability of amiodarone hydrochloride (AMH), a highly lipophilic drug. Stabilizer (Pluronic F-127)-coated AMH nanocrystals (AMH-NCs) were developed by a combination of antisolvent precipitation and homogenization techniques. The optimized formulation comprised pluronic F-127 and AMH at the concentration of 4% and 2% w/v, respectively. The particle size (PS), zeta potential (ZP) and polydispersity index (PDI) of the optimized formulation was found to be 221 ± 1.2 nm, 35.3 mV and 0.333, respectively. The optimized formulation exhibited a rough surface morphology with particles in colloidal dimensions and a significant reduction in crystallinity of the drug. AMH-NCs showed a marked increase in the saturation solubility as well as rapid dissolution rate when compared with the AMH and marketed product. The stability study displayed that the formulation was stable for 3 months, with no significant change in the PS, ZP and PDI. The in vivo pharmacokinetic study demonstrated the ability of AMH-NCs to significantly (p < 0.05) improve the oral bioavailability (2.1-fold) of AMH in comparison with AMH solution, indicating that the production of AMH-NCs using a combination of antisolvent precipitation and homogenization techniques could enhance the bioavailability of the drug. Full article

Pharmaceutical and medicinal printing technologies allow personalization and on-demand manufacturing of drug and medicinal products. Being able to manufacture patient tailored dosage forms or medical devices in a pharmacy, medical office, dental laboratory, or hospital at the point of care raises new demands on quality control procedures. For Fused Deposition Modeling, for example, it must be ensured that the starting materials, the (drug-loaded) filaments, are not accidentally exchanged by the operator. This study investigated the potential of colorimetric measurements for direct and indirect determination of the identity of extruded filaments consisting of polymer matrix, different API and/or coloring agents. Since reflection measurements were affected by surface properties of the filaments, a self-constructed filament holder was utilized with an optical fiber positioned in a 180° angle to a white light LED to perform transmission measurements. It was possible to distinguish filaments with different API concentrations by their color values, taking into account that transmission partially decreased by increased API concentration. Therefore, the intensity of the light source had to be adjusted depending on the transparency of the filament. It was shown that colorimetry can be used as a quality control tool to detect differences in drug-loading and is able to distinguish various extruded batches. Additionally, if differences in API/polymer concentrations do not lead to significant changes in L*a*b values, coloring agents were used as additives in low concentrations to color code filaments. In future studies, the setup must be supplemented with a standardized light source and obscuring filters for light intensity adjustments. Full article

Ursodeoxycholate (UDCA) has low oral bioavailability and pH-dependent solubility and permeability. Thus, we developed a pH-modified extended-release formulation of UDCA using Na₂CO₃ as the alkalizing agent and hydroxypropyl methylcellulose (HPMC) as the release-modifying agent. The optimized pH-modified controlled-release UDCA formulation, with the UDCA:HPMC:Na₂CO₃ ratio of 200:600:150 (w/w/w), was prepared using a spray-drying method. Then, the formulation’s solubility, dissolution, and pharmacokinetic properties were characterized. In a pH-modified extended-release formulation of UDCA, the solubility of UDCA was increased to 8 mg/mL with a sustained dissolution for 12 h. Additionally, the spray-dried formulation exhibited amorphous states without molecular interaction among UDCA, Na₂CO₃, and HPMC. Moreover, the plasma UDCA concentration of the formulation maintained a higher UDCA concentration for up to 48 h than that of UDCA itself or the non-extended-release UDCA formulation. Consequently, the formulation significantly increased the AUC compared to UDCA or the non-extended-release UDCA formulation in rats. In conclusion, we have improved UDCA’s solubility and dissolution profile by preparing a pH-modified extended-release formulation with the UDCA:HPMC:Na₂CO₃ ratio of 200:600:150 (w/w/w), which effectively increased the oral bioavailability of UDCA by 251% in rats. Full article

The purpose of this work was to evaluate the suitability of recent US Food and Drug Administration (US-FDA)-approved and marketed oral liquid, powder, or granule products for children in North America, to identify the next group of Active Pharmaceutical Ingredients (APIs) that have high potential for development as commercially available FDA-approved finished liquid dosage forms, and to propose lists of compounded nonsterile preparations (CNSPs) that should be developed as commercially available FDA-approved finished liquid dosage forms, as well as those that pharmacists should continue to compound extemporaneously. Through this identification and categorization process, the pharmaceutical industry, government, and professionals are encouraged to continue to work together to improve the likelihood that patients will receive high-quality standardized extemporaneously compounded CNSPs and US-FDA-approved products. Full article

Amorphization, typically in the form of amorphous solid dispersion (ASD), represents a well-established solubility enhancement strategy for poorly soluble drugs. Recently, two amorphous drug formulations, i.e., the amorphous drug–polyelectrolyte nanoparticle complex (nanoplex) and co-amorphous system, have emerged as promising alternatives to circumvent the issues faced by ASD (i.e., large dosage requirement, high hygroscopicity). In the present work, the nanoplex was benchmarked against the co-amorphous system in terms of the preparation efficiency, drug payload, thermal stability, dissolution rate, supersaturation generation, and accelerated storage stability. Weakly acidic curcumin (CUR) and weakly basic ciprofloxacin (CIP) were used as the model poorly soluble drugs. The CUR and CIP nanoplexes were prepared using chitosan and sodium dextran sulfate as the polyelectrolytes, respectively. The co-amorphous CUR and CIP were prepared using tannic acid and tryptophan as the co-formers, respectively. The benchmarking results showed that the amorphous drug nanoplex performed as well as, if not better than, the co-amorphous system depending on the drug in question and the aspects being compared. The present work successfully established the nanoplex as an equally viable amorphous drug formulation as the more widely studied co-amorphous system to potentially serve as an alternative to ASD. Full article

The importance of roller compaction is recently increasing. This study evaluates the combined effects of formulation factors, process parameters, and selected quality attributes on drug release from roller-compacted hypromellose-based matrix tablets containing carvedilol as a model drug. The influence of selected factors was statistically assessed and good predictive models were developed for various time points of the release profile. The results show that the release profile is mostly affected by the particle size distribution of granules and roll speed. This indicates that the roller compaction process has a major impact on drug release, which is also formulation dependent. A higher d50 and lower d90 value of spatial filtering technique-based particle size distribution results, a lower roll speed, increased hypromellose content, using microcrystalline cellulose as a filler, and higher tablet hardness, resulted in a decrease in the drug release rate. On the other hand, the effect of the roll pressure, size of screen apertures, and d10 values on drug release was insignificant. The significance of the factors was further explained by granule shape, their porosity, and friability evaluation, and by compressibility and compactibility studies of compression mixtures. Additionally, the spatial filtering technique demonstrated to be a promising tool in controlling the roller compaction process. Full article

The aim of the present study was to systematically examine the effects of variations in the process parameters of the antisolvent precipitation method employed in the preparation of excipient-free pure nanoparticles of five existing/potential psychotropic drugs, namely amitriptyline hydrochloride (AMI), coumarin 6 (COU), curcumin (CUR), nortriptyline hydrochloride (NOR), and prochlorperazine dimaleate (PRO). In the preparation protocols employed, AMI and NOR were expected to be charged enough to be identified as surface-active molecules. Through the employment of five different preparation protocols, the effects of varying the flow rate, the compound concentration in the solvent solution $C_0^{solvent}$, the solvent:antisolvent ratio (SAS-ratio), and pH of the antisolvent on the final size of the particles $D_H^f$ were investigated in detail and the results were explained using available theories for the antisolvent precipitation method. We found that $D_H^f$ increased with the average of the octanol-water partition coefficients (logP)_av of the compound. Moreover, the average of the final particle sizes ${\left(D_H^f\right)}_{av}$ increased linearly with (logP)_av. These findings are useful for predicting the size of nanodrugs prepared through the antisolvent precipitation method. Full article

(1) Background: The ex vivo porcine ear model is often used for the determination of the dermal penetration efficacy of chemical compounds. This study investigated the influence of the post-slaughter storage time of porcine ears on the dermal penetration efficacy of chemical compounds. (2) Methods: Six different formulations (curcumin and different fluorescent dyes in different vehicles and/or nanocarriers) were tested on ears that were (i) freshly obtained, (ii) stored for 24 or 48 h at 4 °C after slaughter before use and (iii) freshly frozen and defrosted 12 h before use. (3) Results: Results showed that porcine ears undergo post-mortem changes. The changes can be linked to rigor mortis and all other well-described phenomena that occur with carcasses after slaughter. The post-mortem changes modify the skin properties of the ears and affect the penetration efficacy. The onset of rigor mortis causes a decrease in the water-holding capacity of the ears, which leads to reduced penetration of chemical compounds. The water-holding capacity increases once the rigor is released and results in an increased penetration efficacy for chemical compounds. Despite different absolute penetration values, no differences in the ranking of penetration efficacies between the different formulations were observed between the differently aged ears. (4) Conclusions: All different types of ears can be regarded to be suitable for dermal penetration testing of chemical compounds. The transepidermal water loss (TEWL) and/or skin hydration of the ears were not correlated with the ex vivo penetration efficacy because both an impaired skin barrier and rigor mortis cause elevated skin hydration and TEWL values but an opposite penetration efficacy. Other additional values (for example, pH and/or autofluorescence of the skin) should, therefore, be used to select suitable and non-suitable skin areas for ex vivo penetration testing. Finally, data from this study confirmed that smartFilms and nanostructured lipid carriers (NLC) represent superior formulation strategies for efficient dermal and transdermal delivery of curcumin. Full article

Low amounts of minoxidil in oral dosage forms are commonly prescribed as anti-alopecic pharmacological treatments. Side effects are usually related to individual susceptibility. However, poor drug content and mass uniformity can lead to a potential risk of overdosing, and higher chances to experience side effects. The impacts of four formulation variables on drug content and mass pharmaceutical quality attributes were studied with an experimental design at two levels. The first variable (A) was the particle size of the direct compression microcrystalline cellulose (MCC) used as a diluent (Avicel^® PH 101 vs. LP 200). The second variable (B) was the type of production process (direct filling vs. wet granulation). The third variable (C) was the particle size of riboflavin added as a color mixture indicator agent (granular vs. milled). The fourth variable (D) was the type of oral solid dosage form (capsule vs. tablet). In half of the formulations, the mean minoxidil content and minoxidil uniformity were out of the specification limits of the Pharmacopoeia, demonstrating the importance of carefully selecting the excipients as well as the utilized process when manufacturing low oral dosage minoxidil formulations. The best minoxidil content uniformity was achieved when using MCC LP 200, wet granulation, granular riboflavin, and capsules. However, tablets are the recommended dosage form when utilizing Avicel^® PH 101 or direct filling. Meeting these criteria, the content and mass uniformity are more likely to meet the specification limits of the Pharmacopeia. Techniques such as NIR spectroscopy should be implemented to control the quality of extemporaneous compounding formulations with a low dose of active ingredient. Full article

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. Full article

A crucial aspect of pharmaceutical development is the demonstration of long-term stability of the drug product. Biopharmaceuticals, such as proteins or peptides in liquid formulation, are typically administered via parental routes and should be stable over the shelf life, which generally includes a storing period (e.g., two years at 5 °C) and optionally an in-use period (e.g., 28 days at 30 °C). Herein, we present a case study where chemical degradation of SAR441255, a therapeutic peptide, in different formulations in combination with primary packaging materials was analyzed under accelerated conditions to derive long-term stability predictions for the recommended storing conditions (two years at 5 °C plus 28 days at 30 °C) using advanced kinetic modeling. These predictions served as a crucial decision parameter for the entry into clinical development. Comparison with analytical data measured under long-term conditions during the subsequent development phase demonstrated a high prediction accuracy. These predictions provided stability insights within weeks that would otherwise take years using measurements under long-term stability conditions only. To our knowledge, such in silico studies on stability predictions of a therapeutic peptide using accelerated chemical degradation data and advanced kinetic modeling with comparisons to subsequently measured real-life long-term stability data have not been described in literature before. Full article

The surface of Ti₃C₂ MXene nanosheets (TC NSs) was first modified with the antioxidants sodium ascorbate (SA) and dopamine (DA) (DSTC NS) to improve their stability in oxidative and hydration environments and thereby improve their bioapplications. This novel approach not only improved MXene stability by arresting oxidation but also increased the available functional groups for further functionalization with various biomolecules. The DSTC NSs were then sequentially conjugated with enzyme glucose oxidase (GOx) and photosensitizer Ce6 to render the obtained CGDSTC NSs with glucose starvation and photodynamic therapeutic properties and thus attain high efficiency in killing cancer cells through the cooperative effect. The as-synthesized CGDSTC NSs demonstrated tremendous photothermal effect with conversion efficiency of 45.1% and photodynamic (ROS generation) properties upon irradiation with 808 and 671 nm lasers. Furthermore, it was observed that the enzymatic activity of CGDSTC NSs increased upon laser irradiation due to enhanced solution temperature. During in vitro studies, the CGDSTC NSs exhibited cytocompatability to HePG2 and HeLa cells under nonstimulus conditions. However, they elicited more than 90% cell-killing efficiency in the presence of glucose and laser irradiation via the cooperative effect between starvation therapy and phototherapy. These results indicate that CGDSTC NSs could be used as potential therapeutic agents to eradicate cancers with no or few adverse effects. This surface modification approach is also simple and facile to adopt in MXene-based research. Full article

Topical therapy of antifungals is primarily restricted due to the low innate transport of drugs through the thick multi-layered keratinized nail plate. The objective of this investigation was to develop a gel formulation, and to optimize and evaluate the transungual delivery of terbinafine using the constant voltage iontophoresis technique. Statistical analysis was performed using Box–Behnken design to optimize the transungual delivery of terbinafine by examining crucial variables namely concentration of polyethylene glycol, voltage, and duration of application (2–6 h). Optimization data in batches (F1–F17) demonstrated that chemical enhancer, applied voltage, and application time have influenced terbinafine nail delivery. Higher ex vivo permeation and drug accumulation into the nail tissue were noticed in the optimized batch (F8) when compared with other batches (F1–F17). A greater amount of terbinafine was released across the nails when the drug was accumulated by iontophoresis than the passive counterpart. A remarkably higher zone of inhibition was observed in nails with greater drug accumulation due to iontophoresis, as compared to the passive process. The results here demonstrate that the optimized formulation with low voltage iontophoresis could be a viable and alternative tool in the transungual delivery of terbinafine, which in turn could improve the success rate of topical nail therapy in onychomycosis. Full article

Curcumin (CUR) has been used in the treatment of various diseases such as cough, fever, skin disease, and infection because of various biological benefits such as anti-inflammatory, antiviral, antibacterial, and antitumor activity. However, CUR is a BCS class 4 group and has a limitation of low bioavailability due to low solubility and permeability. Therefore, the purpose of this study is to prepare a nanosuspension (NSP) loaded with CUR (CUR-NSP) using a statistical design approach to improve the oral bioavailability of CUR, and then to develop CUR-NSP coated with tannic acid to increase the mucoadhesion in the GI tract. Firstly, the optimized CUR-NSP, composed of sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone/vinyl acetate (PVP/VA), was modified with tannic acid (TA). The particle size and polydispersity index of the formulation measured by laser scattering analyzer were 127.7 ± 1.3 nm and 0.227 ± 0.010, respectively. In addition, the precipitation in distilled water (DW) was 1.52 ± 0.58%. Using a differential scanning calorimeter and X-ray diffraction analysis, the stable amorphous form of CUR was confirmed in the formulation, and it was confirmed that CUR-NSP formulation was coated with TA through a Fourier transform-infrared spectroscopy. In the mucoadhesion assay using the turbidity, it was confirmed that TA-CUR-NSP had higher affinity for mucus than CUR-NSP under all pH conditions. This means that the absorption of CUR can be improved by increasing the retention time in the GI tract of the formulation. In addition, the drug release profile showed more than 80% release, and in the cellular uptake study, the absorption of the formulation (TA-CUR-NSP) containing TA acting as an inhibitor of P-gp was increased by 1.6-fold. In the evaluation of antioxidant activity, the SOD activity of TA-CUR-NSP was remarkably high due to TA, which improves cellular uptake and has antioxidant activity. In the pharmacokinetic evaluation, the maximum drug plasma concentration of the TA-coated NSP formulation was 7.2-fold higher than that of the pure drug. In all experiments, it was confirmed that the TA-CUR-NSP is a promising approach to overcome the low oral bioavailability of CUR. Full article

In response to the increasing application of machine learning (ML) across many facets of pharmaceutical development, this pilot study investigated if ML, using artificial neural networks (ANNs), could predict the apparent degree of supersaturation (aDS) from two supersaturated LBFs (sLBFs). Accuracy was compared to partial least squares (PLS) regression models. Equilibrium solubility in Capmul MCM and Maisine CC was obtained for 21 poorly water-soluble drugs at ambient temperature and 60 °C to calculate the aDS ratio. These aDS ratios and drug descriptors were used to train the ML models. When compared, the ANNs outperformed PLS for both sLBF_Capmul^MC (r² 0.90 vs. 0.56) and sLBF_Maisine^LC (r² 0.83 vs. 0.62), displaying smaller root mean square errors (RMSEs) and residuals upon training and testing. Across all the models, the descriptors involving reactivity and electron density were most important for prediction. This pilot study showed that ML can be employed to predict the propensity for supersaturation in LBFs, but even larger datasets need to be evaluated to draw final conclusions. Full article

We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions by the bead mill method, and we evaluated the bioavailability (BA) in the oral administration of the nanocrystalline drug. The mean particle size of the IRB-NC suspensions was approximately 140 nm, and the crystalline structure of irbesartan in these suspensions was different using the bead mill method. The aggregation and degradation of irbesartan were not observed for one month, and the solubility increased. Moreover, the inclusion complex formation of IRB-NC suspensions with 2-hydroxypropyl-β-cyclodextrin was higher than that in traditional IRB powder (IRB-P). In addition, the intestinal absorption of IRB-NC suspensions was higher than that of IRB-P suspensions, and the reducing effect on blood pressure in spontaneously hypertensive SHR-SP rats orally administered IRB-NC suspensions was significantly higher than in those administered IRB-P suspensions. On the other hand, the intestinal penetration of IRB-NC suspensions was attenuated by the inhibitors of clathrin-dependent endocytosis (CME). In conclusion, we improved the low oral BA of irbesartan by preparing IRB-NC suspensions and showed that both the solubility and CME are related to the enhanced intestinal absorption of IRB-NC suspensions, resulting in an increase in their antihypertensive effect. These findings provide significant information for the development of oral nanomedicines. Full article

Taxifolin, also known as dihydroquercetin, possesses several interesting biological properties. The purpose of the study was to identify polymorphs of taxifolin prepared using crystallization in different solvents. Data from X-ray powder diffraction, differential scanning calorimetry, and thermogravimetry enabled us to detect six different crystalline phases for taxifolin. Besides the already known fully hydrated phase, one partially hydrated phase, one monohydrated phase, two anhydrous polymorphs, and one probably solvated phase were obtained. The unit cell parameters were defined for three of them, while one anhydrous polymorph was fully structurally characterized by X-ray powder diffraction data. Scanning electron microscopy and hot stage microscopy were also employed to characterize the crystallized taxifolin powders. The hydrate and anhydrous forms showed remarkable stability in drastic storage conditions, and their solubility was deeply evaluated. The anhydrous form converted into the hydrate form during the equilibrium solubility study and taxifolin equilibrium solubility was about 1.2 mg/mL. The hydrate taxifolin intrinsic dissolution rate was 56.4 μg cm⁻² min⁻¹. Using Wood’s apparatus, it was not possible to determine the intrinsic dissolution rate of anhydrous taxifolin that is expected to solubilize more rapidly than the hydrate form. In view of its high stability, its use can be hypothesized. Full article

The development of personalised paediatric dosage forms using 3D printing technologies has gained significant interest over the last few years. In the current study extruded filaments of the highly bitter Diphenhydramine Hydrochloride (DPH) were fabricated by using suitable hydrophilic carries such as hydroxypropyl cellulose (Klucel ELF^TM) and a non-ionic surfactant (Gelucire 48/16^TM) combined with sweetener (Sucralose) and strawberry flavour grades. The thermoplastic filaments were used to print 3D fruit-chew designs by Fused Deposition Modelling (FDM) technology. Physicochemical characterisation confirmed the formation of glass solution where DPH was molecularly dispersed within the hydrophilic carriers. DPH was released rapidly from the 3D printed fruit-chew designs with >85% within the first 30 min. Trained panellists performed a full taste and sensory evaluation of the sweetener intensity and the strawberry aroma. The evaluation showed complete taste masking of the bitter DPH and revealed a synergistic effect of the sweetener and the strawberry flavour with enhanced sweet strawberry, fruity and aftertaste perception. The findings of the study can be used for the development of paediatric dosage forms with enhanced organoleptic properties, palatability and medication adherence. Full article

A biodegradable copolyester, poly(butylene succinate-co-ε-caprolactone) (PBS_CL), was used for first time as an excipient for pharmaceutical dosage forms using direct compression and hot processing techniques (ultrasound-assisted compression (USAC) and hot melt extrusion (HME)). Robust binary systems were achieved with hot processing techniques, allowing a controlled release of the drug. With only 12% v/v of PBS_CL, controlled release forms were obtained using USAC whereas in HME over 34% v/v of excipient is necessary. Amounts over 23% v/v allowed a long-extended release for more than 72 h following diffusional kinetic. Thanks to the high melting point of theophylline and the physicochemical properties of PBS_CL selected and synthesized, the structure of the excipient inside the USAC tablets and HME filaments corresponds to a continuum medium. A percolation threshold around 23% v/v was estimated, which agrees with a continuum percolation model. The polymer shows a high excipient efficiency value using HME and USAC. A nanostructured matrix with wall thicknesses lower than 0.1 µm was obtained. This leads to a very effective coating of the drug particles by the excipient, providing a slow and reproducible release. The present study therefore supports the use of PBS_CL, for the preparation of controlled release dosage forms using hot processing techniques. Full article

Quantitative pharmacology brings important advantages in the design and conduct of pediatric clinical trials. Herein, we demonstrate the application of a model-based approach to select doses and pharmacokinetic sampling scenarios for the clinical evaluation of a novel oral suspension of spironolactone in pediatric patients with edema. A population pharmacokinetic model was developed and qualified for spironolactone and its metabolite, canrenone, using data from adults and bridged to pediatrics (2 to <17 years old) using allometric scaling. The model was then used via simulation to explore different dosing and sampling scenarios. Doses of 0.5 and 1.5 mg/kg led to target exposures (i.e., similar to 25 and 100 mg of the reference product in adults) in all the reference pediatric ages (i.e., 2, 6, 12 and 17 years). Additionally, two different sampling scenarios were delineated to accommodate patients into sparse sampling schemes informative to characterize drug pharmacokinetics while minimizing phlebotomy and burden to participating children. Full article

Highly hygroscopic pharmaceutical and nutraceutical solids are prone to significant changes in their physicochemical properties due to chemical degradation and/or solid-state transition, resulting in adverse effects on their therapeutic performances and shelf life. Moisture absorption also leads to excessive wetting of the solids, causing their difficult handling during manufacturing. In this review, four formulation strategies that have been employed to tackle hygroscopicity issues in oral solid dosage forms of pharmaceuticals/nutraceuticals were discussed. The four strategies are (1) film coating, (2) encapsulation by spray drying or coacervation, (3) co-processing with excipients, and (4) crystal engineering by co-crystallization. Film coating and encapsulation work by acting as barriers between the hygroscopic active ingredients in the core and the environment, whereas co-processing with excipients works mainly by adding excipients that deflect moisture away from the active ingredients. Co-crystallization works by altering the crystal packing arrangements by introducing stabilizing co-formers. For hygroscopic pharmaceuticals, coating and co-crystallization are the most commonly employed strategies, whereas coating and encapsulation are popular for hygroscopic nutraceuticals (e.g., medicinal herbs, protein hydrolysates). Encapsulation is rarely applied on hygroscopic pharmaceuticals, just as co-crystallization is rarely used for hygroscopic nutraceuticals. Therefore, there is potential for improved hygroscopicity reduction by exploring beyond the traditionally used strategy. Full article

Amorphous solid dispersions stabilized by one or more polymer(s) have been widely used for delivering amorphous drugs with poor water solubilities, and they have gained great market success. Polymer selection is important for preparing robust amorphous solid dispersions, and considerations should be given as to how the critical attributes of a polymer can enhance the physical stability, and the in vitro and in vivo performances of a drug. This article provides a comprehensive overview for recent developments in the understanding the role of polymers in amorphous solid dispersions from the aspects of nucleation, crystal growth, overall crystallization, miscibility, phase separation, dissolution, and supersaturation. The critical properties of polymers affecting the physical stability and the in vitro performance of amorphous solid dispersions are also highlighted. Moreover, a perspective regarding the current research gaps and novel research directions for better understanding the role of the polymer is provided. This review will provide guidance for the rational design of polymer-based amorphous pharmaceutical solids with desired physicochemical properties from the perspective of physical stability and in vitro performance. Full article

Small interfering RNA (siRNA) can selectively suppress the expression of disease-causing genes, holding great promise in the treatment of human diseases, including malignant cancers. In recent years, with the development of chemical modification and delivery technology, several siRNA-based therapeutic drugs have been approved for the treatment of non-cancerous liver diseases. Nevertheless, the clinical development of siRNA-based cancer therapeutics remains a major translational challenge. The main obstacles of siRNA therapeutics in oncology include both extracellular and intracellular barriers, such as instability under physiological conditions, insufficient tumor targeting and permeability (particularly for extrahepatic tumors), off-target effects, poor cellular uptake, and inefficient endosomal escape. The development of clinically suitable and effective siRNA delivery systems is expected to overcome these challenges. Herein, we mainly discuss recent strategies to improve the delivery and efficacy of therapeutic siRNA in cancer, including the application of non-viral nanoparticle-based carriers, the selection of target genes for therapeutic silencing, and the combination with other therapeutic modalities. In addition, we also provide an outlook on the ongoing challenges and possible future developments of siRNA-based cancer therapeutics during clinical translation. Full article

Dermal disorders such as psoriasis and eczema are associated with modifications in the chemical and molecular composition of the skin. Clobetasol propionate (CP), a superpotent topical glucocorticoid, is widely used for the therapeutic management of various skin conditions, owing to its strong anti-inflammatory, antipruritic, vasoconstrictive, and antiproliferative activities. Safety studies demonstrated that CP is safer for a shorter period, however, with prolonged application, it shows secondary side effects such as photosensitivity, Cushing-like syndrome, allergic contact dermatitis, osteonecrosis, hypopigmentation, steroid acne, and skin atrophy. Therefore, the US FDA (United States Food and Drug Administration) has restricted the usage of CP to not more than 15 days. Research scientists addressed its several formulations and drug delivery issues, such as low water solubility, less stability, photodegradation, and poor absorption, by incorporating them into novel nanobased delivery platforms. With the utilization of these technologies, these drawbacks of CP have been resolved to a large extent to reestablish this moiety. This article explores the physicochemical properties and mechanism of action of CP. Additionally, an attempt has been made to discover and highlight the possible features of the novel nanosystems, including nanoemulsions, nanosponges, solid lipid nanoparticles, nanostructured lipid carriers, and nanogels, reported for CP. The stability and safety concerns of CP, along with its commercial status, are also discussed. Full article

Amorphization technology has been the subject of continuous attention in the pharmaceutical industry, as a means to enhance the solubility of poorly water-soluble drugs. Being in a high energy state, amorphous formulations generally display significantly increased apparent solubility as compared to their crystalline counterparts, which may allow them to generate a supersaturated state in the gastrointestinal tract and in turn, improve the bioavailability. Conventionally, hydrophilic polymers have been used as carriers, in which the amorphous drugs were dispersed and stabilized to form polymeric amorphous solid dispersions. However, the technique had its limitations, some of which include the need for a large number of carriers, the tendency to recrystallize during storage, and the possibility of thermal decomposition of the drug during preparation. Therefore, emerging amorphization technologies have focused on the investigation of novel amorphous-stabilizing carriers and preparation methods that can improve the drug loading and the degree of amorphization. This review highlights the recent pharmaceutical approaches utilizing drug amorphization, such as co-amorphous systems, mesoporous particle-based techniques, and in situ amorphization. Recent updates on these technologies in the last five years are discussed with a focus on their characteristics and commercial potential. Full article

Buccal mucosal membrane offers an attractive drug-delivery route to enhance both systemic and local therapy. This review discusses the benefits and drawbacks of buccal drug delivery, anatomical and physiological aspects of oral mucosa, and various in vitro techniques frequently used for examining buccal drug-delivery systems. The role of mucoadhesive polymers, penetration enhancers, and enzyme inhibitors to circumvent the formulation challenges particularly due to salivary renovation cycle, masticatory effect, and limited absorption area are summarized. Biocompatible mucoadhesive films and patches are favored dosage forms for buccal administration because of flexibility, comfort, lightness, acceptability, capacity to withstand mechanical stress, and customized size. Preparation methods, scale-up process and manufacturing of buccal films are briefed. Ongoing and completed clinical trials of buccal film formulations designed for systemic delivery are tabulated. Polymeric or lipid nanocarriers incorporated in buccal film to resolve potential formulation and drug-delivery issues are reviewed. Vaccine-enabled buccal films have the potential ability to produce both antibodies mediated and cell mediated immunity. Advent of novel 3D printing technologies with built-in flexibility would allow multiple drug combinations as well as compartmentalization to separate incompatible drugs. Exploring new functional excipients with potential capacity for permeation enhancement of particularly large-molecular-weight hydrophilic drugs and unstable proteins, oligonucleotides are the need of the hour for rapid advancement in the exciting field of buccal drug delivery. Full article