3D Printed Flavor-Rich Chewable Pediatric Tablets Fabricated Using Microextrusion for Point of Care Applications.

Over the past few years, 3D printing technologies have gained interest in the development of medicinal products for personalized use at the point of care. The printing of drug products offers personalization and flexibility in dose, shape/design, and flavor, potentially enhancing acceptability in pediatric populations. In this study, we present the design and development of ibuprofen (IBU) chewable flavor-rich personalized dosage forms by using microextrusion for the processing of powdered blends. The optimization processing parameters such as applied pneumatic pressure and temperature resulted in high quality printable tablets of various designs with a glossy appearance. Physicochemical characterization of the printed dosages revealed that IBU was molecularly dispersed in the methacrylate polymer matrix and the formation of H bonding. A panelist's study demonstrated excellent taste masking and aroma evaluation when using strawberry and orange flavors. Dissolution studies showed very fast IBU dissolution rates of more than 80% within the first 10 min in acidic media. Microextrusion is a 3D printing technology that can be effectively used to generate pediatric patient centric dosage forms at the point of care.

Comparative taste-masking evaluation of microencapsulated bitter drugs using Smartseal 30D and ReadyMix for paediatric dosage forms.

The taste of drug substances plays a key role in the development of paediatric formulations with suitable organoleptic properties. The aim of the study was to evaluate the taste masking effectiveness of Smartseal 30D and ReadyMix on a range of bitter drug substances such as diphenhydramine HCl (DPD), ibuprofen lysine (IBU-LS), and phenylephrine HCl (PPH) for the development of paediatric dosage forms. The drugs were microencapsulated in the polymer carriers at 10-20% loadings using spray-drying processing. Spray drying of drug formulations was optimized in terms of percent yield and encapsulation efficiency followed by physicochemical characterization in order to identify the drugs' physical state in the polymer microparticles. The in vivo taste masking efficiency was evaluated using human test panel and showed noticeable reduction of drug's bitterness at all loadings in comparison to the bulk substances.

Drug-Smectite Clay Amorphous Solid Dispersions Processed by Hot Melt Extrusion.

The aim of this study was to introduce smectite clay matrices as a drug delivery carrier for the development of amorphous solid dispersions (ASD). Indomethacin (IND) was processed with two different smectite clays, magnesium aluminium and lithium magnesium sodium silicates, using hot melt extrusion (HME) to prepare solid dispersions. Scanning electron microscopy (SEM), powdered X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) were used to examine the physical form of the drug. Energy-dispersive X-ray (EDX) spectroscopy was used to investigate the drug distribution, and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopic analysis was done to detect any chemical interaction between these two kinds. Both PXRD and DSC analyses showed that drug-clay solid dispersion contained IND in amorphous form. EDX analysis showed a uniform IND dispersion in the extruded powders. ATR-FTIR data presented possible drug and clay interactions via hydrogen bonding. In vitro drug dissolution studies revealed a lag time of about 2 h in the acidic media and a rapid release of IND at pH 7.4. The work demonstrates that preparation of amorphous solid dispersion using inorganic smectite clay particles can effectively increase the dissolution rate of IND.

3D Printed "Starmix" Drug Loaded Dosage Forms for Paediatric Applications.

PURPOSE: Three- dimensional (3D) printing has received significant attention as a manufacturing process for pharmaceutical dosage forms. In this study, we used Fusion Deposition Modelling (FDM) in order to print "candy - like" formulations by imitating Starmix® sweets to prepare paediatric medicines with enhanced palatability. METHODS: Hot melt extrusion processing (HME) was coupled with FDM to prepare extruded filaments of indomethacin (IND), hypromellose acetate succinate (HPMCAS) and polyethylene glycol (PEG) formulations and subsequently feed them in the 3D printer. The shapes of the Starmix® objects were printed in the form of a heart, ring, bottle, ring, bear and lion. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infra-red Spectroscopy (FT-IR) and confocal Raman analysis were used to assess the drug - excipient interactions and the content uniformity. RESULTS: Physicochemical analysis showed the presence of molecularly dispersed IND in the printed tablets. In vivo taste masking evaluation demonstrated excellent masking of the drug bitterness. The printed forms were evaluated for drug dissolution and showed immediate IND release independently of the printed shape, within 60 min. CONCLUSIONS: 3D printing was used successfully to process drug loaded filaments for the development of paediatric printed tablets in the form of Starmix® designs.

Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients.

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben® product.

Development and Biological Evaluation of Inkjet Printed Drug Coatings on Intravascular Stent.

Inkjet-printing technology was used to apply biodegradable and biocompatible polymeric coatings of poly(d,l-lactide) with the antiproliferative drugs simvastatin (SMV) and paclitaxel (PCX) on coronary metal stents. A piezoelectric dispenser applied coating patterns of very fine droplets (300 pL) and inkjet printing was optimized to develop uniform, accurate and reproducible coatings of high yields on the stent strut. The drug loaded polymeric coatings were assed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and transition thermal microscopy (TTM) where a phase separation was observed for SMV/PLA layers while PCX showed a uniform distribution within the polymer layers. Cytocompatibility studies of PLA coatings showed excellent cell adhesion with no decrease of cell viability and proliferation. In vivo stent implantation studies showed significant intrastent restenosis (ISR) for PCX/PLA and PLA plain coatings similar to marketed Presillion (bare metal) and Cypher (drug eluting) stents. The investigation of several cytokine levels after 7 days of stent deployment showed no inflammatory response and hence no in vivo cytotoxicity related to PLA coatings. Inkjet printing can be employed as a robust coating technology for the development of drug eluting stents compared to the current conventional approaches.

Current Trends on Medical and Pharmaceutical Applications of Inkjet Printing Technology.

Inkjet printing is an attractive material deposition and patterning technology that has received significant attention in the recent years. It has been exploited for novel applications including high throughput screening, pharmaceutical formulations, medical devices and implants. Moreover, inkjet printing has been implemented in cutting-edge 3D-printing healthcare areas such as tissue engineering and regenerative medicine. Recent inkjet advances enabled 3D printing of artificial cartilage and skin, or cell constructs for transplantation therapies. In the coming years inkjet printing is anticipated to revolutionize personalized medicine and push the innovation portfolio by offering new paths in patient - specific treatments.

Increased dissolution rates of carbamazepine--gluconolactone binary blends processed by hot melt extrusion.

Carbamazepine (CBZ) shows a poor dissolution, therefore, it is important to enhance its dissolution in GI tract to improve its bioavailability. In the present study, a new hydrophilic carrier, d-gluconolactone (GNL), was extruded with CBZ at various molar ratios to produce granules by using hot melt extrusion (HME) processing. The granular extrudates were characterised by X-ray powder diffraction, differential scanning calorimetry and hot stage microscopy to determine the solid state of CBZ. It was found that bulk CBZ (Form-III) transformed to the polymorphic Form-I during the HME processing. GNL was proved to be an efficient carrier for CBZ to enhance the dissolution rate. The increase in the dissolution rate was observed for both physical mixtures and the extrudates of CBZ-GNL. However, the extrudates showed faster dissolution rates compared to physical mixtures in an ascending order of 2:1 < 1:1 < 1.5:1 (CBZ:GNL). The increase in the dissolution rates was attributed to the transformation of CBZ III to Form-I and also to the increased drug wettability/solubilisation in the presence of the carrier.

Novel Controlled Release Polymer-Lipid Formulations Processed by Hot Melt Extrusion.

The aim of the study was to investigate the effect of novel polymer/lipid formulations on the dissolution rates of the water insoluble indomethacin (INM), co-processed by hot melt extrusion (HME). Formulations consisted of the hydrophilic hydroxypropyl methyl cellulose polymer (HPMCAS) and stearoyl macrogol-32 glycerides-Gelucire 50/13 (GLC) were processed with a twin screw extruder to produce solid dispersions. The extrudates characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and hot stage microscopy (HSM) indicated the presence of amorphous INM within the polymer/lipid matrices. In-line monitoring via near-infrared (NIR) spectroscopy revealed significant peak shifts indicating possible interactions and H-bonding formation between the drug and the polymer/lipid carriers. Furthermore, in vitro dissolution studies showed a synergistic effect of the polymer/lipid carrier with 2-h lag time in acidic media followed by enhanced INM dissolution rates at pH > 5.5.

Molecular modeling as a predictive tool for the development of solid dispersions.

In this study molecular modeling is introduced as a novel approach for the development of pharmaceutical solid dispersions. A computational model based on quantum mechanical (QM) calculations was used to predict the miscibility of various drugs in various polymers by predicting the binding strength between the drug and dimeric form of the polymer. The drug/polymer miscibility was also estimated by using traditional approaches such as Van Krevelen/Hoftyzer and Bagley solubility parameters or Flory-Huggins interaction parameter in comparison to the molecular modeling approach. The molecular modeling studies predicted successfully the drug-polymer binding energies and the preferable site of interaction between the functional groups. The drug-polymer miscibility and the physical state of bulk materials, physical mixtures, and solid dispersions were determined by thermal analysis (DSC/MTDSC) and X-ray diffraction. The produced solid dispersions were analyzed by X-ray photoelectron spectroscopy (XPS), which confirmed not only the exact type of the intermolecular interactions between the drug-polymer functional groups but also the binding strength by estimating the N coefficient values. The findings demonstrate that QM-based molecular modeling is a powerful tool to predict the strength and type of intermolecular interactions in a range of drug/polymeric systems for the development of solid dispersions.

A review on the taste masking of bitter APIs: hot-melt extrusion (HME) evaluation.

The majority of active pharmaceutical ingredients (APIs) found in oral dosage forms have a bitter taste. Masking the unpleasant taste of bitter, APIs is a major challenge in the development of such oral dosage forms. Taste assessment is an important quality-control parameter for evaluating taste-masked formulations of any new molecular entity. Hot-melt extrusion (HME) techniques, have very recently, been accepted from an industrial compliance viewpoint in relation to both manufacturing operations and development of pharmaceuticals. HME achieves taste masking of bitter APIs via various mechanisms such as the formation of solid dispersions and inter-molecular interactions and this has led to its wide-spread use in pharmaceutical formulation research. In this article, the uses of various taste evaluation methods and HME as continuous processing techniques for taste masking of bitter APIs used for the oral delivery of drugs are reviewed.

Personalised oral dosage forms using an ultra-compact tablet press at the point of care.

Over the last 10 years there is an increasing need for the design of personalised medicines at the point of care (PoC) that meet the specific needs of individual patients. A plethora of technologies has been introduced for making affordable personalised pharmaceutical products, which however, do not address manufacturing and regulatory challenges. Here we introduce a novel ultra-compact tablet press which was used for the design and compression of rosuvastatin-aspirin and amiloride-lysonipril bilayer tablets respectively. By applying precision dosing, it was feasible to manufacture tablets of different dose strengths and control features such as hardness, friability and disintegration times. The compaction of on-demand personalised multidrug pills that meet quality standards could revolutionised the treatment of patients at the point of care.

Exosome-like genistein-loaded nanoparticles developed by thin-film hydration and 3D-printed Tesla microfluidic chip: A comparative study.

Exosomes are naturally derived information carriers that present interest as drug delivery systems. However, their vague cargo and isolation difficulties hinder their use in clinical practice. To overcome these limitations, we developed exosome-like nanoparticles, consisted of the main lipids of exosomes, using two distinct methods: thin-film hydration and 3D-printed microfluidics. Our novel microfluidic device, fabricated through digital light processing printing, demonstrated a favorable architecture to produce exosome-like nanoparticles. We compared these two techniques by analyzing the physicochemical characteristics (size, size distribution, and ζ-potential) of both unloaded and genistein-loaded exosome-like nanoparticles, using dynamic and electrophoretic light scattering. Our findings revealed that the presence of small lipophilic molecules, cholesterol and/or genistein, influenced the characteristics of the final formulations differently based on the development approach. Regardless of the initial differences of the formulations, all exosome-like nanoparticles, whether loaded with genistein or not, exhibited remarkable colloidal stability over time. Furthermore, an encapsulation efficiency of over 87% for genistein was achieved in all cases. Additionally, thermal analysis uncovered the presence of metastable phases within the membranes, which could impact the drug delivery efficiency. In summary, this study provides a comprehensive comparison between conventional and innovative methods for producing complex liposomal nanosystems, exemplified by exosome-like nanoparticles.

In Vitro Profile of Hydrocortisone Release from Three-Dimensionally Printed Paediatric Mini-Tablets.

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone (HCT) mini-tablets for paediatric patients. For the developed formulations, Gelucire® 44/14 and Precirol® ATO 5 were used as the main inks at three different ratios: 70%/30%, 60%/40% and 50%/50%, respectively. The printing parameters (temperature and pressure) were altered accordingly for each ratio to achieve printability. The printed mini-tablets exhibited excellent printing quality, featuring consistent layer thicknesses and smooth surfaces. Dissolution tests were performed, and the results indicated a successful modified release of HCT from the mini-tablets. In summary, micro-extrusion exhibited favourable processing abilities for powder blends, facilitating quick printing and the fabrication of potential personalized dosages.

Mesoporous silica nanoparticles in nanotechnology.

Mesoporous silica nanoparticles (MSNs) are a versatile drug delivery system that can be used for loading of different guest molecules such as peptides, proteins, anticancer agents, and genetic material. MSNs are considered promising drug carriers due to their tuneable particle size, pore structure, and surface functionalization. Thus, MSNs provide opportunities for their effective application in a wide variety of fields. In the current review, we discuss both conventional and advanced MSNs synthesis methods, including their applications for drug delivery, gatekeepers, and biosensors. In addition, the research progress in biocompatibility, cytotoxicity, and internalization mechanisms is reported.

Sirolimus encapsulated liposomes for cancer therapy: physicochemical and mechanical characterization of sirolimus distribution within liposome bilayers.

Sirolimus has recently been introduced as a therapeutic agent for breast and prostate cancer. In the current study, conventional and Stealth liposomes were used as carriers for the encapsulation of sirolimus. The physicochemical characteristics of the sirolimus liposome nanoparticles were investigated including the particle size, zeta potential, stability and membrane integrity. In addition atomic force microscopy was used to study the morphology, surface roughness and mechanical properties such as elastic modulus deformation and deformation. Sirolimus encapsulation in Stealth liposomes showed a high degree of deformation and lower packing density especially for dipalmitoyl-phosphatidylcholine (DPPC) Stealth liposomes compared to unloaded. Similar results were obtained by differential scanning calorimetry (DSC) studies; sirolimus loaded liposomes were found to result in a distorted state of the bilayer. X-ray photon electron (XPS) analysis revealed a uniform distribution of sirolimus in multilamellar DPPC Stealth liposomes compared to a nonuniform, greater outer layer lamellar distribution in distearoylphosphatidylcholine (DSPC) Stealth liposomes.

In vivo evaluation of nanostructured lipid carrier systems (NLCs) in mice bearing prostate cancer tumours.

Nanostructure lipid carriers (NLCs) were developed for the delivery of curmumin (CRN), a potent anticancer agent with low bioavailability, for the treatment of prostate cancer. NLCs prepared using high pressure homogenization (HPH) with around 150 nm particle size, - 40 V ζ-potential and excellent long-term stability. Cellular uptake of CRN-SLN showed nanoparticle localization in the cytoplasm around the nucleus. CRN-NLCs were assessed using flow cytometry and found to cause early and late apoptotic events at 100 µg/ml CRN concentrations. CRN-NLC nanoparticles were administrated to nude mice with LNCaP prostate cancer xenografts and demonstrated substantial tumour volume suppression (40%) with no weight loss compared to pure CRN (ethanolic solution). Overall, NLCs were proved a suitable carrier for passive drug delivery and cancer treatment.

3D printing of LEGO® like designs with tailored release profiles for treatment of sleep disorder.

3D printed LEGO®-like designs are an attractive approach for the development of compartmental delivery systems due to their potential for dose personalisation through the customisation of drug release profiles. Additive manufacturing technologies such as Fused Deposition Modelling (FDM) are ideal for the printing of structures with complex geometries and various sizes. This study is a paradigm for the fabrication of 3D printed LEGO® -like tablets by altering the design of the modular units and the filament composition for the delivery of different drug substances. By using a combination of placebo and drug loaded compartments comprising of immediate release (hydroxypropyl cellulose) and pH dependant polymers (hypromellose acetate succinate) we were able to customise the release kinetics of melatonin and caffeine that can potentially be used for the treatment of sleep disorders. The LEGO® -like compartments were designed to achieve immediate release of melatonin followed by variable lag times and controlled release of caffeine.

Three-Dimensionally Printed Vaginal Rings: Perceptions of Women and Gynecologists in a Cross-Sectional Survey.

Three-dimensional printing technologies can be implemented for the fabrication of personalized vaginal rings (VRs) as an alternative approach to traditional manufacturing. Although several studies have demonstrated the potential of additive manufacturing, there is a lack of knowledge concerning the opinions of patients and clinicians. This study aimed to investigate the perception of women and gynecologists regarding VRs with personalized shapes. The devices were printed with different designs (traditional, "Y", "M", and flat circle) by Fused Deposition Modeling for a cross-sectional survey with 155 participants. Their anticipated opinion was assessed through a questionnaire after a visual/tactile analysis of the VRs. The findings revealed that most women would feel comfortable using some of the 3D-printed VR designs and demonstrated good acceptability for the traditional and two innovative designs. However, women presented multiple preferences when the actual geometry was assessed, which directly related to their age, previous use of the vaginal route, and perception of comfort. In turn, gynecologists favored prescribing traditional and flat circle designs. Overall, although there was a difference in the perception between women and gynecologists, they had a positive opinion of the 3D-printed VRs. Finally, the personalized VRs could lead to an increase in therapeutic adherence, by meeting women's preferences.

3D Printing of Personalised Carvedilol Tablets Using Selective Laser Sintering.

Selective laser sintering (SLS) has drawn attention for the fabrication of three-dimensional oral dosage forms due to the plurality of drug formulations that can be processed. The aim of this work was to employ SLS with a CO2 laser for the manufacturing of carvedilol personalised dosage forms of various strengths. Carvedilol (CVD) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) blends of various ratios were sintered to produce CVD tablets of 3.125, 6.25, and 12.5 mg. The tuning of the SLS processing laser intensity parameter improved printability and impacted the tablet hardness, friability, CVD dissolution rate, and the total amount of drug released. Physicochemical characterization showed the presence of CVD in the amorphous state. X-ray micro-CT analysis demonstrated that the applied CO2 intensity affected the total tablet porosity, which was reduced with increased laser intensity. The study demonstrated that SLS is a suitable technology for the development of personalised medicines that meet the required specifications and patient needs.