Advanced biotherapeutic systems such as gene therapy, mRNA lipid nanoparticles, antibody–drug conjugates, fusion proteins, and cell therapy have proven to be promising platforms for delivering targeted biologic therapeutics. Preserving the intrinsic stability of these advanced therapeutics is essential to maintain their innate structure, functionality, and shelf life. Nevertheless, various challenges and obstacles arise during formulation development and throughout the storage period due to their complex nature and sensitivity to various stress factors. Key stability concerns include physical degradation and chemical instability due to various factors such as fluctuations in pH and temperature, which results in conformational and colloidal instabilities of the biologics, adversely affecting their quality and therapeutic efficacy. This review emphasizes key stability issues associated with these advanced biotherapeutic systems and approaches to identify and overcome them. In gene therapy, the brittleness of viral vectors and gene encapsulation limits their stability, requiring the use of stabilizers, excipients, and lyophilization. Keeping cells viable throughout the whole cell therapy process, from culture to final formulation, is still a major difficulty. In mRNA therapeutics, stabilization strategies such as the optimization of mRNA nucleotides and lipid compositions are used to address the instability of both the mRNA and lipid nanoparticles. Monoclonal antibodies are colloidally and conformationally unstable. Hence, buffers and stabilizers are useful to maintain stability. Although fusion proteins and monoclonal antibodies share structural similarities, they show a similar pattern of instability. Antibody–drug conjugates possess issues with conjugation and linker stability. This review outlines the stability issues associated with advanced biotherapeutics and provides insights into the approaches to address these challenges.

Amorphous solid dispersions (ASD) have gained tremendous attention over the past two decades as one of the most promising techniques for enhancing the solubility of poorly water-soluble drugs. However, low drug loading is one of the major challenges of ASD technology that limits its commercialization to only a few drug candidates. Increasing the drug loading increases the risk of recrystallization during storage (solid state) and/or during dissolution (solution state). Various formulation and process-related strategies have been explored that open the possibility of formulating high drug-loaded ASDs without the risk of recrystallization. Here, we review various formulation approaches, such as the use of surfactants, mesoporous silicas, polymer combinations, in situ thermal crosslinking, structural modification of polymeric carriers, and surface nanocoating using minerals. We also discuss the mechanisms by which these approaches inhibit solid state and/or solution state recrystallization.

mRNA vaccines have been demonstrated as a powerful alternative to traditional conventional vaccines because of their high potency, safety and efficacy, capacity for rapid clinical development, and potential for rapid, low-cost manufacturing. These vaccines have progressed from being a mere curiosity to emerging as COVID-19 pandemic vaccine front-runners. The advancements in the field of nanotechnology for developing delivery vehicles for mRNA vaccines are highly significant. In this review we have summarized each and every aspect of the mRNA vaccine. The article describes the mRNA structure, its pharmacological function of immunity induction, lipid nanoparticles (LNPs), and the upstream, downstream, and formulation process of mRNA vaccine manufacturing. Additionally, mRNA vaccines in clinical trials are also described. A deep dive into the future perspectives of mRNA vaccines, such as its freeze-drying, delivery systems, and LNPs targeting antigen-presenting cells and dendritic cells, are also summarized.

COVID19 has caused a significant socioeconomic burden worldwide. Opioid crisis was further intensified with the increasing number of opioid overdose/misuse related deaths in last two years. Abusers have adopted newer/ efficient methods for manipulating and abusing commercial opioid formulations. Food and Drug Administration (FDA) has been strategizing tirelessly to prevent misuse/abuse of prescription opioids. One of the strategies is to develop an abuse deterrent formulation (ADF). The current study aims to develop a novel 3D printed drug releasing capsule shell filled with an aversion liquid (3D-RECAL). Primarily, metformin hydrochloride (MT, model drug) loaded printable filaments of polyvinyl alcohol was prepared using hot melt extrusion. Following extrusion, a 3D printed capsule shell was designed and fabricated using a single nozzle fuse deposition modelling 3D printer. An aversion liquid to be filled in 3D-RECAL capsules was prepared by combining sudan black and sodium polyacrylamide starch in oil base. Mechanical analysis of extruded filaments suggested that the filaments with 20%w/w MT had a higher mechanical strength compared to other drug loadings. Instantaneous gelling and large black non-snortable particles were formed during solvent extraction and physical manipulation studies, respectively. Due to the drug being embedded in the capsule shell, MT release was immediately started with >85% of MT release within 45 mins in 0.1 N HCl. Due to the everlasting need for the newer efficient ADF technologies, 3D-RECAL can be a step in the right direction towards saving lives, providing safe and effective measures to deterring abusers.

Amorphous solid dispersions (ASDs) are among the most popular and widely studied solubility enhancement techniques. Since their inception in the early 1960s, the formulation development of ASDs has undergone tremendous progress. For instance, the method of preparing ASDs evolved from solvent-based approaches to solvent-free methods such as hot melt extrusion and Kinetisol®. The formulation approaches have advanced from employing a single polymeric carrier to multiple carriers with plasticizers to improve the stability and performance of ASDs. Major excipient manufacturers recognized the potential of ASDs and began introducing specialty excipients ideal for formulating ASDs. In addition to traditional techniques such as differential scanning calorimeter (DSC) and X-ray crystallography, recent innovations such as nano-tomography, transmission electron microscopy (TEM), atomic force microscopy (AFM), and X-ray microscopy support a better understanding of the microstructure of ASDs. The purpose of this review is to highlight the recent advancements in the field of ASDs with respect to formulation approaches, methods of preparation, and advanced characterization techniques

The purpose of this study was to optimize the melt granulation process of fenofibrate using twin-screw granulator. Initial screening was performed to select the excipients required for melt granulation process. A 3 × 3 factorial design was used to optimize the processing conditions using the % drug loading (X1) and screw speed (X2) as the independent parameters and granule friability (Y1) % yield (Y2) as the dependent parameters. The effect of the independent parameters on the dependent parameters was determined using response surface plots and contour plots. A linear relationship was observed between % drug loading (X1) and % friability (Y1) and a quadratic relationship was observed between the independent parameters (X1 and X2) and % yield (Y2). The processing conditions for optimum granules were determined using numerical and graphical optimization and it was found that 15% drug loading at 50 rpm results in maximum % yield of 82.38% and minimum friability of 7.88%. The solid-state characterization of the optimized granules showed that the drug turned from crystalline state to amorphous state during melt granulation process. The optimized granules were compressed into tablets using Purolite® as the super disintegrating agent. The optimized formulation showed >85% drug release in 0.75% SLS solution within 60 min.

Death from an accidental or intentional overdose of sleeping tablets has increased exponentially in the USA. Furthermore, the simultaneous consumption of sleeping tablets with alcoholic beverages not only intensifies the effect of sleeping tablets but also leads to blackouts, sleepwalking, and death in many cases. In this article, we proposed a unique and innovative technology to prevent multi-tablet and alcohol-associated abuse of sleeping tablet. Agonist- and antagonist-loaded polymeric filaments of appropriate Eudragit® polymers were prepared using hot melt extrusion. Metoprolol tartrate and hydrochlorothiazide were used as model drugs in place of zolpidem tartrate (agonist-BCS class I) and flumazenil (antagonist-BCS class IV), respectively. Crushed filaments were converted into a tablet with a novel rapidly soluble co-processed alkalizing agent. Dissolution studies of single tablet and multiple tablets (5) in fasted state simulated gastric fluid (FaSSGF) confirmed that the release of the agonist was significantly (p < 0.0001) reduced in multi-tablet dissolution. Furthermore, the release of antagonist was significantly higher when tablet was exposed to FaSSGF+20% ethanol and various alcoholic beverages. Thus, appropriate use of Eudragit® polymer’s chemistry could help design a tablet to prevent the release of agonist in case of overdose and simultaneous release of antagonist when consumed with alcohol.

Prescription opioid abuse also known as opioid epidemic has been an ever-growing problem in the United States. It has been associated with numerous emergencies and mortality with significant burden on healthcare system. Amongst various approaches proposed by FDA, development of an abuse deterrent formulation is one of the key strategies to address this opioid crisis. Existing abuse deterrent technologies have several deficiencies which enable abusers to manipulate/bypass it. The proposed study aims to develop and optimize an abuse-deterrent immediate release bilayer film (ADRIFT). A novel material with distinct process engineering was employed to achieve immediate drug release with nasal/intravenous abuse deterrent properties. Drug layer (DL) composed of a rapidly soluble film forming polymer polyvinyl alcohol (PVA) while various solvent system and biocompatible polymers were screened to incorporate sodium polyacrylamide starch (KPX) in abuse deterrent layer (AL). Mechanical analysis of ADRIFT suggested that individual excipients played significant role in improving the mechanical strength of ADRIFT. Spontaneous formation of highly viscous gels in different solvents and resistance to mill into fine powder support the injection and snorting abuse deterrent potential, respectively. Immediate release (>85% release) was achieved in < 30mins, indicating that there was no interference between either of the layers towards their specific purposes. Hence, our novel yet simple ADRIFT oral film technology could potentially be useful in manufacturing immediate release abuse-deterrent formulation of opioid drugs.

Aim: The aim of this work was to investigate the effect of printing pattern on physical attributes and dissolution of fused deposition modeling 3D printed caplets. Methods: Hydrochlorothiazide-loaded polyvinyl alcohol filaments were prepared by hot melt extrusion. Caplets printed in hexagonal (HexCap), diamond infill (DiaCap) in three different sizes using fused deposition modeling 3D printer and evaluated for hardness, disintegration and dissolution. Results: DiaCaps exhibited higher hardness than HexCaps. Disintegration time for HexCaps was <20 mins. while DiaCaps took 25–40 mins. DiaCaps showed 20–30% lower release at all time points compared with HexCaps. Conclusion: Although composition, processing parameters were same, mere change in printing pattern alters disintegration and dissolution. Findings of this study can be invaluable in developing patient-tailored medicines.

Opioid abuse is a growing problem and has become a national healthcrisis over the past decade in the USA. Oral ingestion, snorting, and injection arethe most commonly employed routes of abuse for an immediate release product. Tocircumvent these issues, we have developed an egg-shaped tablet (egglet) using fuseddeposition modeling (FDM) 3D printing technology. Drug-loaded polymeric filaments(1.5 mm) were prepared using hot melt extrusion (HME) followed by printing intoegglets of different sizes and infill densities. Based on printability and crushresistance, polyvinyl alcohol (PVA) was found to be the most suitable polymer forthe preparation of abuse deterrent egglets. Further, egglets were evaluated andoptimized for mechanical manipulation using household equipment, milling, particlesize distribution, solvent extraction, and drug release as per the FDA guidance(November 2017). A multifactorial design was used to optimize egglets for solventextraction and drug release. Extreme hardness (> 500 N) and very large particlesize (> 1 mm) on mechanical manipulation confirmed the snorting deterringproperty while less than 15% drug extraction in 5 min (% Sext) demonstrated the deterrence forinjection abuse. Quality target product profile D85 < 30 min and % Sext < 15 was achieved withegglets of 6 mm diameter, 45% infill density, and 15% w/w drug loading. Dose of drugcan be easily customized by varying dimension and infill density without alteringthe composition. HME coupled with FDM 3D printing could be a promising tool in thepreparation of patient-tailored, immediate release abuse deterrentformulation.

Pediatric population is a sensitive sector of the healthcare and pharmaceutical field with additional needs compared to the adult population. Extemporaneous formulations for children are generally prepared by manipulating adult formulations, but medication errors can result in suboptimal efficacy and with significant safety concerns. The aim of proposed project was to explore a 3D printing technology for the development of customized minicaplets of baclofen for the pediatric population. Based on results of 3-point bend test, polyvinyl alcohol (PVA) with sorbitol (10% w/w) were selected for preparation of baclofen loaded filaments using hot melt extrusion (HME). Effect of dimension, infill percentage and infill pattern on dose, disintegration time and release profile were investigated. Characteristic crystalline peaks of baclofen were absent in DSC thermograms and XRD pattern of filament and minicaplets. Minicaplets printed in diamond (fast) infill pattern with 100% infill showed higher disintegration time (38 mins) compared to linear, sharkfill and hexagonal pattern. 3(2) full factorial orthogonal design suggested that baclofen release (D50 and D85) was marginally affected by infill percentage but significantly affected by caplet dimension (p < 0.05). Thus, low cost FDM 3D printing technique can be a promising alternative for preparation of dose and release customized pediatric dosage forms.

Loperamide, an over the counter anti-diarrheal drug, also infamously referred to as "poor man's methadone". Due to the ease of availability and low price, people/patients abuse it by consuming more than 30 tablets to achieve euphoric effect and to combat opioid withdrawal. But supratherapeutic doses of loperamide result in severe respiratory depression, cardiac dysrhythmia and mortality. To address this issue, we developed a unique and innovative technology to deter multi-dose oral abuse. The concept is to design a tablet which can immediate release loperamide in diarrheic patients (single tablet) while stops loperamide release in case of intentional multi-dose ingestion. Loperamide was molecularly dispersed into gastric soluble cationic polymers - Eudragit (R) EPO and Kollicoat (R) Smartseal 100P using hot melt extrusion to obtain filament. Filaments were milled and compressed into tablets ((Eudragit (R) EPO (SJU1) and Kollicoat (R) Smartseal (SJU2)) with optimized amount of L-Arginine. Dissolution in 250 mL of Fasted state simulated gastric fluid (FaSSGF) revealed that single tablet of Imodium (R) (marketed formulation) and SJU1 showed > 85% of release within 15 min. Most importantly, in multi-unit dissolution (15 tablets), Imodium (R) exhibited > 90% release but SJU tablets showed < 2% of drug release thus demonstrating its ability to deter multi-dose oral abuse.