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In the recent decade, three-dimensional (3D) printers started to grow strongly in the field of drug delivery and personalized medicine, as they can tailor dosage forms according to the needs of each individual. This review gives an overview on the basic principles of layer-by-layer building of pharmaceutical dosage forms using different types of 3D printers. Also, the effect of infill percentage and pattern, raster orientation, layer thickness, thermal processing parameters on the printed formulations is highlighted. Additionally, the complex designs constructed by the 3D printers in order to modify the product shape, density, mucoadhesion and drug release are recapitulated. This review summarizes numerous applications for 3D printing in building drug-loaded structures including tablets, scaffolds, implants, microneedles, capsules, films, hydrogels, mouthguards, tubes, stents, vaginal suppositories and rings as well as in pediatric field. Finally, we suggest further investigational researches to aid in the widespread of 3D printing in the industrial pharmaceutical field. The 3D printing technology is expected to revolutionize drug delivery systems through customization of pharmaceutical formulations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO 3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing., 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.)

Osteoarthritis is a major problem in elder people. Etoricoxib-loaded bio-adhesive hybridized nanoparticles were prepared using polylactic acid (PLA) and chitosan hydrochloride (CS-HCl) in presence of Captex®200 as a liquid oil, polyvinyl alcohol (PVA) and Tween®80 as surfactants. The study aimed to present a new intra-articular treatment of osteoarthritis with anti-inflammatory as well as bone rebuilding effects. Hybridized nanoparticles were fabricated applying the emulsion solvent evaporation technique then assessed for particle size, zeta potential, entrapment efficiency and in-vitro drug release. Furthermore, FT-IR and DSC in addition to morphological examination were done. Results revealed that the formulation composed of PLA:Captex®200 in ratio 1:2 (w/w), 1%w/v Tween®80, 0.3% w/v CS-HCl and 3%w/v PVA possessed the smallest particle size and the most sustained drug release, thus was sorted for further analyses. The selected formulation ability to interact with the negatively charged sodium fluroscein was evaluated to predict its binding with the naturally occurring hyaluronic acid in the knee joint where promising results were obtained. Results showed the cytocompatibility of the formulation when tested using MC3T3-E1 normal bone cell line, enhanced ALP activity and increased calcium ion deposition and binding. Results suggested that the presented formulation can be considered as an innovative approach for osteoarthritis., 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.)

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries., (Copyright © 2019. Published by Elsevier B.V.)

Mucoadhesive olaminosomes are novel nanocarriers designed to control agomelatine release and enhance its bioavailability. Olaminosomes were prepared using oleic acid, oleylamine and sorbitan monooleate adopting thin film hydration technique. Chitosan HCl was added to impart the mucoadhesive properties to the olaminosomes. Mucoadhesive olaminosomes were characterized for their particle size, in-vitro drug release and irritation potentiality in rabbit eyes. The reduction in intraocular pressure (IOP) through 8 h in male New Zealand Albino rabbits was measured after administration of the selected formulations. Histopathological changes in rabbits' eye were also evaluated. Results revealed that increasing the amount of the added oleylamine decreased the particle size of the resulted vesicles and increased the drug release rate. Olaminosomes showed enhanced drug absorption, hence more reduction in IOP was observed. Moreover, using chitosan HCl might increase the residence time of the formulation in the eye and hence improved the absorption of the drug. No histopathological changes in rabbits' eye were detected after the application of mucoadhesive olaminosomes concluding their safety on the ocular tissues. In conclusion, mucoadhesive olaminosomes succeeded in enhancing agomelatine bioavailability in rabbits' eyes confirming the development of a novel ocular nanocarrier for insoluble drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Periapical lesions are considered one of the common pathological conditions affecting alveolar bone. The primary focus of this study was to investigate the effectiveness of formulating an injectable in-situ forming scaffold-loaded with risedronate (bone resorption inhibitor) and with lornoxicam (anti-inflammatory drug) for the non-surgical treatment of periapical lesions. The scaffolds were prepared using solvent-induced phase inversion technique. Two insoluble copolymers were investigated namely; PLGA (ester-terminal) and PLGA-A (acid-terminal), additionally, SAIB was added as a high viscosity water-insoluble carrier. The addition of porogenic agents like hydrolyzed collagen was also investigated. The prepared scaffolds were characterized by analyzing their in-vitro release, DSC and rheological properties, besides their morphological properties. The results showed that the scaffolds prepared using 30% (w/v) PLGA or combined PLGA: SAIB (1:1, w/w) with total polymer concentration of 30% (w/v) possessed the most sustained drug release profile. Selected scaffolds were tested for their therapeutic effect to study the effect of porogenic agent, anti-inflammatory drug and risedronate in periapical lesions induced in dogs' teeth. Results declared that the selected scaffolds succeeded in improving the inflammation and enhancing the formation of new bony regions confirming the success of the prepared scaffolds as an innovative approach in the treatment of bone defects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Lipotomes were designed to enhance lacidipine's oral bioavailability by improving its solubility and enhancing the oral lymphatic uptake. Lipotomes were prepared using cetyl alcohol and Tween(®) 80 using a thin film hydration technique. Cetyl alcohol was chosen for imparting a lipophilic environment that would enforce the lymphatic uptake while Tween(®) 80 would improve drug solubility within the lipotomes. Lipotomes were characterized by analyzing their particle size, solubilization efficiency and in-vitro drug release. Central composite design was applied to statistically optimize the formulations using Design-Expert(®) software. The optimum formula (OLT) was made up of excipients:drug ratio of 36.59:1 w/w and Tween(®) 80:cetyl alcohol ratio of 4:1 w/w. OLT was lyophilized and filled into Eudragit(®) L100 enteric coated capsules. Mannitol (10% w/v) was the ideal cryoprotectant to retain the physicochemical characteristics of the OLT formulation after lyophilization. In conclusion, the selected lyophilized formula (L3) succeeded in enhancing drug's oral bioavailability in human volunteers compared to the commercial product confirming the success of lipotomes as a novel oral nanocarrier for insoluble drugs having extensive first pass metabolism., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Econazole nitrate (ECO) is a poorly water soluble antifungal drug. Having low aqueous solubility affects negatively its use for ocular treatment. This work aimed to prepare ocular supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) of ECO employing hydroxypropyl methylcellulose as a precipitation inhibitor to improve the drug solubility by avoiding its precipitation after administration. Various oils, surfactants and co-surfactants were used to construct SNEDDS. The SNEDDS were evaluated for globule size, polydispersity index and their irritation potential using hen's egg test-chorioallantoic membrane (HET-CAM). The best SNEDDS was loaded with ECO and HPMC to prepare S-SNEDDS. In-vitro precipitation test of the S-SNEDDS was done to study the effect of the precipitation inhibitor. ECO permeation in rabbits' eyes from the selected S-SNEDDS (with and without HPMC) was evaluated. The results showed that SNEDDS-X consisting of 20% Capmul(®) MCM C10 as an oil, 60% Cremophor RH40(®) as a surfactant and 20% Transcutol(®) HP as co-surfactant possessed the lowest PDI value and a non-irritant effect on the CAM. The in-vitro precipitation test showed that the use of HPMC successfully sustained the supersaturated state by avoiding ECO precipitation. Higher Cmax, AUC0-8 and longer tmax confirm the development of a successful ECO-loaded S-SNEDDS., (Copyright © 2013 Elsevier B.V. All rights reserved.)