Bohemian Rhapsody of Future Drug Delivery Systems: Rational Changes Necessary for the Next Revolution.

Controlled drug delivery technology has matured for more than 70 years, starting from a twice-a-day oral formulation to 6 month long-acting injectable formulations. Further technological advances require superior formulations to treat various diseases more efficiently. Developing future formulations with practical innovations for treating existing and new diseases necessitates our continued efforts to overcome at least three main hurdles. They include (i) drug delivery with reduced side effects, (ii) long-term treatment of chronic diseases, and (iii) the overcoming of biological barriers. Such efforts start with the improved ability to accurately test drug delivery efficacy using proper controls. Future development can be aided by artificial intelligence if used properly. The next revolution of drug delivery systems will be augmented if implementation is given equal weight as discovery. Such a process can be accelerated with the systemic revamp of the research funding structure and cultivating a new generation of scientists who can think differently.

Treatment efficacy of 532-nm diode laser glottoplasty in patients with sulcus vocalis: a prospective study.

PURPOSE: This study prospectively assessed the efficacy and safety of 532-nm diode laser glottoplasty in patients with sulcus vocalis. METHODS: A prospective human trial was performed from August 2016 to September 2021. 532-nm diode laser glottoplasty was performed in 30 consecutive patients with sulcus vocalis who suffered from voice problems. Patients underwent acoustic aerodynamic, perceptual, stroboscopic, and Voice Handicap Index-10 (VHI-10) evaluations before and 1, 6, and 12 months after laser glottoplasty. RESULTS: Most subjective parameters showed significant improvement (P < 0.05) at 6 months after laser glottoplasty and remained stable at 12 months. Most objective parameters showed significant improvement (P < 0.05) at 12 months after laser glottoplasty. Complications during follow-up included mild vocal fold vibration reduction in 3.3% of patients (1/30) and persistent vocal fold edema in 3.3% of patients (1/30). CONCLUSIONS: Statistically significant voice improvement at 12 months after 532-nm diode laser glottoplasty was achieved without serious complications.

A Novel Intervention That Prevents Vocal Fold Scarring.

OBJECTIVES: We evaluated the preventive efficacy of stromal vascular fraction (SVF) for vocal fold scar in a rabbit model. STUDY DESIGN: Animal model. METHODS: The study included 40 male New Zealand white rabbits: 20 received vocal fold scar surgery served as normal controls (control group). The other 20 received the same vocal fold scar surgery with SVF injection (SVF group) Histological and high-speed video analyses of vocal fold vibration were performed 4 weeks after scar surgery and SVF injection. The maximum amplitude of vocal fold vibration was used to assess vocal fold vibration. A real-time PCR study was also performed to evaluate the scar regeneration and remodeling including TGF-ß1, IL-6, procollagen-1, MMP-2, 9, and HAS-2, 3. RESULTS: Vocal fold vibration analyses indicated that the maximum amplitude differences in the vibration of the SVF group were significantly higher than the control group. The histological findings showed that the collagen density ratio were significantly lower in the SVF group compared to the control group. Real-time Polymerase Chain Reaction (PCR) study showed significant increases of MMP-2, 9 and HAS-2, 3, and a decrease of TGF-ß1, IL-6, procollagen-1 in the SVF group compared to the control group. CONCLUSIONS: Based on the vocal fold vibration study, histological findings, and real-time PCR study, SVF injection showed preventive activity and improvement of vocal fold vibration for vocal fold scar in a rabbit model.

The Impact of Post-Processing Temperature on PLGA Microparticle Properties.

PURPOSE: Biodegradable poly(lactide-co-glycolide) (PLGA) microparticles loaded with either risperidone or naltrexone were prepared from an emulsification homogenization process. The objective of this study was to determine the impact the post-treatment temperature has on the properties and subsequent performance of the microparticles. METHODS: The post-treatment temperature of an ethanolic solution was characterized from 10 ~ 35ºC for the naltrexone and risperidone micropartilces. RESULTS: The wash temperature resulted in a typical triphasic in vitro release pattern at low wash temperatures or a biphasic pattern consisting of an elevated release rate at higher post-treatment temperatures. The post-treatment temperature largely influences the particle morphology, residual solvent levels, glass transition temperature, and drug loading and is molecule dependent, whereby these characteristics subsequently influence the drug release rate. CONCLUSION: The study highlights the importance of both the post-treatment process and control during manufacturing to obtain a formulation within the desired product profile.

Control of drug release kinetics from hot-melt extruded drug-loaded polycaprolactone matrices.

Sustained local delivery of meloxicam by polymeric structures is desirable for preventing subacute inflammation and biofilm formation following tissue incision or injury. Our previous study demonstrated that meloxicam release from hot-melt extruded (HME) poly(ε-caprolactone) (PCL) matrices could be controlled by adjusting the drug content. Increasing drug content accelerated the drug release as the initial drug release generated a pore network to facilitate subsequent drug dissolution and diffusion. In this study, high-resolution micro-computed tomography (HR µCT) and artificial intelligence (AI) image analysis were used to visualize the microstructure of matrices and simulate the drug release process. The image analysis indicated that meloxicam release from the PCL matrix was primarily driven by diffusion but limited by the amount of infiltrating fluid when drug content was low (i.e., the connectivity of the drug/pore network was poor). Since the drug content is not easy to change when a product has a fixed dose and dimension/geometry, we sought an alternative approach to control the meloxicam release from the PCL matrices. Here, magnesium hydroxide (Mg(OH)2) was employed as a solid porogen in the drug-PCL matrix so that Mg(OH)2 dissolved with time in the aqueous environment creating additional pore networks to facilitate local dissolution and diffusion of meloxicam. PCL matrices were produced with a fixed 30 wt% meloxicam loading and variable Mg(OH)2 loadings from 20 wt% to 50 wt%. The meloxicam release increased in proportion to the Mg(OH)2 content, resulting in almost complete drug release in 14 d from the matrix with 50 wt% Mg(OH)2. The porogen addition is a simple strategy to tune drug release kinetics, applicable to other drug-eluting matrices with similar constraints.

Multiphysics Simulation of Local Transport and Absorption Coupled with Pharmacokinetic Modeling of Systemic Exposure of Subcutaneously Injected Drug Solution.

INTRODUCTION: Subcutaneous (SC) injectables have become more acceptable and feasible for administration of biologics and small molecules. However, efficient development of these products is limited to costly and time-consuming techniques, partially because absorption mechanisms and kinetics at the local site of injection remain poorly understood. OBJECTIVE: To bridge formulation critical quality attributes (CQA) of injectables with local physiological conditions to predict systemic exposure of these products. METHODOLOGY: We have previously developed a multiscale, multiphysics computational model to simulate lymphatic absorption and whole-body pharmacokinetics of monoclonal antibodies. The same simulation framework was applied in this study to compute the capillary absorption of solubilized small molecule drugs that are injected subcutaneously. Sensitivity analyses were conducted to probe the impact by key simulation parameters on the local and systemic exposures. RESULTS: This framework was capable of determining which parameters had the biggest impact on small molecule absorption in the SC. Particularly, membrane permeability of a drug was found to have the biggest impact on drug absorption kinetics, followed by capillary density and drug diffusivity. CONCLUSION: Our modelling framework proved feasible in predicting local transport and systemic absorption from the injection site of small molecules. Understanding the effect of these properties and how to model them may help to greatly expedite the development process.

Comparison of humoral and cellular immune responses between ChAd-BNT heterologous vaccination and BNT-BNT homologous vaccination following the third BNT dose: A prospective cohort study.

Introduction: The differential immune responses after two additional BNT162b2 (BNT) booster doses between ChAdOx1 nCoV-10 (ChAd)-primed and BNT-primed groups have not been elucidated. The aim of this study was to compare vaccine-induced humoral and cellular immune responses and evaluate breakthrough infection between the two vaccination strategies. Methods: In 221 healthy subjects (111 in the ChAd group), longitudinal immune responses were monitored at 3, 4, and 6 months after the 2nd dose and 1, 3, and 6 months after the 3rd dose. Humoral immunity was measured by two fully automated chemiluminescent immunoassays (Elecsys and Abbott) and a surrogate virus neutralization test (sVNT). Cellular immunity was assessed by two interferon-γ (IFN-γ) release assays (QuantiFERON SARS-CoV-2 and Covi-FERON). Results: After the 2nd dose of BNT vaccination, total antibody levels were higher in the ChAd group, but IgG antibody and sVNT results were higher in the BNT group. Following the 3rd dose vaccination, binding antibody titers were significantly elevated in both groups (ChAD-BNT; 15.4 to 17.8-fold, BNT-BNT; 22.2 to 24.6-fold), and the neutralizing capacity was increased by 1.3-fold in both cohorts. The ChAd-BNT group had lower omicron neutralization positivity than the BNT-BNT group (P = 0.001) at 6 months after the 3rd dose. Cellular responses to the spike antigen also showed 1.7 to 3.0-fold increases after the 3rd dose, which gradually declined to the levels equivalent to before the 3rd vaccination. The ChAd cohort tended to have higher IFN-γ level than the BNT cohort for 3-6 months after the 2nd and 3rd doses. The frequency of breakthrough infection was higher in the ChAd group (44.8%) than in the BNT group (28.1%) (P = 0.0219). Breakthrough infection induced increased humoral responses in both groups, and increase of cellular response was significant in the ChAd group. Discussion: Our study showed differential humoral and cellular immune responses between ChAd-BNT-BNT heterologous and BNT-BNT-BNT homologous vaccination cohorts. The occurrence of low antibody levels in the ChAd-primed cohort in the humoral immune response may be associated with an increased incidence of breakthrough infections. Further studies are needed on the benefits of enhanced cellular immunity in ChAd-primed cohorts.

Preparation and evaluation of injectable microsphere formulation for longer sustained release of donepezil.

In this study, donepezil-loaded PLGA and PLA microspheres (Dp-PLGA-M/Dp-PLA-M) and Dp-PLA-M wrapped in a polyethylene glycol-b-polycaprolactone (PC) hydrogel (Dp-PLA-M/PC) were prepared to reduce the dosing frequency of injections to treat Alzheimer's disease patients. Dp-PLGA-M and Dp-PLA-M with a uniform particle size distribution were repeatably fabricated in nearly quantitative yield and with high encapsulated Dp yields using an ultrasonic atomizer. The injectability and in vitro and in vivo Dp release, biodegradation, and inflammatory response elicited by the Dp-PLGA-M, Dp-PLA-M, and Dp-PLA-M/PC formulations were then compared. All injectable formulations showed good injectability with ease of injection, even flow, and no clogging using a syringe needle under 21-G. The injections required a force of <1 N. According to the biodegradation rate of micro-CT, GPC and NMR analyses, the biodegradation of Dp-PLA-M was slower than that of Dp-PLGA-M, and the biodegradation rate of Dp-PLA-M/PC was also slower. In the Dp release experiment, Dp-PLA-M sustained Dp for longer compared with Dp-PLGA-M. Dp-PLA-M/PC exhibited a longer sustained release pattern of two months. In vivo bioavailability of Dp-PLA-M/PC was almost 1.4 times higher than that of Dp-PLA-M and 1.9 times higher than that of Dp-PLGA-M. The variations in the Dp release patterns of Dp-PLGA-M and Dp-PLA-M were explained by differences in the degradation rates of PLGA and PLA. The sustained release of Dp by Dp-PLA-M/PC was attributed to the fact that the PC hydrogel served as a wrapping matrix for Dp-PLA-M, which could slow down the biodegradation of PLA-M, thus delaying the release of Dp from Dp-PLA-M. Dp-PLGA-M induced a higher inflammatory response compared to Dp-PLA-M/PC, suggesting that the rapid degradation of PLGA triggered a strong inflammatory response. In conclusion, Dp-PLA-M/PC is a promising injectable Dp formulation that could be used to reduce the dosing frequency of Dp injections.

Development of poly(lactide-co-glycolide) microparticles for sustained delivery of meloxicam.

Poly(lactide-co-glycolide) (PLGA) polymers have been widely used for drug delivery due to their biodegradability and biocompatibility. One of the objectives of encapsulating a drug in PLGA microparticles (MPs) is to achieve an extended supply of the drug through sustained release, which can range from weeks to months. Focusing on the applications needing a relatively short-term delivery, we investigated formulation strategies to achieve a drug release from PLGA MPs for two weeks, using meloxicam as a model compound. PLGA MPs produced by the traditional oil/water (O/W) single emulsion method showed only an initial burst release with minimal increase in later-phase drug release. Alternatively, encapsulating meloxicam as solid helped reduce the initial burst release. The inclusion of magnesium hydroxide [Mg(OH)2] enhanced later-phase drug release by neutralizing the developing acidity that limited the drug dissolution. The variation of solid meloxicam and Mg(OH)2 quantities allowed for flexible control of meloxicam release, yielding MPs with distinct in vitro release kinetics. When subcutaneously injected into rats, the MPs with relatively slow in vitro drug release kinetics showed in vivo drug absorption profiles consistent with in vitro trend. However, the MPs that rapidly released meloxicam showed an attenuated in vivo absorption, suggesting premature precipitation of fast-released meloxicam. In summary, this study demonstrated the feasibility of controlling drug release from the PLGA MPs over weeks based on the physical state of the encapsulated drug and the inclusion of Mg(OH)2 to neutralize the microenvironmental pH of the MPs.

Challenging the fundamental conjectures in nanoparticle drug delivery for chemotherapy treatment of solid cancers.

Nanomedicines for cancer treatment have been studied extensively over the last few decades. Yet, only five anticancer nanomedicines have received approvals from the United States Food and Drug Administration (FDA) for treating solid tumors. This drastic mismatch between effort and return calls into question the basic understanding of this field. Various viewpoints on nanomedicines have been presented regarding their potentials and inefficiencies. However, the underlying logics of nanomedicine research and its inadequate translation to the successful use in the clinic have not been thoroughly examined. Tumor-targeted drug delivery was used to understand the shortfalls of the nanomedicine field in general. The concept of tumor-targeted drug delivery by nanomedicine has been based on two conjectures: (i) increased drug delivery to tumors provides better efficacy, and (ii) decreased drug delivery to healthy organs results in fewer side effects. The clinical evidence gathered from the literature indicates that nanomedicines bearing classic chemotherapeutic drugs, such as Dox, cis-Pt, CPT and PTX, have already reached the maximum drug delivery limit to solid tumors in humans. Still, the anticancer efficacy and safety remain unchanged despite the increased tumor accumulation. Thus, it is understandable to see few nanomedicine-based formulations approved by the FDA. The examination of FDA-approved nanomedicine formulations indicates that their approvals were not based on the improved delivery to tumors but mostly on changes in dose-limiting toxicity unique to each drug. This comprehensive analysis of the fundamentals of anticancer nanomedicines is designed to provide an accurate picture of the field's underlying false conjectures, hopefully, thereby accelerating the future clinical translations of many formulations under research.

Implications of particle size on the respective solid-state properties of naltrexone in PLGA microparticles.

A thorough understanding of the complexities in formulating and manufacturing polymeric microspheres is required for new and generic drug applications. Specifically, for an ANDA application for polymeric microsphere-based products, the applicant must meet Q1 (qualitative) and Q2 (quantitative) sameness, and in some cases, Q3 (e.g., microstructural) sameness. Herein, we report the naltrexone crystallinity in a PLGA microparticle system prepared from a dichloromethane-benzyl alcohol solvent system results in a crystallinity dependence as a function of microparticle size from the same batch - illustrating intrabatch microstructural variability. As the particle size increases, the crystallinity increases, with additional polymorphic forms more readily noted at the large particle sizes. Furthermore, during dissolution, a polymorphic transition and/or crystallization occurs at larger size fractions. This study highlights the importance of controlling the manufacturing parameters during microparticle formation, specifically solvent extraction and particle size control. Furthermore, with the approval of generic microparticles formulations on the horizon, this study highlights the importance of Q3, the same components in the same concentration with the same arrangement of matter, whereby microparticles can have varying microstructural properties across particle sizes from the same batch.

Surface analysis of sequential semi-solvent vapor impact (SAVI) for studying microstructural arrangements of poly(lactide-co-glycolide) microparticles.

Biodegradable poly(lactide-co-glycolide) (PLGA) microparticles have been used as long-acting injectable (LAI) drug delivery systems for more than three decades. Despite extensive use, few tools have been available to examine and compare the three-dimensional (3D) structures of microparticles prepared using different compositions and processing parameters, all collectively affecting drug release kinetics. Surface analysis after sequential semi-solvent impact (SASSI) was conducted by exposing PLGA microparticles to different semi-solvent in the liquid phase. The use of semi-solvent liquids presented practical experimental difficulties, particularly in observing the same microparticles before and after exposure to semi-solvents. The difficulties were overcome by using a new sequential semi-solvent vapor (SSV) method to examine the morphological changes of the same microparticles. The SASSI method based on SSV is called surface analysis of semi-solvent vapor impact (SAVI). Semi-solvents are the solvents that dissolve PLGA polymers depending on the polymer's lactide:glycolide (L:G) ratio. A sequence of semi-solvents was used to dissolve portions of PLGA microparticles in an L:G ratio-dependent manner, thus revealing different structures depending on how microparticles were prepared. Exposing PLGA microparticles to semi-solvents in the vapor phase demonstrated significant advantages over using semi-solvents in the liquid phase, such as in control of exposure conditions, access to imaging, decreasing the time for sequential exposure of semi-solvents, and using the same microparticles. The SSV approach for morphological analysis provides another tool to enhance our understanding of the microstructural arrangement of PLGA polymers. It will improve our comprehensive understanding of the factors controlling drug release from LAI formulations based on PLGA polymers.

Smart capsule for targeted proximal colon microbiome sampling.

The gastrointestinal (GI) tract, particularly the colon region, holds a highly diverse microbial community that plays an important role in the metabolism, physiology, nutrition, and immune function of the host body. Accumulating evidence has revealed that alteration in these microbial communities is the pivotal step in developing various metabolic diseases, including obesity, inflammatory bowel disease (IBD), and colorectal cancer. However, there is still a lack of clear understanding of the interrelationship between microbiota and diet as well as the effectiveness of chemoprevention strategies, including pre and probiotic agents in modifying the colonic microbiota and preventing digestive diseases. Existing methods for assessing these microbiota-diet interactions are often based on samples collected from the feces or endoscopy techniques which are incapable of providing information on spatial variations of the gut microbiota or are considered invasive procedures. To address this need, here we have developed an electronic-free smart capsule that enables site-specific sampling of the gut microbiome within the proximal colon region of the GI tract. The 3D printed device houses a superabsorbent hydrogel bonded onto a flexible polydimethylsiloxane (PDMS) disk that serves as a milieu to collect the fluid in the gut lumen and its microbiome by rapid swelling and providing the necessary mechanical actuation to close the capsule after the sampling is completed. The targeted colonic sampling is achieved by coating the sampling aperture on the capsule with a double-layer pH-sensitive enteric coating, which delays fluid in the lumen from entering the capsule until it reaches the proximal colon of the GI tract. To identify the appropriate pH-responsive double-layer coating and processing condition, a series of systematic dissolution characterizations in different pH conditions that mimicked the GI tract was conducted. The effective targeted microbial sampling performance and preservation of the smart capsule with the optimized design were validated using both realistic in vitro GI tract models with mixed bacteria cultures and in vivo with pigs as an animal model. The results from 16s rRNA and WideSeq analysis in both in vitro and in vivo studies showed that the bacterial population sampled within the retrieved capsule closely matched the bacterial population within the targeted sampling region (proximal colon). Herein, it is envisioned that such smart sampling capsule technology will provide new avenues for gastroenterological research and clinical applications, including diet-host-microbiome relationships, focused on human GI function and health. STATEMENT OF SIGNIFICANCE: The colonic microbiota plays a major role in the etiology of numerous diseases. Extensive efforts have been conducted to monitor the gut microbiome using sequencing technologies based on samples collected from feces or mucosal biopsies that are typically obtained by colonoscopy. Despite the simplicity of fecal sampling procedures, they are incapable of preserving spatial and temporal information about the bacteria through the gastrointestinal (GI) tract. In contrast, colonoscopy is an invasive and impractical approach to frequently assess the effect of dietary and therapeutic intake on the microbiome and their impact on the health of the patient. Here, we developed a non-invasive capsule that enables targeted sampling from the ascending colon, thereby providing crucial information for disease prediction and monitoring.

Scanning Analysis of Sequential Semisolvent Vapor Impact To Study Naltrexone Release from Poly(lactide-co-glycolide) Microparticles.

Poly(lactide-co-glycolide) (PLGA)-based microparticle formulations have been a mainstay of long-acting injectable drug delivery applications for decades. Despite a long history of use, tools and techniques to analyze and understand these formulations are still under development. Recently, a new characterization method was introduced known as the surface analysis after sequential semisolvent impact using sequential semisolvent vapors. The vapor-based technique is named, for convenience, surface analysis of (semisolvent) vapor impact (SAVI). In the SAVI method, discretely controlled quantities of selected organic semisolvents in the vapor phase were applied to PLGA microparticles to track particle morphological changes by laser scanning confocal microscopy. Subsequently, the morphological images were analyzed to calculate mean peak height (Sa), core height (Sk), kurtosis (Sku), dale void volume (Vvv), the density of peaks (Spd), maximum height (Hm), and the shape ratio (Rs). Here, the SAVI method was applied to naltrexone-loaded microparticles manufactured internally and Vivitrol, a commercial formulation. SAVI analysis of these microparticles indicated that the two primary mechanisms controlling the naltrexone release were the formation of discrete, self-crystallized portions of naltrexone within the PLGA structure and the degradation of PLGA chains through nucleophilic substitution. The relatively higher amounts of naltrexone crystals resulted in prolonged release than lower amounts of crystals. Data from gel permeation chromatography, differential scanning calorimetry, and in vitro release measurements all point to the importance of naltrexone crystal formation. This study highlights the utility of SAVI for gaining further insights into the microstructure of PLGA formulations and using SAVI data to support research, product development, and quality control applications for microparticle formulations of pharmaceuticals.

Transitioning from a lab-scale PLGA microparticle formulation to pilot-scale manufacturing.

The complexity of scale-up manufacturing of PLGA microparticles creates a significant challenge when transitioning from benchtop-scale formulation development into larger clinical scale batches. Minor changes in the initial formulation composition (e.g., PLGA molecular weight, solvent type, and drug concentration) and processing parameters (e.g., extraction kinetics and drying condition) during scale-up production can result in significantly different performance of the prepared microparticles. The objectives of the present study were to highlight the in vitro and in vivo performance of a candidate benchtop-scale batch created with a rotor-stator mixer, transitioned into an in-line manufacturing process at ~15× scale of a long-acting naltrexone formulation. Physicochemical properties (such as drug loading, residual benzyl alcohol content, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microparticles between the benchtop-scale and in-line process pilot-scale were determined. The pharmacokinetics of the naltrexone microspheres were investigated using the rat model. The results demonstrate that while the morphologies of the particles were different from a visual assessment and slight differences were observed in the in vitro release profiles, the in vivo pharmacokinetics illustrate similar kinetics. Our study shows that scale-up production having the same drug release kinetics can be made by controlling the formulation and processing parameters.

The First Case Report of Bilateral Vagal Neuropathy Presenting With Dysphonia Following COVID-19 Infection.

Coronavirus disease 2019 (COVID-19) is a pandemic with a variety of symptoms and complications. Impairments of taste and smell caused by COVID-19 are well known as otolaryngological sequelae. However, dysphonia due to bilateral vagal neuropathy has not been well described as a presenting symptom or complication of COVID-19 infection. In this paper, we report a case of a 47-year-old patient who experienced dysphonia after remission of COVID-19 infection and diagnosed bilateral vagal neuropathy.

Development of hot-melt extruded drug/polymer matrices for sustained delivery of meloxicam.

For effective resolution of regional subacute inflammation and prevention of biofouling formation, we have developed a polymeric implant that can release meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, in a sustained manner. Meloxicam-loaded polymer matrices were produced by hot-melt extrusion, with commercially available biocompatible polymers, poly(ε-caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), and poly(ethylene vinyl acetate) (EVA). PLGA and EVA had a limited control over the drug release rate partly due to the acidic microenvironment and hydrophobicity, respectively. PCL allowed for sustained release of meloxicam over two weeks and was used as a carrier of meloxicam. Solid-state and image analyses indicated that the PCL matrices encapsulated meloxicam in crystalline clusters, which dissolved in aqueous medium and generated pores for subsequent drug release. The subcutaneously implanted meloxicam-loaded PCL matrices in rats showed pharmacokinetic profiles consistent with their in vitro release kinetics, where higher drug loading led to faster drug release. This study finds that the choice of polymer platform is crucial to continuous release of meloxicam and the drug release rate can be controlled by the amount of drug loaded in the polymer matrices.

Evolution of drug delivery systems: From 1950 to 2020 and beyond.

Modern drug delivery technology began in 1952 with the advent of the Spansule® sustained-release capsule technology, which can deliver a drug for 12 h after oral administration through an initial immediate dose followed by the remaining released gradually. Until the 1980s, oral and transdermal formulations providing therapeutic durations up to 24 h for small molecules dominated the drug delivery field and the market. The introduction of Lupron Depot® in 1989 opened the door for long-acting injectables and implantables, extending the drug delivery duration from days to months and occasionally years. Notably, the new technologies allowed long-term delivery of peptide and protein drugs, although limited to parenteral administration. The introduction of the first PEGylated protein, Adagen®, in 1990 marked the new era of PEGylation, resulting in Doxil® (doxorubicin in PEGylated liposome) in 1995, Movantik® (PEGylated naloxone - naloxegol) in 2014, and Onpattro® (Patisiran - siRNA in PEGylated lipid nanoparticle) in 2018. Drug-polymer complexes were introduced, e.g., InFed® (iron-dextran complex injection) in 1974 and Abraxane® (paclitaxel-albumin complex) in 2005. In 2000, both Mylotarg™ (antibody-drug conjugate - gemtuzumab ozogamicin) and Rapamune® (sirolimus nanocrystal formulation) were introduced. The year 2000 also marked the launching of the National Nanotechnology Initiative by the U.S. government, which was soon followed by the rest of the world. Extensive work on nanomedicine, particularly formulations designed to escape from endosomes after being taken by tumor cells, along with PEGylation technology, ultimately resulted in the timely development of lipid nanoparticle formulations for COVID-19 vaccine delivery in 2020. While the advances in drug delivery technologies for the last seven decades are breathtaking, they are only the tip of an iceberg of technologies that have yet to be utilized in an approved formulation or even to be discovered. As life expectancy continues to increase, more people require long-term care for various diseases. Filling the current and future unmet needs requires innovative drug delivery technologies to overcome age-old familiar hurdles, e.g., improving water-solubility of poorly soluble drugs, overcoming biological barriers, and developing more efficient long-acting depot formulations. The lessons learned from the past are essential assets for developing future drug delivery technologies implemented into products. As the development of COVID-19 vaccines demonstrated, meeting the unforeseen crisis of the uncertain future requires continuous cumulation of failures (as learning experiences), knowledge, and technologies. Conscious efforts of supporting diversified research topics in the drug delivery field are urgently needed more than ever.

Initial Formation of the Skin Layer of PLGA Microparticles.

Poly(lactide-co-glycolide) (PLGA) has been extensively used in making long-acting injectable formulations. The critical factors affecting the PLGA formulation properties have been adjusted to control the drug release kinetics and obtain desirable properties of PLGA-based drug delivery systems. The PLGA microparticle formation begins as soon as the drug/PLGA-dissolved in the organic solvent phase (oil phase) is exposed to the water phase. The initial skin (or shell) formation on the oil droplets occurs very quickly, sometimes in the matter of milliseconds, and studying the process has been difficult. The skin formation on the PLGA emulsion droplet surface that can affect the subsequent hardening steps is examined. PLGA droplets with different compositions are prepared. Using collimated light and a high-speed camera made it possible to detect the diffusion of acetonitrile from the oil phase into the water phase during the oil droplet formation. Although the skin formation is not visible on the surface of the oil phase droplet with the current setup, the droplet shapes, solid strand formation, and the difference in the spreading time suggest that the initial contact time between the oil and water phases in the range of a few seconds is critical to the properties of the skin.