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Intravaginal rings (IVRs) are long-acting drug device systems designed for controlled drug release in the vagina. Commercially available IVRs employ a one-size-fits-all development approach, where all patients receive the same drug in similar doses and frequencies, allowing no space for dosage individualization for specific patients' needs. To allow flexibility for dosage individualization, this study explores the impact of infill-density on critical characteristics of personalized IVRs, manufactured using droplet deposition modeling three-dimensional (3D) printing technology. The model drug was dispersed on the surface of thermoplastic polyurethane pellets using an oil coating method. IVR infill-density ranged from 60 to 100 %. The compatibility of the drug and matrix was assessed using thermal and spectroscopic analyses. The IVRs were evaluated for weight, porosity, surface morphology, mechanical properties, and in vitro drug release. The results demonstrated high dimensional accuracy and uniformity of 3D-printed IVRs, indicating the robustness of the printing process. Increasing infill-density resulted in greater weight, storage modulus, Young's modulus, Shore hardness, and compression strength, while reducing the porosity of IVRs. All IVRs showed a controlled drug release pattern when tested under accelerated conditions of temperature for 25 days. Notably, greater infill-densities were associated with a decrease in the percentage of drug released. Overall, the study demonstrated that infill-density was an important parameter for personalizing the critical characteristics of the 3D-printed IVRs to fit individual patient needs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Rifampicin (RIF) is commonly used in the treatment of tuberculosis (TB), a bacterium that currently infects one fourth of the world's population. Despite the effectiveness of RIF in treating TB, current RIF treatment regimens require frequent and prolonged dosing, leading to decreased patient compliance and, ultimately, increased mortality rates. This project aims to provide an alternative to oral RIF by means of an inhalable spray-dried formulation. TB uses alveolar macrophages to hide and replicate until the cells rupture, further spreading the bacteria. Therefore, delivering RIF directly to the lungs can increase the drug concentration at the site of infection while reducing off-site side effects. Cyclodextrin (CD) was used to create a RIF-CD inclusion complex to increase RIF solubility and biodegradable RIF-loaded NP (RIF NP) were developed to provide sustained release of RIF. RIF NP and RIF-CD inclusion complex were spray dried to form a dry powder nanocomposite microparticles (nCmP) formulation (RIF-CD nCmP). RIF-CD nCmP displayed appropriate aerosol dispersion characteristics for effective deposition in the alveolar region of the lungs (4.0 µm) with a fine particle fraction of 89 %. The nCmP provided both a burst release of RIF due to the RIF-CD complex and pH-sensitive release of RIF due to the RIF NP incorporated into the formulation. RIF-CD nCmP did not adversely affect lung epithelial cell viability and RIF NP were able to effectively redisperse from the nCmP after spray drying. These results suggest that RIF-CD nCmP can successfully deliver RIF to the site of TB infection while providing both immediate and sustained release of RIF. Overall, the RIF-CD nCmP formulation has the potential to improve the efficacy for the treatment of TB., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The utilization of three-dimensional (3D) printing technology is prevalent in the fabrication of oral sustained release preparations; however, there is a lack of research on 3D-printed osmotic pump tablets. A 3D-printed core-shell structure bezafibrate osmotic pump tablet was developed based on the characteristics of rapid absorption and short half-life of bezafibrate, utilizing semisolid extrusion (SSE) 3D printing technology. First, the properties of different shell materials were investigated to define the composition of the shell, and ultimately, the optimal formulation was found to be ethyl cellulose:cellulose acetate:polyethylene glycol = 2:1:2. The formulation of the tablet core was defined based on the printing performance and release behavior. The formulation consisted of bezafibrate, lactis anhydrous, sodium bicarbonate, sodium alginate, polyethylene oxide and sodium dodecyl sulfate at a ratio of 400:400:300:80:50:50. The tablet was capable of achieving zero-order release. The physicochemical properties were also characterized. The pharmacokinetic data analysis indicated that there were no statistically significant differences in the pharmacokinetic parameters between the 3D-printed tablets and the reference listed drugs. There was a strong correlation between the in vitro and in vivo results for the 3D-printed tablets. The results showed that SSE printing is a practical approach for manufacturing osmotic pump tablets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Long-acting parenteral drug products are a popular choice for therapeutic areas requiring long term treatment. These products range from dispersed systems such as drug suspensions and polymeric microspheres to in situ forming polymeric implants. The lack of reliable drug release testing methods for these drug products not only impedes the development of new drug products but also affects generic drug development. Current release methods suffer from a range of problems such as high variability, poor reproducibility, poor discriminatory ability, lack of depot-like structure formation (that could mimic the in vivo situation). Moreover, shorter duration (less than a week) of release renders them unsuitable for in vitro-in vivo correlations (IVIVCs). To overcome these issues, novel adapters were developed for both USP-type-II & IV apparatus. These adapters were validated and assessed using the long-acting injectable (LAI) suspension drug product Depo Provera 150® as well as its Q1/Q2 equivalents. For USP-type-IV apparatus, two open adapter designs (conical and ellipsoidal shaped cavity with volume capacities of 50 µl and 1 ml, respectively) were developed. A closed conical adapter design with a volume capacity of 0.05 ml was developed for USP apparatus type-II. All three novel adapter designs effectively retained the suspensions, achieved release durations of 3-6 weeks with good reproducibility, minimal variability (RSD≤5%) and had good discriminatory ability. Based on this, the adapter-based dissolution methods were deemed suitable for IVIVC development of long-acting injectables. A successful Level A IVIVC was developed for Depo SubQ Provera 104® and its Q1Q2 equivalents using USP apparatus type IV with a conical adapter design. The closed adapter design for apparatus type-II was also investigated for suitability with risperidone in situ forming implants. The adapter was able to securely retain and maintain the shape of the in situ forming implants and resulted in release profiles of up to one month with good discriminatory ability and low standard error (RSD≤5%). These novel adapters hold promise of wide use for in vitro release testing of different long-acting parenteral drug products., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Nileshkumar Malavia, Quanying Bao, Diane J Burgess has patent pending to University of Connecticut. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hot melt extrusion (HME) processed Poly (lactic-co-glycolic acid) (PLGA) implant is one of the commercialized drug delivery products, which has solid, well-designed shape and rigid structures that afford efficient locoregional drug delivery on the spot of interest for months. In general, there are a variety of material, processing, and physiological factors that impact the degradation rates of PLGA-based implants and concurrent drug release kinetics. The objective of this study was to investigate the impacts of PLGA's material characteristics on PLGA degradation and subsequent drug release behavior from the implants. Three model drugs (Dexamethasone, Carbamazepine, and Metformin hydrochloride) with different water solubility and property were formulated with different grades of PLGAs possessing distinct co-polymer ratios, molecular weights, end groups, and levels of residual monomer (high/Viatel TM and low/ Viatel TM Ultrapure). Physicochemical characterizations revealed that the plasticity of PLGA was inversely proportional to its molecular weight; moreover, the residual monomer could impose a plasticizing effect on PLGA, which increased its thermal plasticity and enhanced its thermal processability. Although the morphology and microstructure of the implants were affected by many factors, such as processing parameters, polymer and drug particle size and distribution, polymer properties and polymer-drug interactions, implants prepared with Viatel TM PLGA showed a smoother surface and a stronger PLGA-drug intimacy than the implants with Viatel TM Ultrapure PLGA, due to the higher plasticity of the Viatel TM PLGA. Subsequently, the implants with Viatel TM PLGA exhibited less burst release than implants with Viatel TM Ultrapure PLGA, however, their onset and progress of the lag and substantial release phases were shorter and faster than the Viatel TM Ultrapure PLGA-based implants, owing to the residual monomer accelerated the water diffusion and autocatalyzed PLGA hydrolysis. Even though the drug release profiles were also influenced by other factors, such as composition, drug properties and polymer-drug interaction, all three cases revealed that the residual monomer accelerated the swelling and degradation of PLGA and impaired the implant's integrity, which could negatively affect the subsequent drug release behavior and performance of the implants. These results provided insights to formulators on rational PLGA implant design and polymer selection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to develop a 3D-printed fixed-dose combination tablet featuring differential release of two drugs using double-melt extrusion (DME). The hot-melt extrusion (HME) process was divided into two steps to manufacture a single filament containing the two drugs. In Step I, a sustained-release matrix of acetaminophen (AAP) was obtained through HME at 190 °C using Eudragit® S100, a pH-dependent polymer with a high glass transition temperature. In Step II, a filament containing both sustained-release AAP from Step I and solubilized ibuprofen (IBF) was fabricated via HME at 110 °C using a mixture of hydroxy propyl cellulose (HPC-LF) and Eudragit® EPO, whose glass transition temperatures make them suitable for use in a 3D printer. A filament manufactured using DME was used to produce a cylindrical 3D-printed fixed-dose combination tablet with a diameter and height of 9 mm. To evaluate the release characteristics of the manufactured filament and 3D-printed tablet, dissolution tests were conducted for 10 h under simulated gastrointestinal tract conditions using the pH jump method with the United States Pharmacopeia apparatus II paddle method at 37 ± 0.5 °C and 50 rpm. Dissolution tests confirmed that both the sustained-release and solubilized forms of AAP and IBF within the filament and 3D-printed tablet exhibited distinct drug-release behaviors. The physicochemical properties of the filament and 3D-printed tablet were confirmed by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy. HME transforms crystalline drugs into amorphous forms, demonstrating their physicochemical stability. Scanning electron microscopy and confocal laser scanning microscopy indicated the presence of sustained AAP granules within the filament, confirming that the drugs were independently separated within the filament and 3D-printed tablets. Finally, sustained-release AAP and solubilized IBF were independently incorporated into the filaments using DME technology. Therefore, a dual-release 3D-printed fixed-dose combination was prepared using the proposed filament., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The push-pull osmotic pump tablet is a promising drug delivery approach, offering advantages over traditional dosage forms in achieving consistent and predictable drug release rates. In the current study, the drug release process of push-pull osmotic pump tablets is modelled for the first time using the discrete element method (DEM) incorporated with a microscopic diffusion-induced swelling model. The effects of dosage and formulation design, such as delivery orifice size, drug-to-polymer ratio, tablet surface curvature, friction between particles and cohesion of polymer particles, on the drug release performance are systematically analysed. Numerical results reveal that an enlarged delivery orifice significantly increases both the total drug release and the drug release rate. Moreover, the larger the swellable particle component in the tablet, the higher the drug release rate. Furthermore, the tablet surface curvature is found to affect the drug release profile, i.e. the final drug release percentage increases with the increasing tablet surface curvature. It is also found that the drug release rate could be controlled by adjusting the inter-particle friction and the cohesion of polymer particles in the formulation. This DEM study offers valuable insights into the mechanisms governing drug release in push-pull osmotic pump tablets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC-mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC-mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC-mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150-200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC-mannitol ratios. Co-processed HPMC-mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christina Yong Xin Kang, Wen Chin Foo, Kwan Hang Lam, Keat Theng Chow, Yuan Siang Lui, Hui Ping Goh, Antoine Salome, Baptiste Boit, Philippe Lefevre, and Rajeev Gokhale are current/past employees of Roquette and may own Roquette stock. In addition, Baptiste Boit and Philippe Lefevre have patent issued to Roquette Freres SA., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study focuses on the combination of three-dimensional printing (3DP) and amorphous solid dispersion (ASD) technologies for the manufacturing of gastroretentive floating tablets. Employing hot melt extrusion (HME) and fused deposition modeling (FDM), the study investigates the development of drug-loaded filaments and 3D printed (3DP) tablets containing felodipine as model drug and hydroxypropyl methylcellulose (HPMC) as the polymeric carrier. Prior to fabrication, solubility parameter estimation and molecular dynamics simulations were applied to predict drug-polymer interactions, which are crucial for ASD formation. Physical bulk and surface characterization complemented the quality control of both drug-loaded filaments and 3DP tablets. The analysis confirmed a successful amorphous dispersion of felodipine within the polymeric matrix. Furthermore, the low infill percentage and enclosed design of the 3DP tablet allowed for obtaining low-density systems. This structure resulted in buoyancy during the entire drug release process until a complete dissolution of the 3DP tablets (more than 8 h) was attained. The particular design made it possible for a single polymer to achieve a zero-order controlled release of the drug, which is considered the ideal kinetics for a gastroretentive system. Accordingly, this study can be seen as an advancement in ASD formulation for 3DP technology within pharmaceutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glaucoma, the second most common cause of blindness worldwide, requires the development of new and effective treatments. This study introduces a novel controlled-release system utilizing elastin-like recombinamers (ELR) and the Supercritical Antisolvent (SAS) technique with supercritical CO2. Acetazolamide (AZM), a class IV drug with limited solubility and permeability, is successfully encapsulated in an amphiphilic ELR at three different ELR:AZM ratios, yielding up to 62 %. Scanning electron microscopy (SEM) reveals spherical microparticles that disintegrate into monodisperse nanoparticles measuring approximately 42 nm under physiological conditions. The nanoparticles, as observed via Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), do not exhibit aggregates, a fact confirmed by the zeta potential displaying a value of -33 mV over a period of 30 days. Transcorneal permeation tests demonstrate a 10 % higher permeation level compared to the control solution, which increases to 30 % after 2 h. Ocular irritation tests demonstrate no adverse effects or damage. Intraocular pressure (IOP) tests conducted on hypertensive rabbits indicate greater effectiveness for all three analyzed formulations, suggesting enhanced drug bioavailability during treatment. Consequently, the combination of recombinant biopolymers and high-pressure techniques represents a promising approach for advancing glaucoma therapy, emphasizing its potential clinical significance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) polymeric micelles show interesting properties for ocular administration thanks to their solubilization capability, nanometric size and tissue penetration ability. However, micelles formulations are generally characterized by low viscosity, poor adhesion and very short retention time at the administration site. Therefore, the idea behind this work is the preparation and characterization of a crosslinked film based on xanthan gum that contains TPGS micelles and is capable of controlling their release. The system was loaded with melatonin and cyclosporin A, neuroprotective compounds to be delivered to the posterior eye segment. Citric acid and heating at different times and temperatures were exploited as crosslinking approach, giving the possibility to tune swelling, micelles release and drug release. The biocompatibility of the platform was confirmed by HET-CAM assay. Ex vivo studies on isolated porcine ocular tissues, conducted using Franz cells and two-photon microscopy, demonstrated the potential of the xanthan gum-based platform and enlightened micelles penetration mechanism. Finally, the sterilization step was approached, and a process to simultaneously crosslink and sterilize the platform was developed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Personalized medicine aims to effectively and efficiently provide customized drugs that cater to diverse populations, which is a significant yet challenging task. Recently, the integration of artificial intelligence (AI) and three-dimensional (3D) printing technology has transformed the medical field, and was expected to facilitate the efficient design and development of customized drugs through the synergy of their respective advantages. In this study, we present an innovative method that combines AI and 3D printing technology to design and fabricate customized capsules. Initially, we discretized and encoded the geometry of the capsule, simulated the dissolution process of the capsule with classical drug dissolution model, and verified it by experiments. Subsequently, we employed a genetic algorithm to explore the capsule geometric structure space and generate a complex multi-layer structure that satisfies the target drug release profiles, including stepwise release and zero-order release. Finally, Two model drugs, isoniazid and acetaminophen, were selected and fused deposition modeling (FDM) 3D printing technology was utilized to precisely print the AI-designed capsule. The reliability of the method was verified by comparing the in vitro release curve of the printed capsules with the target curve, and the f 2 value was more than 50. Notably, accurate and autonomous design of the drug release curve was achieved mainly by changing the geometry of the capsule. This approach is expected to be applied to different drug needs and facilitate the development of customized oral dosage forms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Polypharmacy is a common issue, especially among elderly patients resulting in administration errors and patient inconvenience. Hypertension is a prevalent health condition that frequently leads to polypharmacy, as its treatment typically requires the co-administration of more than one different Active Pharmaceutical Ingredients (API's). To address these issues, floating hollow torus-shaped dosage forms were developed, aiming at providing prolonged gastric retention and sustained drug release. The dosage forms (polypills) containing three anti-hypertensive API's (diltiazem (DIL), propranolol (PRP) and hydrochlorothiazide (HCTZ)) were created via Fused Deposition Modelling 3D printing. A multitude of the dosage forms were loaded into a capsule and the resulting formulation achieved prolonged retention times over a 12-hour period in vitro, by leveraging both the buoyancy of the dosage forms, and the "cheerios effect" that facilitates the aggregation and retention of the dosage forms via a combination of surface tension and shape of the objects. Physicochemical characterization methods and imaging techniques were employed to investigate the properties and the internal and external structure of the dosage forms. Furthermore, an ex vivo porcine stomach model revealed substantial aggregation, adhesion and retention of the 3D printed dosage forms in porcine stomach. In vitro dissolution testing demonstrated almost complete first-order release of PRP and DIL (93.52 % and 99.9 %, respectively) and partial release of HCTZ (65.22 %) in the 12 h timeframe. Finally, a convolution-based single-stage approach was employed in order to predict the pharmacokinetic (PK) parameters of the API's of the formulation and the resemblance of their PK behavior with previously reported data., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hydrogen bonding, ionic interactions, and dipole-dipole interactions have been extensively studied to control drug release from patches. However, metal coordination bonding has not been fully explored for the control of transdermal drug release. In this study, metal coordination-based acrylic pressure-sensitive adhesives (PSAs) were designed and synthesized in order to systemically elucidate the effect of metal coordination on drug release from acrylic PSAs. Ketoprofen (KET) and donepezil (DNP) were selected as model drugs. Results showed that the burst release rate of KET was controlled by N-[tris(hydroxymethyl)methyl]acrylamide (NAT) and Fe 3+ , while the DNP release rate had no significant changes. It was found that the PSA-drug interaction, rather than the molecular mobility of PSA, played a dominant role in the controlled release process of KET. The hydrogen bond interaction between NAT and KET controlled the release process, while the coordination bond interaction between Fe 3+ and KET further slowed down the release of KET. In conclusion, it was found that the controlled release of KET was achieved by the synergistic effect of coordination bonding and hydrogen bonding, which opens up a facile but powerful avenue for the design of brand-new controlled release systems and new opportunities for their application in transdermal drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In this work, the capabilities of a state-of-the-art fast Raman imaging apparatus are exploited to gain information about the concentration and particle size of hydroxypropyl methylcellulose (HPMC) in sustained release tablets. The extracted information is utilized to predict the in vitro dissolution profile of the tablets. For the first time, convolutional neural networks (CNNs) are used for the processing of the chemical images of HPMC distribution and to directly predict the dissolution profile based on the image. This new method is compared to wavelet analysis, which gives a quantification of the texture of HPMC distribution, carrying information regarding both concentration and particle size. A total of 112 training and 32 validation tablets were used, when a CNN was used to characterize the particle size of HPMC, the dissolution profile of the validation tablets was predicted with an average f 2 similarity value of 62.95. Direct prediction based on the image had an f 2 value of 54.2, this demonstrates that the CNN is capable of recognizing the patterns in the data on its own. The presented methods can facilitate a better understanding of the manufacturing processes, as detailed information becomes available with fast measurements., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Dihydromyricetin (DHM) is an important natural flavonoid. However, most of DHM preparations have shown shortcomings such as low drug loading, poor drug stability, and/or large fluctuations in blood concentration. This study aimed to develop a gastric floating tablet with a double-layered structure for zero-order controlled release of DHM (DHM@GF-DLT). The final product DHM@GF-DLT showed a high average cumulative drug release at 24 h that best fit the zero-order model, and had a good floating ability in the stomach of the rabbit with a gastric retention time of over 24 h. The FTIR, DSC, and XRPD analyses indicated the good compatibility among the drug and the excipients in DHM@GF-DLT. The pharmacokinetic study revealed that DHM@GF-DLT could prolong the retention time of DHM, reduce the fluctuation of blood drug concentration, and enhance the bioavailability of DHM. The pharmacodynamic studies demonstrated that DHM@GF-DLT had a potent and long-term therapeutic effect on systemic inflammation in rabbits. Therefore, DHM@GF-DLT had the potential to serve as a promising anti-inflammatory agent and may develop into a once-a-day preparation, which was favorable to maintain a steady blood drug concentration and a long-term drug efficacy. Our research provided a promising development strategy for DHM and other natural products with a similar structure to DHM for improving their bioavailability and therapeutic effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The purpose of this study was to investigate the effect of the physicochemical parameters of drugs on their own release behaviors in polyisobutylene pressure sensitive adhesive (PIB PSA), which provided a theoretical guidance for the application of PIB in transdermal drug delivery system (TDDS). Seven drugs with different physicochemical parameters including clonidine (CLO), flurbiprofen (FLU), diclofenac (DIC), ibuprofen (IBU), zolmitriptan (ZOL), lidocaine (LID), tulobuterol (TUL) and the mixed adhesive (7:3, w/w) of Oppanol® B 15 N (M.W. = 108,000 Da) and Oppanol® N 50 (M.W. = 565,000 Da) were selected for in vitro drug release and skin permeation studies. Regression analysis was used to study the relationship between physicochemical parameters and release behaviors. The release behaviors of drugs were a negative correlation with polarizability and dipole moment per molecular volume (μ/V), which represented van der Waals and dipole-dipole interaction, respectively. Fourier transform infrared spectroscopy (FT-IR), modulated temperature differential scanning calorimetry (MDSC) and molecular dynamics simulation were used to provide molecular details of the interaction between the drug and PIB. The free volume and molecular mobility of PIB were characterized using mechanical property tests, rheology study, MDSC and molecular dynamics simulation. Based on the above results, drugs with high polarizability and μ/V had stronger van der Waals and dipole-dipole interaction with PIB, reducing the free volume and molecular mobility of PIB, so that the drug struggled to release from PIB. In addition, the diffusion activation energy of the drug was calculated by using the variable temperature release study to characterize the ease of drug release from the kinetic aspect. And the trends of in vitro drug release and skin penetration profiles were basically similar. Thus, it was thought that the physicochemical parameters of the drug played a vital role in the drug release behavior of PIB PSAs and would affect the skin penetration process, which provided a reference for the design and application of patches based on PIB PSAs in TDDS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Press-coated tablets are an advantageous technology to achieve delayed releases of active ingredients. They are characterized by a core-shell structure, that makes it possible to tune the lag-time and release kinetics in order to meet the chronotherapeutical goals. Thus, these features are the most important quality attributes to be controlled when designing a press-coated tablet. Many studies have focused on the influence of the formulation on the release attributes. This work aims to study the influence of geometrical and process parameters on the release attributes of press-coated tablets, while keeping a constant formulation. In particular, the variation of compression pressure, layer thickness and band thickness made it possible to vary the lag-time from 1 h to 10 h. These parameters also have an influence on the release kinetics after the lag-time. Indeed, two main opening modes were observed during the dissolution test that correspond to fast or slow release rates. The opening mode obtained depends on the density distribution in the shell, which is directly influenced by the process parameters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In a previous study, we developed electrospun antimicrobial microfiber scaffolds for wound healing composed of a core of zein protein and a shell containing polyethylene oxide. While providing a promising platform for composite nanofiber design, the scaffolds showed low tensile strengths, insufficient water stability, as well as burst release of the antimicrobial drug tetracycline hydrochloride, properties which are not ideal for the use of the scaffolds as wound dressings. Therefore, the aim of the present study was to develop fibers with enhanced mechanical strength and water stability, also displaying sustained release of tetracycline hydrochloride. Zein was chosen as core material, while the shell was formed by the hydrophobic polymer polycaprolactone, either alone or in combination with polyethylene oxide. As compared to control fibers of pristine polycaprolactone, the zein-polycaprolactone fibers exhibited a reduced diameter and hydrophobicity, which is beneficial for cell attachment and wound closure. Such fibers also demonstrated sustained release of tetracycline hydrochloride, as well as water stability, ductility, high mechanical strength and fibroblast attachment, hence representing a step towards the development of biodegradable wound dressings with prolonged drug release, which can be left on the wound for a longer time., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The purpose of this study was to develop a once-daily, bilayer matrix tablet with immediate (IR) and sustained release (SR) layers of poorly water-soluble and absorption site dependent rebamipide (RBM) to substitute three times a day IR tablet. Owing to the pH-dependent poor water solubility of RBM in low pH condition, salt-caged nanosuspensions (NSPs) consisting of RBM and poloxamer 407 (POX 407) or poloxamer 188 (POX 188) were prepared using an acid-base neutralization method to increase the dissolution rate, which was subsequently applied to the immediate-release (IR) layer. Polyethylene oxide (PEO) with different molecular weights (PEO 100,000 and PEO 5,000,000) and hydroxypropyl methylcellulose 4000 (HPMC 4000) were then investigated as SR agents to incorporate into the SR layer with pure RBM via wet granulation method. The dissolution profile of the optimized bilayer tablet having 50% IR and 50% SR layer of 300 mg RBM showed that the IR layer could rapidly disintegrate in pH 1.2 buffer solution within 2 h, reaching 50% of drug release from the tablet, followed by an extended drug release from the SR layer in pH 6.8 buffer over 24 h. An in vivo pharmacokinetic study was carried out in beagle dogs to compare the optimal formulation (300 mg RBM bilayer tablet) and the commercial tablet (Mucosta® 100 mg) as a reference. Unexpectedly, despite enhanced dissolution rate in a controlled manner, a designed bilayer tablet had no dose- and dosage form dependent in vivo bioavailability in beagle dogs as compared with IR 100 mg RBM reference tablet. It was evident that solubility in low pH condition, gastric residence time and absorption site of RBM should be carefully considered for designing specific SR or gastroretentive dosage form to improve therapeutic outcomes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cardiovascular diseases constitute a number of conditions which are the leading cause of death globally. To combat these diseases and improve the quality and duration of life, several cardiac implants have been developed, including stents, vascular grafts and valvular prostheses. The implantation of these vascular prosthesis has associated risks such as infection or blood clot formation. In order to overcome these limitations medicated vascular prosthesis have been previously used. The present paper describes a 3D printing method to develop medicated vascular prosthesis using fused deposition modelling (FDM) technology. For this purpose, rifampicin (RIF) was selected as a model molecule as it can be used to prevent vascular graft prosthesis infection. Thermoplastic polyurethane (TPU) and RIF were combined using hot melt extrusion (HME) to obtain filaments containing RIF concentrations ranging between 0 and 1% (w/w). These materials are capable of providing RIF release for periods ranging between 30 and 80 days. Moreover, TPU-based materials containing RIF were capable of inhibiting the growth of Staphylococcus aureus. This behaviour was observed even for TPU-based materials containing RIF concentrations of 0.1% (w/w). TPU containing 1% (w/w) of RIF showed antimicrobial properties even after 30 days of RIF release. Alternatively, these methods were used to prepare dipyridamole containing TPU filaments. Finally, using a dual extrusion 3D printer vascular grafts containing both drugs were prepared., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Localized delivery to oral mucositis ulcerations requires specialized dosage forms, (e.g. in situ forming gels) delivered to the site in relatively low volumes. However, this is challenging for drugs with low solubility such as Bupivacaine γ-Linoleate (Bup-γL). The objective of this study is to develop an in situ forming gel with enhanced loading of Bup-γL for oral mucositis pain control. Two co-solvents (PEG400 and ethanol) and eight solubilizers (Tween 80, sodium lauryl sulfate, Cremophor® RH40, Cremophor® EL, Kolliphor® HS 15, Soluplus®, PEG 3350 and PEG8000) were screened for their capability to solubilize Bup-γL. Among all tested solubilizers, sodium lauryl sulfate (SLS) showed the highest solubilizing capacity (8.83 ± 0.94 mg/mL). This was considered to be a consequence of the similarity between the structure of SLS and Bup-γL. On the addition of SLS to the in situ forming gels, the drug loading was enhanced from ~6.5 to ~10.5 mg/ml. The formulations were characterized for their gelation temperature, rheological properties, in vitro drug release and short-term storage stability. The gelation temperatures of the in situ forming gel formulations were significantly reduced with enhanced drug loading. The in vitro drug release profiles showed good fit to both the first order and the Higuchi models. Formulations with SLS demonstrated sustained drug release (time to plateau ~7 h) compared with formulations without SLS (time to plateau ~3.5 h). This study offers an effective strategy to enhance drug loading of in situ forming gels. The enhanced drug loading will reduce the dosing volume and as such is expected to reduce any unwanted numbing of the healthy mucosa., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Patients' genetic characteristics, age, gender, diet, and lifestyle affect the success of medical treatment. The treatment's effectiveness can be increased by using personalized medication; however, using conventional large-scale drug production methods can restrict tablet geometry and drug dosage combinations. To create these personalized drugs, 3D printing has been studied as an alternative production method. In this study, stereolithography 3D printing is used to create custom tablet geometries using a novel biocompatible photochemistry consisting of ascorbic acid (AA) encapsulated in a poly(ethylene glycol) dimethacrylate (PEGDMA)-based polymer network and polymerized using riboflavin as a photoinitiator. The printing process is customized for the chemistry and different geometries (small and large tablet, coaxial annulus, 4-circle pattern and honeycomb pattern) with surface area to volume ratios ranging from 0.6 to 1.83 are fabricated. The tablets' microstructures are examined and the cumulative release rates in gastrointestinal conditions are analyzed periodically for 6 h. After 1 h of release, honeycomb and coaxial annulus tablet gels exhibit higher release rates at approximately 80%. The experimental data is fitted to empirical release kinetic models and the Higuchi model is shown to yield the best fitting results. Overall, by using a novel biocompatible photochemistry and 3D printing we have shown that it is possible to successfully load and release ascorbic acid as a model agent, opening up a new class of manufacturing protocols to encapsulate ascorbic acid and other water-soluble vitamins as well as many different drugs for drug delivery applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nanogels are currently considered as promising nanosized drug delivery carriers. Nanogels are made of a crosslinked polymeric network which could encapsulate both hydrophilic and hydrophobic drugs due to their tunable nature. The ability of nanogels to control drug release is vastly described in the literature and researchers are consistently improving the control of drug release from nanogel by designing new polymers having specific sensitivity to a chemical or physical stimulus. In this review, we briefly discuss the definition of nanogels, their release profiles, their specific gel-based characteristics and the pathways of dug release from nanogels. We have focused on the stimuli responsive nanogels and their release profile. This compilation opens the window for understanding the influence of chemical composition and design of various nanogel on their release in the presence and absence of corresponding stimuli such as temperature, pH, enzymes and others. The uniqueness of this review is that it highlights the data of release profiles in terms of the different nanogel composition and triggers. It also points the high potential of nanogels in the list of candidates for drug delivery systems, thanks to their properties regarding drug encapsulation and release, combined advantages of nano-size and swelling characteristics of hydrogel., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chitosan nanofibrous membranes have immense potential in tissue engineering and drug delivery applications because of their increased surface area, high degree of biocompatibility, and their ability to mimic the extracellular matrix. However, their use is often limited due to their extreme hydrophilic nature causing them to lose their nanofibrous structure in vivo. In the present study, chitosan membranes were modified either by acylation reactions using fatty acids of different chain lengths or tert-butyloxycarbonyl (tBOC) protecting groups to increase the hydrophobicity of the membranes and protect the nanofibrous structure. The modified membranes were characterized using scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, water contact angle and elemental analysis to confirm the addition of the modification groups. These membranes were then evaluated to control the release of a hydrophobic osteogenic drug-simvastatin (SMV). The interaction between SMV and the polymer was determined using molecular modeling. Pure SMV and SMV loaded membranes were examined for their in vitro cytotoxicity and osteogenic potential using preosteoblast mouse bone marrow stromal cells. From results, it was evident that as the fatty acid chain length increased from two to six methylene groups, the hydrophobicity of the membranes increased (59.2 ± 8.2° to 94.3 ± 8.5° water contact angle). The amount of drug released from the membranes could be controlled by changing the amount of initial drug loaded and/or the type of modifications. After 4 weeks, for a 500 μg loading, the short chain fatty acid modified membranes released 17.8 ± 3.2% of the drug whereas a long chain fatty acid released only 4.8 ± 0.8%. Similarly, for a 50 μg loading, short chain modified membranes released more (73.3 ± 33.3%) of the loaded drug as compared to the long chain membranes (43.0 ± 3.5%). The long chain fatty acid membranes released SMV for extended time periods of up to 90 days. This data was further supported by molecular modeling, which revealed that SMV was more compatible with more hydrophobic membranes. Cell studies showed that pure SMV from 75 to 600 ng/ml range possessed osteogenic potential in a dose dependent manner and the amount of SMV released from the most hydrophobic FA treated membranes was not cytotoxic and supported osteogenic differentiation. Therefore, this study demonstrates our ability to control the release of a hydrophobic drug from modified chitosan membranes as per the clinical need., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Controlled release tablets are important dosage forms enabling a slower release of the drug and better pharmacokinetics for some drugs and hydrophilic matrix tablets utilizing hydroxypropyl methylcellulose (HPMC) are one of the most common types. One of the main challenges with using HPMC is its poor flow when implemented in a direct compression process or when utilized for continuous manufacturing for which novel grades of direct compression have been developed. In this work, three different direct compression (DC) grades of HPMC (K4M, K15M and K100M) were characterized and compared to their standard grade (CR) counterparts. These materials were compared in terms of density, particle size, morphology, surface area and powder flow using multiple techniques. Results showed that the materials were almost identical in terms of particle shape and although the DC grades had better flow, the particle size was slightly smaller with an unexpectedly higher surface area, which most likely resulted from the inclusion of co-processed silicon dioxide in the DC grades. The bulk, tapped and true densities were slightly higher for all of the DC grades. Of the eleven different parameters used to characterize the flow of the materials the DC grades showed better flow than their standard CR counterparts for nine of the parameters (Carr's Index, Erweka flow, FT4 Flow Rate Index, Mean Avalanche Time, Avalanche Scatter, Number of Avalanches, Shear Cell Uni-axial Compressive Strength and Shear Cell Flow Function Coefficient). Only the FT4 Basic Flowability Energy and Specific Energy showed the opposite trend which can be explained from the testing methodology. It is recommended to evaluate the DC grades of HPMC for processes where better flowing material would have an advantage, such as direct compression, continuous manufacturing, and roller compaction if the powder flow into the rolls is problematic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Colloidal stability and the regularity of the release kinetics benefit from the high circularity and the narrow size dispersion of polymeric particles as drug delivery carriers. A method for obtaining such particles composed of poly(lactide-co-glycolide) (PLGA), averaging at 1.0 ± 0.3 µm in size, is reported here, along with the analysis of the effects of different synthesis parameters on their morphological characteristics. As in agreement with the classical nucleation theory, the particle size and the degree of cohesion were inversely proportional to supersaturation. Consequently, the optimal conditions for the precipitation of small and narrowly dispersed particles involved an abrupt elevation of supersaturation. Owing to the high colloidal stability of the particles, centrifugation exhibited a counterintuitive effect on them, refining their morphological features and promoting their individuation. Polyvinyl alcohol (PVA) was used as a steric repulsion additive and its effect on the stability of PLGA spheres was concentration-dependent, with the particles aggregating, partially coalescing and losing their distinct features both with no PVA in the system and at PVA concentrations higher than the optimal. At its narrowest, the particle size distribution was bimodal, exhibiting the average circularity of 0.997 ± 0.003 and the average roundness of 0.913 ± 0.054. PLGA spheres were loaded with an inhibitor of EhCP4, a cysteine protease from E. histolytica, a parasite causing amoebic dysentery in the tropical and developing world. The burst release of the drug at early time points was followed by a zero-order release period, yielding a biphasic profile that can be of benefit in the delivery of anti-infective agents. The release profile fitted poorly with the Hixson-Crowell kinetic model and excellently with the Higuchi and the Korsmeyer-Peppas ones, indicating that the release is conditioned by diffusion rather than by the degradation of the polymer. The release and the erosion proceeded independently from one another, suggesting that the pore formation, water penetration and swelling are the primary driving forces for the release of the drug., Competing Interests: Declaration of Competing Interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Extruded 3D printing is emerging as an attractive fabrication technology in the field of personalized oral medicines. The objective of this study was to develop a tunable extruded 3D printing platform based on thermo-sensitive gelatin pastes to meet the needs of achieving different drug release characteristics with flexible dosing and design. The printability and mechanisms of extrusion and deposition of the gelatin pastes were systematically studied. Ibuprofen and diclofenac sodium were used as model drugs for immediate- and sustained-release formulations, respectively. Following the optimization of formulation and process parameters, ibuprofen immediate-release formulations with different designs, and reservoir-type diclofenac sodium sustained-release formulations were printed. Target drug release patterns were successfully obtained for both model drugs. Rheological studies revealed that additives such as microcrystalline cellulose and hydroxypropyl methylcellulose can act as both thickeners and proppants of gelatin matrix. Furthermore, computational fluid dynamics simulation was used to visualize the printing process, and quantitatively analyze the influence of material viscosity, inlet velocity and nozzle diameter on the pressure and velocity of extrusion flow field. The present study demonstrated the great potential of extruded 3D printing technology using the thermo-sensitive gelatin paste platform for personalized oral medicines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A continuous processing platform was developed to produce polymeric micelles. A block copolymer of mPEG (5kD)-PCL (2kD) was used as the model drug carrier. The polymeric micelles were produced using an innovative co-axial turbulent jet with co-flow continuous technology to precisely control the physicochemical properties of the micelles. A 3 × 3 × 4 full factorial design of experiment (DoE) study was conducted to optimize the polymeric micelle processing to achieve the desired critical quality attributes such as particle size and polydispersity index (PDI). Curcumin was used as a hydrophobic model drug as polymeric micelles are traditionally used to improve solubility and chemical stability of hydrophobic drug molecules. A second DoE study was conducted to achieve maximal drug loading. The average size of the optimized curcumin-loaded polymeric micelles was 29.1 ± 0.51 d.nm with a PDI value in the range of 0.05 ± 0.02 and a maximum drug loading of 11.1 ± 0.81% (w/w). When compared to polymeric micelles prepared using a manual ethanol injection method the particle size, PDI and drug loading for curcumin-loaded polymeric micelles was 74.8 ± 8.68 d.nm, and 0.46 ± 0.12 and 8.12 ± 1.23%, respectively. These data show that the continuous processing method provided significant improvement in controlling the key quality attributes. The curcumin-loaded polymeric micelles exhibited a sustained release profile during dissolution of about 50% drug released in 12 h compared to the free drug, which was completely released within 10 h. The curcumin-loaded polymeric micelles were characterized for other key quality attributes such as critical micelle concentration (CMC), and morphology by transmission electron microscopy, X-ray powder crystallography, polarized light microscopy, and differential scanning calorimetry. A novel method for determining the CMC of the polymer was developed using dynamic light scattering (DLS). Curcumin-loaded polymeric micelles were further processed by lyophilization to prevent hydrolytic cleavage of the polymers and maintain long term stability. The current study highlighted the potential advantages of transitioning from manual batch processing to continuous processing and serves as an example of improving processing efficiency as well as product quality through utilization of advanced processing technologies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Loading of gatifloxacin in contact lenses affects critical lens properties (optical and swelling) owing to drug precipitation in the contact lens matrix. The presence of Pluronic® F-68 in the packaging solution creates in-situ micelles in the contact lens to dissolve gatifloxacin precipitates and provide sustained drug release. The micelles further improved the drug uptake from the drug-packaging solution to create an equilibrium of drug between the lens matrix and the packaging solution. In this study, we optimized gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and gatifloxacin loading capacity as well as sustained drug delivery. Optimization of gatifloxacin-pluronic-loaded contact lens was carried out using a 3 2 factorial design by tailoring the concentration of Pluronic® F-68 in the packaging solution (X 1 ) and the amount of gatifloxacin in the monomer solution (X 2 ) to achieve the desired lens properties. The optimized batch (X 1  = 0.3%w/v and X 2  = 0.3%w/v) showed an optical transmittance of 92.84%, swelling of 92.36% and gatifloxacin loading capacity of 92.56 μg. The in vitro flux data of the optimized batch (GT-Pl-CL) showed sustained release up to 72 h, whereas soaked contact lenses (SM-CL) and direct gatifloxacin-loaded contact lenses (DL-CL) showed a sustained release up to 48 h. The in vivo gatifloxacin release data for rabbit tear fluid showed sustained release with a high gatifloxacin level for the GT-Pl-CL lens in comparison to the SM-CL and the eye drop solution. This study demonstrates the application of the 3 2 full factorial design to optimize gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and drug loading capacity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and "first pass" metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Although solid dispersions have been reported as an efficient drug delivery system, the design of specific dosage forms for pharmaceutical therapy is necessary to improve the solubility and bioavailability of poorly water-soluble drugs. Solid dispersions can be incorporated in general solid dosage forms such as powders, granules, capsules and tablets, but only to enhance solubility and the dissolution rate. However, further development of solid dispersions will be required in certain circumstances for further in vivo drug improvement of those solid dosage forms. In the current review, specific designs of solid dosage forms for controlled drug release will be reported. Moreover, methods and strategies for incorporating these solid dispersions into controlled drug release forms will also be discussed. Overall, the outlook of current studies will provide potential approaches for the further improvement of solid dispersions, especially for clinical developments in pharmaceutical therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Patient to patient variability is one of the issues when administering medications to individuals with different health conditions, pharmacokinetic, age, fitness, gender, and race. This requires introducing smart and personalised drug delivery systems with controlled release profile manufactured using novel approaches. Additive manufacturing (AM) provides opportunities such as full customisation, design freedom, and on-site manufacturing, and materials recycling. As a result, the academic and industrial demand for additive manufacturing for drug delivery has been continuously increasing and showing impressive results for a wide range of products. This paper provides an extensive overview of AM technologies and their applications for drug delivery. The review discusses AM technologies including their working principles, processed materials, as well as current progress in drug delivery to produce personalized dosages for every patient with controlled release profile. AM potentials, industrial scale, and challenges are investigated with regards to practice and industrial applications. The paper covers novel possibilities of AM technologies and their pharmaceuticals applications, which indicate a promising healthcare future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Acne vulgaris is a chronic inflammatory skin disorder affecting mostly females. It has a negative impact on the social life and psychological well-being of the individual. Its pathogenesis involves an exaggerated secretion of sebum, hyperkeratinisation of hair follicles, colonization of anaerobic microbes in the hair follicles, and inflammation. Conventional therapy for acne utilizes antibacterial and anti-inflammatory drugs. Systemic use of these drugs is associated with undesirable toxicities. Hence, topical delivery of anti-acne drugs is desired. However, topical delivery is hindered by poor aqueous solubility of drug and inadequate penetration across stratum corneum. Nanocarriers are endowed with immense potential to facilitate topical delivery of anti-acne drugs as monotherapy or in combination by a myriad of mechanisms including occlusive nature promoting skin hydration, providing sustained drug release thereby decreasing dosing frequency, follicular targeting, and protecting the labile active from degradation. Further, smart nanocarriers can deliver the anti-acne cargo in response to some stimulus present at the disease site precluding undesirable effects at non target sites. Nanocarriers have also been explored in photothermal and photodynamic therapy of acne for destruction of antibiotic resistant bacteria implicated in acne. This review focuses on the potential of a variety of nanocarriers for treatment of acne., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Floating gastro-retentive delivery systems can prolong the gastric residence providing sustained drug release. In this study, we report on self-inflating effervescence-based electrospun nanofiber membranes embedding polyethylene oxide/sodium bicarbonate cast films. In this system, sodium bicarbonate results in an effervescence effect by creating carbon dioxide gas upon contacting an acidic gastric fluid, with the resulting gas bubbles being entrapped within the swollen network of nanofibers. Eudragit RL and RS polymers are utilized as a host material to manipulate release kinetics of incorporated drugs. Pramipexole, a common medication for chronic Parkinson's disease (PD), is used as a model drug. Uniform and bead-free nanofibers with diameters of ~300 nm were obtained. Although floating nanofibers initially exhibited high water contact angles (WCA), water droplets were quickly absorbed into the surface and the WCA decreased to ~0° within 60 s. Floating lag time, total floating time, swelling properties and drug release profiles were investigated both in a simulated gastric fluid (pH 1.2 buffer solution) and in a simulated intestinal fluid (pH 6.8 buffer solution) at 37 °C. All floating nanofiber formulations began to float instantly with nearly zero floating lag time and did not sink into the solution even after 24 h. By comparison, the same formulations without sodium bicarbonate cast films could not maintain continuous floating beyond 15 min. The floating nanofiber pouches presented lower initial release of between 20 and 57 %, compared to that of non-floating nanofiber pouches (40-82% within 2 h). Clearly, floating nanofibers reduced the initial burst release and provided sustained drug release. This demonstrates the potential to result in 'once-a-day' oral introduction of drugs that normally must be taken frequently. Effervescence-based floating nanofibers present a novel and promising prototype delivery system for the drug delivery in the upper gastro-intestinal (GI) tract., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, gastro-retentive porous floating tablets of captopril based on zein are reported using l-menthol as a porogen. Tablets were prepared by the direct compression method. Removing of l-menthol through sublimation process generated pores in tablets, which decreased the density to promote floating over gastric fluid. Prepared tablets showed no floating lag time and prolong total floating time (>24 h). Drug release was found dependent upon porosity of tablets, an increase in porosity of tablets resulted in increased drug release, so it can be tuned by varying concentration of l-menthol. In addition to floating and sustained release properties, porous tablets showed robust mechanical behavior in wet conditions, which can enable them to withstand real gastric environment stress. In vivo studies using New Zealand rabbits also confirmed the prolonged gastric retention (24 h) and plasma drug concentration-time profile showed sustained release of captopril with higher T max and MRT as compared to marketed immediate-release tablets. Overall, it was concluded that effective gastric retention can be achieved using porous zein tablets using l-menthol as a porogen., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

The present study was conducted to harness spray drying technology as a novel method of producing Ciprofloxacin nanocrystals inside liposomes (CNL) for inhalation delivery. Liposomal ciprofloxacin dispersions were spray dried with sucrose as a lyoprotectant in different mass ratios (0.5:1, 1:1 and 2:1 sucrose to lipids), along with 2% w/w magnesium stearate and 5% w/w isoleucine as aerosolization enhancers. Spray drying conditions were: inlet air temperature 50 °C, outlet air temperature 33-35 °C, atomizer rate 742 L/h and aspirator 35 m 3 /h. After spray drying, the formation of ciprofloxacin nanocrystals inside the liposomes was confirmed by cryo- transmission electron microscopy. The physiochemical characteristics of the spray dried powder (particle size, morphology, crystallinity, moisture content, drug encapsulation efficiency (EE), in vitro aerosolization performance and drug release) were determined. The EE of the liposomes was found to vary between 44 and 87% w/w as the sucrose content was increased from 25 to 57% w/w. The powders contained partially crystalline particles with a volume median diameter of ~1 µm. The powders had low water content (~2% wt.) and were stable at high relative humidity. Aerosol delivery using the Osmohaler® inhaler at a flow rate of 100 L/min produced an aerosol fine particle fraction (% wt. <5 µm) of 58-64%. The formulation with the highest sucrose content (2:1 w/w sucrose to lipid) demonstrated extended ciprofloxacin release from liposomes (80% released within 7 h) in comparison to the original liquid formulation (80% released within 2 h). In conclusion, a stable and inhalable CNL powder with controlled drug release was successfully prepared by spray drying., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work is related to a provisional patent for the university of Sydney entitled with “Formation of ciprofloxacin nanocrystals within liposomal vesicles by spray drying for controlled drug release via inhalation” (CDIP Ref. Number IP [2019-024]) created by the originators Prof. Hak-Kim Chan and Ms. Isra Khatib., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Vactosertib is a novel inhibitor of transforming growth factor-β signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The authors had two patents on design and utility of bentonite-based formulation of vactosertib.]., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This work describes the synthesis of calcium zeolites (type A and X) and their use as drug carriers. This is the first example of using calcium zeolites as intelligent carriers that release drugs under the influence of body fluids. Both zeolites and zeolite/drug systems have been extensively characterized. It has been proven that calcium zeolites can be used as carriers of bisphosphonates (drugs against skeletal system diseases). This is due to the fact that phosphonate groups have strong interactions with calcium ions. The sorption of risedronate on zeolites in the sodium form was also carried out, but it was ineffective. The lack of effectiveness of sorption on the sodium zeolites confirms the theoretical assumptions presented in this work. Sorption occurred faster on type A zeolites while the release is faster for type X zeolites. Loading capacity (LC%) were at least 10% for both zeolite forms. The release may take over 100 h depending on the form of zeolite which will be used. The obtained materials have great potential as a drug carrier in enteric-coated tablets as well as an element of implants allowing for controlled drug release., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Skin offers an easily accessible and convenient site for the administration of drugs. Therefore, the development of injectable formulations with controlled drug release properties are now expected to deliver middle- and large-size biomolecules. In the present study, formulations mainly composed of a novel polyol ester with an isoprenoid side chain; mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE), that was capable of forming a non-lamellar liquid crystal (NLLC), were prepared with different types of phospholipid. Then, factors that affected the release of a model entrapped drug, fluorescein-isothiocyanate dextran (FD-4, M.W. 4,000), from the MGE formulations were analyzed with multi-regression analysis. In addition, self-assembly of the NLLC structure was investigated using small-angle X-ray scattering analysis after contacting the MGE formulations with water. NLLC-forming ability of the formulations after s.c. injection into rats was also confirmed using microscopic observations. FD-4 concentrations in blood were determined after s.c. injection of the MGE formulations. The injectable MGE formulations successfully constructed NLLC structures to form a sponge-like gel after contact with water in vitro and in vivo (in rats) as well. In in vitro conditions, the amount of FD-4 released from the formulations was altered by changing the type and concentration of phospholipid in the MGE formulations and can be expressed with parameters such as MGE content and interplanar spacing of the NLLC. A significantly sustained FD-4 level in the blood was observed after s.c. injection of the formulations. These results suggested that injectable MGE formulations may have the potential to achieve controlled release profiles of drugs after s.c. injection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Cocrystallization of chlorbipram (ChBP), a novel phosphodiesterase-4 (PDE) inhibitor with water insoluble property developed in our lab, was performed to improve the physicochemical properties and bioavailability in the present study. Three new cocrystals with fumaric aicd (FA), gentisic acid (GA) and salicylic acid (SA) as coformers were synthesized and fully characterized by using the combination of multi-techniques. The cocrystals are phase stable even under high humidity conditions. In vitro study indicates that the solubility of ChBP-GA and ChBP-SA cocrystals increase to 3724.4 ± 58.7, 2897.4 ± 81.9 μg/mL in comparison with ChBP (2561.3 ± 150.4 μg/mL), the intrinsic dissolution rates (IDRs) of ChBP-GA and ChBP-SA cocrystals (721.3 ± 8.0, 614.4 ± 13.2 μg/min/cm 2 ) are both higher than ChBP (537.9 ± 12.0 μg/min/cm 2 ). The blood concentration peak values of ChBP-GA and ChBP-SA cocrystals (165.8 ± 50.9, 105.3 ± 35.6 ng/mL) are both higher than ChBP (51.3 ± 15.1 ng/mL) in in vivo evaluation. It presents the same order in in vitro/vivo study: ChBP-GA > ChBP-SA > ChBP > ChBP-FA. ChBP-FA cocrystal presents a longer elimination half life (t 1/2  = 10.0 ± 2.6 h), which makes it a potential candidate for prolonged controlled release formulation. ChBP-GA and ChBP-SA cocrystals both present enhanced solubility and bioavailability in comparison with ChBP, making them a better candidate for the solid dosage formulation development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The objective of this study was to develop a thermoresponsive injectable hydrogel for the sustained release of drugs by taking advantage of host-guest interactions between a hydrophobically modified hydroxypropylmethyl cellulose (HM-HPMC) and cyclodextrin (CD). A thermoresponsive injectable hydrogel was prepared by simply adding CDs to HM-HPMC hydrogel. The HM-HPMC hydrogel was converted into a sol with a low viscosity through host-guest interactions with CDs. The HM-HPMC/β-CD hydrogel became a gel near body temperature where the host dissociated from the hydrophobic moieties of the polymer in response to the temperature. The yield stress of the HM-HPMC became progressively lower on the addition of β-CD which was desirable in the case of developing an injectable formulation. When the HM-HPMC/β-CD hydrogel containing indocyanine green (ICG) was subcutaneously administered to mice, the fluorescence of the ICG remained relatively constant for 24 h after the administration, which was substantially longer than that for ICG alone or an HPMC formulation. The plasma insulin level was maintained for a longer period of time when the HM-HPMC/β-CD containing insulin was administered and the MRT value was increased by 1.6 times compared to a solution of insulin alone. In addition, the HM-HPMC/β-CD hydrogel formulation showed a prolonged hypoglycemic effect in response to the insulin which was slowly released from the hydrogel. A thermoresponsive injectable hydrogel was successfully constructed from the highly viscous HM-HPMC and β-CD, and the resulting formulation functioned as a sustained release carrier for drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. The results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the dissolution environment and PEO molecular weight., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Poloxamer 407 (P407)-based nanoparticles were produced by the high pressure homogenization method for the encapsulation and delivery of methotrexate (MTX), aiming intravenous therapeutic applications. The surface of these nanoparticles was functionalized by conjugation of P407 with folic acid (FA) or with MTX, which served as targeting ligand agents. MTX-P407 conjugate was also developed to increase the final drug cargo. Two hydrophobic derivatives of MTX, MTX di-ethylated ester (MTX-OEt) and the ionic complex MTX-dimethyldioctadecylammonium bromide (MTX-DODAB) were produced and entrapped onto P407-based nanoparticles. All formulations developed revealed a monodisperse character comprising small and narrow nanoparticles (<100 nm). P407 nanoparticles (functionalized with FA) and MTX-P407 nanoparticles, both loaded with MTX-OEt, demonstrated a slow drug release profile. The effect of lipase from Aspergillus oryzae on the hydrolysis of the linkage between the P407 and MTX, and consequent MTX release profile, was also evaluated. We observed a controlled and slow release of MTX (<50% of release after 11 days) in the presence of enzyme. These MTX-P407 nanoparticles loaded with MTX-OEt induced a great effect against Caco-2 cancer cells (≈40% of cell death after 72 h of incubation), demonstrating higher efficiency than the free MTX at the same concentration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pseudoephedrine (PSE) extracted from its dosage forms can be used as the starting material to prepare methamphetamine by drug abusers. Recently, some pseudoephedrine drug products marketed under the over the counter (OTC) monograph have been promoted as 'meth-deterrent'. The goal of this investigation was to evaluate the extraction and dissolution of these product against controls of non-meth-deterrent products of pseudoephedrine. Immediate release (IR) PSE OTC Product-C, Product-D and Product-E with meth-deterrent claim on their packaging were selected for this study. Accordingly, OTC IR PSE tablet Product-A and OTC extended release (ER) PSE tablet Product-B, with no meth-deterrent claims, were used as controls. The extraction studies were performed on intact tablets or capsules and on manipulated products employing water, ethanol and 0.l N HCl as solvents. The extraction studies were also performed in water at elevated temperatures by heating the water in an oven and in a microwave. The dissolution studies were performed in water and 0.1 N HCl. The amount of PSE extracted from Product-C was found similar to the amount extracted from the non-meth-deterrent control Product-A. The amount of PSE extracted from Product-D and Product-E was found lower than the amount extracted from control Product-A under the conditions studied. Product-A, Product-B, and Product-C met their respective dissolution acceptance criteria. The IR Products D and E released less than 50% drug in 12 h and did not meet either IR or ER PSE tablet USP dissolution acceptance criteria. In summary, the extraction of Product-C was found to be high (approximately 85% in 30 min) and was similar in extraction to the control Product-A. The extraction of Product-D and Product-E was found less than the extraction of control Product-A. Also, Product-D and Product-E did not exhibit complete drug release. This study showed that PSE can be extracted from Product D and Product E., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

During the pharmaceutical development of pregabalin extended-release tablets, an unknown degradant at a relative retention time (RRT) of 11.7 was observed and its nominal amount exceeded the ICH identification threshold in an accelerated stability study. The aim of this study is to identify the structure and investigate the formation mechanism of this impurity for the purpose of developing a chemically stable pharmaceutical product. By utilizing multi-stage LC-MS analysis in conjunction with mechanism-based stress study, the structure of the RRT 11.7 impurity was rapidly identified as a dimeric degradant that is caused by dimerization of two pregabalin molecules with a methylene bridging the two pregabalin moieties. The structure of the dimer was confirmed by 1D and 2D NMR measurement. The formation pathway of the dimeric degradant was also inferred from the mechanism-based stress study, which implicated that the bridging methylene could originate from formaldehyde which might be the culprit that triggers the dimerization in the first place. The subsequent API-excipients compatibility study indicated that the degradant was indeed formed in the compatibility experiments between pregabalin API and two polymeric excipients (PEO and PVPP) that are known to contain residual formaldehyde, but only in the co-presence of another excipient, colloidal silicon dioxide (SiO 2 ). The kinetic behavior of the degradant formation was also investigated and two kinetic models were utilized based on the Arrhenius and Eyring equations, respectively, to calculate the activation energy (E a ) as well as the enthalpy of activation (△H ‡ ), entropy of activation (△S ‡ ), and Gibbs free energy (△G ‡ ) of the degradation reaction. The results of this study would be useful for the understanding of similar dimeric degradant formation in finished products of drug substances containing primary or secondary amine moieties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study aimed to develop a bilayer gastroretentive (GR) tablet containing an insoluble drug and ascertain the potential of using hydrophobic polymers in GR matrix systems. Highly porous tablets were prepared using a camphor-based sublimation technique. After the screening of several commonly used polymers, two types of GR layers, a conventional hydrophilic GR layer and a hydrophobic GR layer, were designed. The optimal drug layer comprising Metolose® 90SH-100SR and dicalcium phosphate provided not only a gradual matrix erosion but also high strength after hydration. Regarding the GR layers, the hydrophobic layer based on Kollidon® SR was superior to the hydrophilic layer made of PEO 7 M in terms of wet strength, implying a higher resistance to mechanical stresses upon water absorption. Also, the excellent tableting properties of Kollidon® SR and the effects of curing in improving its matrix hardness resulted in porous tablets with better mechanical strength. Moreover, good flowability and low cohesion of Kollidon® SR formulation were advantageous in direct compression. In conclusion, novel bilayer GR tablets were successfully developed, indicating the potential for widening the application of GR systems to insoluble drugs. The results also suggested numerous advantages of incorporating Kollidon® SR into the production of GR tablets., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The potential for zero-order drug-release was evaluated for ethyl cellulose (EC) coated, acetaminophen-layered sugar pellets (Suglets®) of mesh size 18/20 (850-1000 μm). To determine optimal plasticizer/pore-former concentrations for EC films, solvent-cast Aquacoat® ECD (ethyl cellulose dispersion) films were prepared with 0-50% w/w ratios of two triethyl citrate (TEC) or triacetin (TA). Characterization studies showed that films with excipient concentrations ≥20% were homogenous, mechanically strong at room temperature (Young's modulus of 25-35 MPa), and have a glass transition (T g ) in the range of 20-45 °C. Based on these results, a working range of 20-50% weight concentrations was selected for drug release studies. Suglets® were layered with acetaminophen (APAP) using Wurster Glatt GPCG-3 to yield roughly 10% w/w coating (controls). The Controls were coated using the same Wurster process with Aquacoat® ECD containing 20-50% w/w of TEC or TA. Samples were removed periodically at 3-11% weight gain, to evaluate impact of weight gain, and consequently film-formation, on drug release. Dissolution was monitored over a period of 12 h in a media consisting of simulated gastric fluid (first two hours), followed by simulated intestinal fluid. The controls showed near 100% release within the first 30 min, indicating the value of EC-coating to achieve controlled release. Dissolution release profiles showed that TEC is more effective than TA as a plasticizer and pore-former, as linear profiles were apparent at lower concentrations and % weight gain. For a quantitative evaluation of these results, linear regression was fitted to all cumulative release profiles, and R-squared values examined as a function of excipient concentration and % weight gain. The corresponding response surface plots and the second order regression were shown to aid in optimization. The design space for zero-order release was represented as contour plots between excipient concentration and % weight gain., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Herein, a series of new amino acid-functionalized hollow mesoporous silica nanospheres (HMSNs) by post-grafting methods were prepared. These new materials were characterized by different techniques and were studied as matrices for the antineoplastic drug (cisplatin) transport and delivery. The results demonstrate that the surface functionalization of the carriers has a remarkable positive influence on the loading efficiency and release rate of cisplatin. The highest drug entrapment efficiency and the most optimal release properties were observed when the (2-(butylamino) ethyl) glycine groups are grafted on the HMSNs surface (AFS-2-HMSNs sample). Moreover, the in vitro cytotoxic effect of both empty and cisplatin-loaded AFS-2-HMSNs sample (CDDP@AFS-2-HMSNs) on MCF-7 cells (human breast adenocarcinoma cell line) and HepG2 cells (human liver carcinoma cell line) were evaluated by MTT assay. The most important outcome is that the empty carrier revealed no cytotoxicity to cancer cells. However, CDDP@AFS-2-HMSNs caused a notable inhibition of cell viability which was affected from the dose and time. Our results demonstrate that the synthesized materials could be used as carriers for drug delivery with controlled release applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)