Particulate atomisation design methods for the development and engineering of advanced drug delivery systems: A review.

The role and opportunities presented by particulate technologies (due to novel processing methods and advanced materials) have multiplied over the last few decades, leading to promising and ideal properties for drug delivery. For example, the dissolution and bioavailability of poorly soluble drug substances and achieving site- specific drug delivery with a desired release profile are crucial aspects of forming (to some extent) state-of-the-art platforms. Atomisation techniques are intended to achieve efficient control over particle size, improved processing time, improved drug loading efficiency, and the opportunity to encapsulate a broad range of viable yet sensitive therapeutic moieties. Particulate engineering through atomization is accomplished by employing various mechanisms such as air, no air, centrifugal, electrohydrodynamic, acoustic, and supercritical fluid driven processes. These driving forces overcome capillary stresses (e.g., liquid viscosity, surface tension) and transform formulation media (liquid) into fine droplets. More frequently, solvent removal, multiple methods are included to reduce the final size distribution. Nevertheless, a thorough understanding of fluid mechanics, thermodynamics, heat, and mass transfer is imperative to appreciate and predict outputs in real time. More so, in recent years, several advancements have been introduced to improve such processes through complex particle design coupled with quality by-design (QbD) yielding optimal particulate geometry in a predictable manner. Despite these valuable and numerous advancements, atomisation techniques face difficulty scaling up from laboratory scales to manufacturing industry scales. This review details the various atomisation techniques (from design to mechanism) along with examples of drug delivery systems developed. In addition, future perspectives and bottlenecks are provided while highlighting current and selected seminal developments in the field.

Enhancing linezolid activity in the treatment of oral biofilms using novel chitosan microneedles with iontophoretic control.

This study aimed to prepare and assess active microneedle (MN) patches based on a novel biomaterial and their effective coupled (physical and electrical) transdermal delivery of a model drug (Linezoid). Modified MN patches (e.g. fabricated from Linezoid, boronated chitosan, polyvinyl alcohol and D-sorbitol) were engineered using a vacuum micromoulding method. Physicochemical, FTIR (Fourier transform infrared), in-silico, structural and thermal analysis of prepared formulations were conducted to ascertain MN quality, composition and integrity. In-vitro mechanical tests, membrane toxicity, drug release, antibiofilm, ex-vivo mucoadhesion, insertion and in-vivo antibiofilm studies were performed to further validate viability of the coupled system. Optimized MN patch formulation (CSHP3 - comprising of 3 % w/v boronated chitosan, 3.5 % w/v PVA and 10 % w/w D-sorbitol) exhibited sharp-tipped, equi-distant and uniform-surfaced micron-scaled projections with conforming physicochemical features. FTIR analysis confirmed modification (i.e., boronation) of chitosan and compatibility as well as interaction between CSHP3 constituents. In-silico analysis indicated non-covalent interactions between all formulation constituents. Moreover, boronated chitosan-mucin glycoprotein complex showed a stronger bonding (∼1.86 times higher CScore) as compared to linezolid-mucin counterpart. Thermal analysis indicated amorphous nature of CSHP3. A âˆ¼ 1.42 times higher tensile strength was displayed by CSHP3 as compared to control (i.e., pure chitosan, polyvinyl alcohol and D-sorbitol-based MN patch). Membrane toxicity study indicated non-toxic and physiological compatible nature of CSHP3. Within 90 min, 91.99 ± 2.3 % linezolid was released from CSHP3. During release study on agarose gel, CSHP3-iontophoresis treatment resulted in a âˆ¼ 1.78 and âˆ¼ 1.20 times higher methylene blue-covered area and optical density, respectively, within 60 min as compared to CSHP3 treatment alone. Staphylococcus aureus biofilms treated with CSHP3 exhibited 65 ± 4.2 % reduction in their mass. CSHP3 MN patches remained adhered to the rabbit oral mucosa for 6 ± 0.15 h. Mucosa treated with CSHP3 and CSHP3-iontophoresis combination showed a generation of pathways in the epithelium layers without any damage to the underlying lamina propria. Eradication of Staphylococcus aureus from oral mucosal wounds and complete tissue regeneration was recorded following 7-day treatment using CSHP3-iontophoresis coupled approach.

Transcutaneous Delivery of Dexamethasone Sodium Phosphate Via Microneedle-Assisted Iontophoretic Enhancement - A Potential Therapeutic Option for Inflammatory Disorders.

AIM: This study aimed to fabricate dexamethasone sodium phosphate loaded microneedle arrays (MNA) and investigate their efficiency in combination with iontophoresis for the treatment of hind paw oedema in rats. METHODS: Drug loaded polyvinyl alcohol, polyvinyl pyrrolidone and D-sorbitol-based MNA11 were fabricated by vacuum micromolding. Physicochemical, morphological, thermal, in-silico, in-vitro insertion ability (on parafilm) and drug release studies were performed. Ex-vivo permeation, in-vivo insertion and anti-inflammatory studies were performed in combination with iontophoresis. RESULTS: MNA11 displayed sharp-tipped projections and acceptable physicochemical features. Differential scanning calorimetry results indicated that drug loaded MNA11 were amorphous solids. Drug interacted with PVP and PVA predominately via hydrogen bonding. Parafilm displayed conspicuously engraved complementary structure of MNA11. Within 60 min, 91.50 ± 3.1% drug released from MNA11. A significantly higher i.e., 95.06 ± 2.5% permeation of drug was observed rapidly (within 60 min) from MNA11-iontophoresis combination than MNA11 i.e., 84.07 ± 3.5% within 240 min. Rat skin treated using MNA11 and MNA11-iontophoresis showed disruptions / microchannels in the epidermis without any damage to underlying anatomical structures. MNA11-iontophoresis combination led to significant reduction (83.02 ± 3.9%) in paw oedema as compared to MNA11 alone (72.55 ± 4.1%). CONCLUSION: MNA11-iontophoresis combination can act as a promising candidate to deliver drugs transcutaneously for treating inflammatory diseases.

Recent applications of electrical, centrifugal, and pressurised emerging technologies for fibrous structure engineering in drug delivery, regenerative medicine and theranostics.

Advancements in technology and material development in recent years has led to significant breakthroughs in the remit of fiber engineering. Conventional methods such as wet spinning, melt spinning, phase separation and template synthesis have been reported to develop fibrous structures for an array of applications. However, these methods have limitations with respect to processing conditions (e.g. high processing temperatures, shear stresses) and production (e.g. non-continuous fibers). The materials that can be processed using these methods are also limited, deterring their use in practical applications. Producing fibrous structures on a nanometer scale, in sync with the advancements in nanotechnology is another challenge met by these conventional methods. In this review we aim to present a brief overview of conventional methods of fiber fabrication and focus on the emerging fiber engineering techniques namely electrospinning, centrifugal spinning and pressurised gyration. This review will discuss the fundamental principles and factors governing each fabrication method and converge on the applications of the resulting spun fibers; specifically, in the drug delivery remit and in regenerative medicine.

Engineering and characterisation of BCG-loaded polymeric microneedles.

The aim of this study was to fabricate Bacillus Calmette-Guérin (BCG)-loaded microneedle patches using micromould casting technique and compare their efficacy with the injectable counterparts. The microneedle patches were formulated using sodium alginate (10% w/v) and trehalose (20% of polymer). The patches were characterised using optical microscopy, scanning electron microscopy and folding endurance. Serum IgG, TLC, granulocyte count, lymphocyte count and CRP were assessed and results were compared to that of intradermal injections alongside controls. The results showed that polymeric patches had a thickness of 0.8 mm, microneedle projections of 272 ± 12 µm and folding endurance of more than 300. Based on haematological and IgG ELISA assays, microneedle-based BCG administration significantly activated the immune cells and induced production of lymphocytes, granulocytes and peptide-specific IgG in immunised rats that were comparable to injectable counterparts. There was an increase in IgG antibodies from 3 g/L to 5.98 g/L and an increase in leucocytes from 2.6 × 109/L to 18.45 × 109/L. There was also an increase in granulocytes from 14.4% to 29.15% and lymphocyte count from 58.75% to 85.3%. It was concluded that BCG-coated polymeric microneedle patches are suitable for the transdermal delivery of vaccine without inducing discomfort usually observed with injections.

Quality by Design Micro-Engineering Optimisation of NSAID-Loaded Electrospun Fibrous Patches.

The purpose of this study was to apply the Quality by Design (QbD) approach to the electrospinning of fibres loaded with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin (INDO) and diclofenac sodium (DICLO). A Quality Target Product Profile (QTPP) was made, and risk assessments (preliminary hazard analysis) were conducted to identify the impact of material attributes and process parameters on the critical quality attributes (CQAs) of the fibres. A full factorial design of experiments (DoE) of 20 runs was built, which was used to carry out experiments. The following factors were assessed: Drugs, voltage, flow rate, and the distance between the processing needle and collector. Release studies exhibited INDO fibres had greater total release of active drug compared to DICLO fibres. Voltage and distance were found to be the most significant factors of the experiment. Multivariate statistical analytical software helped to build six feasible design spaces and two flexible, universal design spaces for both drugs, at distances of 5 cm and 12.5 cm, along with a flexible control strategy. The current findings and their analysis confirm that QbD is a viable and invaluable tool to enhance product and process understanding of electrospinning for the assurance of high-quality fibres.

Improved transdermal delivery of cetirizine hydrochloride using polymeric microneedles.

PURPOSE: The aim of this study was to design and characterize microneedle patch formulation containing cetirizine hydrochloride. METHODS: Chitosan was co-formulated with cetirizine hydrochloride. Transdermal patches were prepared by casting this solution to microneedle molds. Control patches were formulated by casting this solution to a plain cuvet of same area as mold but lacking microneedles. An array of methods namely; differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and scanning electron microscopy (SEM) were employed for the characterization of the films and the microneedles accordingly whereas in vitro permeation studies were conducted across rat skin. Light microscopy was performed to assess any histological changes upon microneedles application onto the rat skin. RESULTS: The patches had a reproducible thickness (0.86 ± 0.06 mm) and folding endurance. Both the blank and drug loaded patches had 100 microneedles each of 300 micrometre length. In addition, the microneedle patches were ascribed with a two-fold increase in drug permeation across rat skin in the presence of microneedles as compared to the control formulations. Histological examination confirms a minimal invasion of the skin conferred by the microneedles. CONCLUSION: The microneedle patches serve as an alternate route of drug administration in patients with nausea and swelling difficulties. Graphical abstract Microneedle patch manifest a two-fold increase in the skin permeation of Cetirizine Hydrochloride as compared to the control that is drug loaded patch without microneedles.

In Vitro and Ex Vivo Evaluation of Tablets Containing Piroxicam-Cyclodextrin Complexes for Buccal Delivery.

In the current study, the development of mucoadhesive tablets for buccal delivery of a non-steroidal anti-inflammatory drug was investigated. Binary complexes with piroxicam and cyclodextrins (ß-cyclodextrin (ß-CD), methylated-ß-cyclodextrin (Me-ß-CD), and hydroxypropyl-ß-cyclodextrin (HP-ß-CD)) were prepared by the co-evaporation method. All formulations were characterized by means of differential scanning calorimetry, infrared spectroscopy and powder X-ray diffractometry. Mucoadhesive tablets of binary systems were formulated by direct compression using chitosan as mucoadhesive polymer. The in vitro release profiles of tablets were conducted in simulated saliva and, the drug permeation studies, across porcine buccal mucosa. The results suggest that the rank order effect of cyclodextrins for the drug release was Me-ß-CD > HP-ß-CD > ß-CD, whereas the ex vivo studies showed that the tablets containing chitosan significantly increased the transport of the drug compared to their free complexes. Finally, histological assessment revealed loss of the superficial cell layers, which might be attributed to the presence of cyclodextrins.

Stable increased formulation atomization using a multi-tip nozzle device.

Electrohydrodynamic atomization (EHDA) is an emerging technique for the production of micron and nano-scaled particles. The process often involves Taylor cone enablement, which results in a fine spray yielding formulated droplets, which then undergo drying during deposition. In this work, novel multi-tip emitter (MTE) devices were designed, engineered and utilized for potential up-scaled EHDA, by comparison with a conventional single-needle system. To demonstrate this, the active ketoprofen (KETO) was formulated using polyvinylpyrrolidone (PVP) polymer as the matrix material. Here, PVP polymer (5% w/v) solution was prepared using ethanol and distilled water (80:20) as the vehicle. KETO was incorporated as 5% w/w of PVP. Physical properties of resulting solutions (viscosity, electrical conductivity, density and surface tension) were obtained. Formulations were electrosprayed through both single and novel MTEs under EHDA conditions at various flow rates (5-300 µl/min) and applied voltages (0-30 kV). The atomization process using MTEs and single nozzle was monitored at using various process parameters via a digital optical camera. Resulting particles were collected 200 mm below processing heads and were analyzed using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray diffraction (XRD) and scanning electron microscopy (SEM). Digital recordings confirmed stable MTE jetting at higher flow rates. Electron micrographs confirmed particle size variation arising due to nozzle head design and evidenced stable jetting derived greater near-uniform particles. DSC, XRD and TGA confirm KETO molecules were encapsulated and dispersed into PVP polymer particles. In conclusion, novel MTE devices enabled stable atomization even at higher flow rates when compared to conventional single-needle device. This indicates an exciting approach for scaling up (EHDA) in contrast to current efforts focusing on multiple-nozzle and pore-based processing outlets.

Development and characterisation of cellulose based electrospun mats for buccal delivery of non-steroidal anti-inflammatory drug (NSAID).

In this study conventional electrospinning (ESp) was used to prepare a series of buccal films containing indomethacin (INDO, a nonsteroidal anti-inflammatory drug), Ethocel (10), hydroxypropylmethylcellulose (HPMC) and Tween® 80 at various concentrations. The films were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM), fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Drug release behaviour was assessed in vitro (buffer pH6.8). SEM revealed film morphology and mean fibre diameter was dependent on the process formulation. INDO was encapsulated in the amorphous state once electrospun as evidenced from DSC and XRD studies. The presence of other excipients within fibrous matrices was confirmed using FTIR and Raman spectroscopy. Loading and release of INDO from filamentous structures was influenced by formulation composition; indicating potential to 'fine-tune' dosage forms. Given that ESp is a one-step preparation method and operational at ambient conditions; an attractive route for engineering tailored film type dosage forms is presented. This is a valuable approach for optimizing dosage forms as needed in a single step for various age groups.

EHDA Spraying: A Multi-Material Nano-Engineering Route.

Electrohydrodynamic atomization (EHDA) enabling platform technologies have gathered significant momentum over the last two decades. Utilisation of the underpinning jetting process in tandem with desired materials (including polymers, ceramics, metals and even naturally occurring compounds such as peptides, DNA and cells) provides the basis for novel engineered therapies. Through EHDA processes, the generation of a variety of nano-meter and micro-meter scaled structures with control on surface and encapsulation features is attainable in a single step. While a host of adaptable EHDA techniques have evolved (e.g. printing and template patterning), there are two main processes that continue to dominate: electrospraying (ESy) and electrospinning (ESp). Although ESp has drawn considerable researcher interest for nanofibre applications, ESy is an important and timely process for nano- and micro-particle fabrication. Thus, an appropriate evaluation of ESy is vital. This short review focuses on key developments in the ESy field in relation to nanotechnologies with potential healthcare applications using metals, polymers and ceramics. An insight into the process of particle formation (during EHDA spraying or ESy), process parameters and materials specifications, is provided. Emerging biomedical and other healthcare research through nanotechnologies are highlighted.