A 3D printed microneedle system for transdermal drug delivery of anticancer drugs

Background: Transdermal delivery of drugs is an attractive alternative to the conventional route of administration as oral delivery. The hypodermic injections are painful and less patient compliance. Microneedles (MNs) are micron-sized, minimally invasive needles to deliver a wide range of molecules (e.g., small, DNA, vaccines etc.) to the upper portion of the dermis in a sustained and controlled manner, without causing any pain. The introduction of 3D printing technologies in the fabrication of MN will promote one-step manufacturing tools and scale-up for the delivery devices of anticancer drugs. Methods: The 3D printed MN (3DMN) arrays were fabricated using Stereolithography (SLA), a photopolymerization-based technology, using a biocompatible Class I resin. The printed MN arrays were characterized using Scanning Electron Microscopy (SEM) and the coating was evaluated through Fluorescence Microscopy (FM). The penetration efficiency of 3DMN was investigated through the Optical Coherence Tomography (OCT) into the skin in vitro. The delivery efficiencies of MN arrays to release anticancer drugs in vitro were investigated using Franz diffusion cells and vivo animal studies were carried out to determine the delivery of anticancer drugs and tumour regression effect in mice. Results: 3DMN arrays were successfully fabricated using SLA technology and the dimensions were reproducible. OCT studies have shown more than 80% penetration capability. In vitro and in vivo studies demonstrated the rapid transdermal delivery of anticancer drugs and regression of tumours in mice. Conclusions: These 3DMNs may prove to be of great assistance for the delivery of anticancer drugs in near future in a painless, precise and accurate manner

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 60min. Conclusions: 3D printing was used successfully to process drug loaded filaments for the development of paediatric printed tablets in the form of Starmix designs

3D printed chitosan dressing crosslinked with genipin for potential healing of chronic wounds

Recently, various additive manufacturing (3D printing) approaches have been employed to fabricate dressings such as film scaffolds that possess well defined architecture and orientation at the micro level. In this study, crosslinked chitosan (CH) based film matrices were prepared using 3D printing with genipin (GE) as a crosslinker, with glycerol (GLY) and poly ethylene glycol (PEG) as plasticizer. The 3D printed films were functionally characterized using (tensile, fluid handling, mucoadhesion, drug dissolution, morphological properties and cell viability as well physico-chemical characterization using scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. CH-GE-PEG600 3D printed films having the ratio of 1:1 polymer: plasticizer was selected due to their appropriate flexibility. Fourier transform infrared results showed intermolecular interaction between CH, GE and PEG which was confirmed by X-ray diffraction showing amorphous matrix structure. In vitro mucoadhesion studies of CH-GE-PEG600 films showed the capability of the 3D printed film to adhere to the epithelial surface. Scanning electron microscopy images showed that the surface of the plasticised films were smooth indicating content uniformity of CH, GE and PEG whilst micro cracks in unplasticised films confirmed their brittle nature. Plasticised films also showed high swelling capacity which enhanced water absorption. Cytotoxicity (MTT) assay using human skin fibroblast cell lines demonstrated that more than 90% of cells were viable after 48 h confirming non-toxic nature of the 3D printed CH-GE-PEG600 films and therefore promising dressing for chronic wound healing applications

Inkjet printing of insulin microneedles for transdermal delivery

Inkjet printing technology was used to apply insulin polymeric layers on metal microneedles for transdermal delivery. A range of various polymers such as gelatin (GLN), polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol (SOL), poly(2-ethyl-2-oxazoline) (POX) and trehalose (THL) were assessed for their capacity to form thin uniform and homogeneous layers that preserve insulin intact. Atomic force microscopy (AFM) showed homogeneous insulin–polymer layers without any phase separation while SOL demonstrated the best performance. Circular discroism (CD) analysis of rehydrated films showed that insulin’s alpha helices and β–sheet were well preserved for THL and SOL. In contrast, GLN and POX insulin layers revealed small band shifts indicating possible conformational changes. Insulin release in Franz diffusion cells from MNs inserted into porcine skin showed rapid release rates for POX and GLN within the first 20 min. Inkjet printing was proved an effective approach for transdermal delivery of insulin in solid state

A review of hot-melt extrusion: process technology to pharmaceutical products [Review article]

Over the last three decades industrial adaptability has allowed hot-melt extrusion (HME) to gain wide acceptance and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. HME has already been demonstrated as a robust, novel technique to make solid dispersions in order to provide time controlled, modified, extended, and targeted drug delivery resulting in improved bioavailability as well as taste masking of bitter active pharmaceutical ingredients (APIs). This paper reviews the innumerable benefits of HME, based on a holistic perspective of the equipment, processing technologies to the materials, novel formulation design and developments, and its varied applications in oral drug delivery systems

Solid state thermomechanical engineering of high-quality pharmaceutical salts via solvent free continuous processing

Thermomechanical engineering of pharmaceutical salts in the solid state using continuous extrusion processing (ssTME) is a new novel manufacturing approach. In the present work, we introduce a paradigm for the synthesis of ketoconazole - oxalic acid and ciprofloxacin – maleic acid salts by imparting temperature, shear rate and stress in comparison to liquid assisted grinding (LAG) approach. We demonstrated that thermomechanical synthesis is advantageous by producing high quality and pure, solvent-free pharmaceutical salts by tailoring extrusion processing variables

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 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 characterisation showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, the in line NIR studies revealed a possible intermolecular H–bonding formation between the drug and carrier resulting in the increase of dissolution of TLT. The capsules containing TLT extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben® product

A quality by design (QbD) twin—screw extrusion wet granulation approach for processing water insoluble drugs

In this study, a Quality by Design (QbD) approach was used to identify the effect of formulation parameters in a twin screw wet extrusion granulation process for the manufacturing of ibuprofen (IBU) granules with increased dissolution rates. A fractional factorial Design of Experiment (DoE) was used to investigate the effect of the excipient composition, binder amount and liquid to solid (L/S) ratio (independent variables) on drug dissolution rates, median particle size diameter and specific surface area (dependent variables). The intra-granular addition of the binder in inorganic/polymer blends processed with ethanol as granulating liquids facilitated the formation of granules at various particle sizes. DoE regression analysis showed that all formulation parameters affect the dependent variables significantly. The enhanced dissolution rates were attributed not only to the IBU particle size reduction and adsorption in the porous inorganic network but also to the high specific surface area of the produced granules. Dynamic vapour sorption showed increased water absorption for granules with small particle size distribution and high specific surface area

Taste masked thin films printed by jet dispensing

Taste masking of bitter active substances is an emerging area in the pharmaceutical industry especially for paediatric/geriatric medications. In this study we introduce the use of jet – dispensing as a taste masking technology by printing mucosal thin films of three model bitter substances, Cetirizine HCl, Diphenylhydramine HCl and Ibuprofen. The process was used to dispense aqueous drugs/polymer solutions at very high speed where eventually the drugs were embedded in the polymer matrix. The in vivo evaluation of jet – dispensed mucosal films showed excellent taste masking for drug loadings from 20 - 40%. Jet dispensing was proved to make uniform, accurate and reproducible thin films with excellent content uniformity