A Round Trip: The Japanese Contribution to the Development of Sevoflurane.

Sevoflurane was first synthesized independently by Richard Wallin and Bernard Regan at Travenol Laboratories Incorporated and Ross Terrell and Louise Croix at Airco, Inc in the late 1960s, and subsequent animal studies and a phase-1 human trial of the agent published in 1981 showed promising results. Further research in the United States was halted, however, because of concerns regarding potential nephrotoxicity and the introduction of less degradable alternatives. Interest in sevoflurane resumed in Japan when Maruishi Pharmaceutical Company, Limited (Ltd) (Maruishi) decided to continue its development in 1982. They secured approval by the Japanese Ministry of Health, Labor and Welfare for its clinical use in January 1990. Because of its low blood:gas partition coefficient and resulting rapid action, sevoflurane quickly became the anesthetic of choice of Japanese anesthesiologists. In 1992 Abbott Laboratories, now AbbVie, Inc (Abbott, North Chicago, IL) finalized a licensing agreement with Maruishi to seek the US Food and Drug Administration approval for sevoflurane sales in the United States. Approved in June 1995, sevoflurane is now marketed by Abbott in 120 countries and has been administered >120 million times. This report details the Japanese contribution to the development of sevoflurane.

[Advances in Pharmaceutical Manufacturing Process Management -From Physical Pharmaceutics to Automatic Pharmaceutical Production].

Since entering graduate school 43 years ago, I have been studying physical pharmaceutics with a focus on the effects of environmental factors on pharmaceutical properties of solid oral dosage forms during the manufacturing process. I have reported on changes in the characteristics of pharmaceutical products during manufacturing processes, such as grinding, mixing, granulation, and tableting owing to complicated phenomena based on chemical reactions or the crystalline polymorphic transitions of bulk drugs and excipients. To develop modern pharmaceutical manufacturing processes based on process analysis technology (PAT) as a next generation good manufacturing practice, real-time monitoring was introduced in these processes using a non-destructive analytical method, such as the near-infrared spectroscopy combined with chemometrics. Many case studies related to the mixing, granulation, tableting, and coating processes involving PAT have been reported. In those studies, I focused on clarifying the physical and chemical mechanism through "design space" representation. Additionally, non-destructive analytical methods, including X-ray computed tomography, audible acoustic emission, Raman spectroscopy, terahertz spectroscopy, and infrared thermal imaging analysis were applied as novel candidate analytical methods to the pharmaceutical process to monitor critical quality attributes. To achieve this purpose in various pharmaceutical dosage forms, I have been attempting the assembly of a modern manufacturing process managed through a "design space" paradigm involving in-line monitoring using novel analytical methods, multivariate analyses, and feed-back systems.

[Formulation Development for the Purpose of Improving Medication Adherence].

Medication adherence is an important factor in the success or failure of drug treatment. No matter how good a drug is, if a patient cannot or does not want to take it, the therapeutic effect of the drug will not be sufficient and as expected. Therefore, we have been developing formulations with "clinical functionality", namely, formulation characteristics that enhance the likelihood of obtaining the expected therapeutic effect. We researched formulations that are easy to take and deliver expected results; these formulations include gummy drugs as confectionery-like formulations and orally disintegrating (OD) tablets that can be easily swallowed. In particular, OD tablets have been jointly developed with pharmaceutical companies and have been commercialized. Clinical trials with gummy drugs and OD tablets have been conducted to verify the impact of these formulations with clinical functionality on improving medication adherence.

Insulin therapy development beyond 100 years.

The first insulin preparation capable of consistently lowering blood glucose was developed in 1921. But 100 years later, blood glucose control with insulin in people with diabetes is nearly universally suboptimal, with essentially the same molecule still delivered by the same inappropriate subcutaneous injection route. Bypassing this route with oral administration appears to have become technologically feasible, accelerating over the past 50 years, either with packaged insulin peptides or by chemical insulin mimetics. Some of the problems of prospective unregulated absorption of insulin into the circulation from subcutaneous depots might be overcome with glucose-responsive insulins. Approaches to these problems could be modification of the peptide by adducts, or the use of nanoparticles or insulin patches, which deliver insulin according to glucose concentration. Some attention has been paid to targeting insulin preferentially to different organs, either by molecular engineering of insulin, or with adducts. But all these approaches still have problems in even beginning to match the responsiveness of physiological insulin delivery to metabolic requirements, both prandially and basally. As would be expected, for all these technically complex approaches, many examples of abandoned development can be found. Meanwhile, it is becoming possible to change the duration of action of subcutaneous injected insulin analogues to act even more rapidly for meals, and towards weekly insulin for basal administration. The state of the art of all these approaches, and the barriers to success, are reviewed here.

Digital twin of low dosage continuous powder blending - Artificial neural networks and residence time distribution models.

In this paper we present a thorough description of the digital twin development for a continuous pharmaceutical powder blending process in accordance with the Process Analytical Technologies (PAT) and Quality by Design (QbD) guidelines. A low-dosage system of caffeine active pharmaceutical ingredient (API) and dextrose excipient was examined via continuous blending experiments. Near infrared (NIR) spectroscopy-based process analytics were applied; quantitative evaluation of spectra was achieved using multivariate data analysis. The blending system was represented with mechanistic residence time distribution (RTD) models and two types of recurrent artificial neural networks (ANN), experimental datasets were used for model training or fitting and validation. Detailed comparison of the two modelling approaches, the optimization of the model-based digital twin, and efficiency of the soft sensor-based process monitoring is presented through several validating simulations. Both RTD models and nonlinear autoregressive neural networks demonstrated excellent predictive power for the low dosage blending process. RTD models can prove to be more advantageous in industrial development as they are less resource-intensive to develop and prediction accuracy on low concentration levels lacks dependency from the precision of chemometric calibration. Reduced material costs and limited development timeframe render the digital twin an efficient tool in technological development.

Current status of nanoscale drug delivery and the future of nano-vaccine development for leishmaniasis - A review.

The study of tropical diseases like leishmaniasis, a parasitic disease, has not received much attention even though it is the second-largest infectious disease after malaria. As per the WHO report, a total of 0.7-1.0 million new leishmaniasis cases, which are spread by 23 Leishmania species in more than 98 countries, are estimated with an alarming 26,000-65,000 death toll every year. Lack of potential vaccines along with the cost and toxicity of amphotericin B (AmB), the most common drug for the treatment of leishmaniasis, has raised the interest significantly for new formulations and drug delivery systems including nanoparticle-based delivery as anti-leishmanial agents. The size, shape, and high surface area to volume ratio of different NPs make them ideal for many biological applications. The delivery of drugs through liposome, polymeric, and solid-lipid NPs provides the advantage of high biocomatibilty of the carrier with reduced toxicity. Importantly, NP-based delivery has shown improved efficacy due to targeted delivery of the payload and synergistic action of NP and payload on the target. This review analyses the advantage of NP-based delivery over standard chemotherapy and natural product-based delivery system. The role of different physicochemical properties of a nanoscale delivery system is discussed. Further, different ways of nanoformulation delivery ranging from liposome, niosomes, polymeric, metallic, solid-lipid NPs were updated along with the possible mechanisms of action against the parasite. The status of current nano-vaccines and the future potential of NP-based vaccine are elaborated here.

Hot-Melt Extrusion: a Roadmap for Product Development.

Hot-melt extrusion has found extensive application as a feasible pharmaceutical technological option over recent years. HME applications include solubility enhancement, taste masking, and sustained drug release. As bioavailability enhancement is a hot topic of today's science, one of the main applications of HME is centered on amorphous solid dispersions. This review describes the most significant aspects of HME technology and its use to prepare solid dispersions as a drug formulation strategy to enhance the solubility of poorly soluble drugs. It also addresses molecular and thermodynamic features critical for the physicochemical properties of these systems, mainly in what concerns miscibility and physical stability. Moreover, the importance of applying the Quality by Design philosophy in drug development is also discussed, as well as process analytical technologies in pharmaceutical HME monitoring, under the current standards of product development and regulatory guidance. Graphical Abstract.

Opportunities in an Evolving Pharmaceutical Development Landscape: Product Differentiation of Biopharmaceutical Drug Products.

The current perspective reviews the biopharmaceutical market until end of 2020 and highlights the transforming biopharmaceutical landscape during the recent decade. In particular, the rise of biosimilars and the development of new therapeutic modalities through recent advancement in molecular biology research sustainably change the product scenery. The present manuscript describes opportunities for pharmaceutical technical development, highlighting concepts such as product differentiation to succeed in a competitive product landscape. Product differentiation offers the opportunity for numerous life-cycle options and market exclusivity through incremental improvements in standard of care treatment. In particular, different formulation options and formulation-device combinations are described, focusing on systemic delivery of monoclonal antibody products and patient-centered development. The concept of product differentiation is exemplified in a case study about HER2+ breast cancer therapy, underlining pharmaceutical technical solutions and major improvements for the patient.

The promising future of insulin therapy in diabetes mellitus.

The first therapeutic use of insulin by Frederick Banting and Charles Best in 1921 revolutionized the management of type 1 diabetes and considerably changed the lives of many patients with other types of diabetes. In the past 100 years, significant pharmacological advances took place in the field of insulin therapy, bringing closer the goal of optimal glycemic control along with decreased diabetes-related complications. Despite these developments, several challenges remain, such as increasing treatment flexibility, reducing iatrogenic hypoglycemia, and optimizing patient quality of life. Ongoing innovations in insulin therapy (e.g., new insulin analogs, alternative routes of insulin administration, and closed-loop technology) endeavor to overcome these hurdles and change the landscape of diabetes mellitus management. This report highlights recent advances made in the field of insulin therapy and discusses future perspectives.

Oral Drug Delivery: Conventional to Long Acting New-Age Designs.

The Oral route of administration forms the heartwood of the ever-growing tree of drug delivery technology. It is one of the most preferred dosage forms among patients and controlled release community. Despite the high patient compliance, the deliveries of anti-cancerous drugs, vaccines, proteins, etc. via the oral route are limited and have recorded a very low bioavailability. The oral administration must overcome the physiological barriers (low solubility, permeation and early degradation) to achieve efficient and sustained delivery. This review aims at highlighting the conventional and modern-age strategies that address some of these physiological barriers. The modern age designs include the 3D printed devices and formulations. The superiority of 3D dosage forms over conventional cargos is summarized with a focus on long-acting designs. The innovations in Pharmaceutical organizations (Lyndra, Assertio and Intec) that have taken giant steps towards commercialization of long-acting vehicles are discussed. The recent advancements made in the arena of oral peptide delivery are also highlighted. The review represents a comprehensive journey from Nano-formulations to micro-fabricated oral implants aiming at specific patient-centric designs.

High global consumption of potentially inappropriate fixed dose combination antibiotics: Analysis of data from 75 countries.

Antibiotic fixed dose combinations (FDCs) can have clinical advantages such as improving effectiveness and adherence to therapy. However, high use of potentially inappropriate FDCs has been reported, with implications for antimicrobial resistance (AMR) and toxicity. We used a pharmaceutical database, IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS®), to estimate sales of antibiotic FDCs from 75 countries in 2015. Antibiotic consumption was estimated using standard units (SU), defined by IQVIA as a single tablet, capsule, ampoule, vial or 5ml oral suspension. For each FDC antibiotic, the approval status was assessed by either registration with the United States Food and Drug Administration (US FDA) or inclusion on the World Health Organization (WHO) Essential Medicines List (EML). A total of 119 antibiotic FDCs were identified, contributing 16.7 x 109 SU, equalling 22% of total antibiotic consumption in 2015. The most sold antibiotic FDCs were amoxicillin-clavulanic acid followed by trimethoprim/sulfamethoxazole and ampicillin/cloxacillin. The category with the highest consumption volume was aminopenicillin/ß-lactamase inhibitor +/- other agents. The majority of antibiotic FDCs (92%; 110/119) were not approved by the US FDA. Of these, the most sold were ampicillin/cloxacillin, cefixime/ofloxacin and metronidazole/spiramycin. More than 80% (98/119) of FDC antibiotics were not compatible with the 2017 WHO EML. The countries with the highest numbers of FDC antibiotics were India (80/119), China (25/119) and Vietnam (19/119). There is high consumption of FDC antibiotics globally, particularly in middle-income countries. The majority of FDC antibiotic were not approved by either US FDA or WHO EML. International initiatives such as clear guidance from the WHO EML on which FDCs are not appropriate may help to regulate the manufacturing and sales of these antibiotics.

Evolution of drug-eluting biomedical implants for sustained drug delivery.

In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems associated with this type of delivery is that the drug concentration is controlled by first pass metabolism, and therefore may not always remain within the therapeutic window. Implantable drug delivery systems (IDDSs) are an excellent alternative to traditional delivery because they offer the ability to precisely control the drug release, deliver drugs locally to the target tissue, and avoid the toxic side effects often experienced with systemic administration. Since the creation of the first FDA-approved IDDS in 1990, there has been a surge in research devoted to fabricating and testing novel IDDS formulations. The versatility of these systems is evident when looking at the various biomedical applications that utilize IDDSs. This review provides an overview of the history of IDDSs, with examples of the different types of IDDS formulations, as well as looking at current and future biomedical applications for such systems. Though there are still obstacles that need to be overcome, ever-emerging new technologies are making the manufacturing of IDDSs a rewarding therapeutic endeavor with potential for further improvements.

Stability of Biologics and the Quest for Polysorbate Alternatives.

Most biopharmaceutical formulations use polysorbates: surfactants that are highly efficient but difficult to manage in terms of compositional variability, quality, and stability. Alternatives, such as poloxamers, albumin, and cyclodextrin, are becoming popular and are being explored for their potential to protect biopharmaceuticals against physical and mechanical stresses.

Vaccine formulations in clinical development for the prevention of severe acute respiratory syndrome coronavirus 2 infection.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented effort toward the development of an effective and safe vaccine. Aided by extensive research efforts into characterizing and developing countermeasures towards prior coronavirus epidemics, as well as recent developments of diverse vaccine platform technologies, hundreds of vaccine candidates using dozens of delivery vehicles and routes have been proposed and evaluated preclinically. A high demand coupled with massive effort from researchers has led to the advancement of at least 31 candidate vaccines in clinical trials, many using platforms that have never before been approved for use in humans. This review will address the approach and requirements for a successful vaccine against SARS-CoV-2, the background of the myriad of vaccine platforms currently in clinical trials for COVID-19 prevention, and a summary of the present results of those trials. It concludes with a perspective on formulation problems which remain to be addressed in COVID-19 vaccine development and antigens or adjuvants which may be worth further investigation.

Automated compounding technology and workflow solutions for the preparation of chemotherapy: a systematic review.

OBJECTIVES: The current systematic review (SR) was undertaken to summarise the published literature reporting the clinical and economic value of automation for chemotherapy preparation management to include compounding workflow software and robotic compounding systems. METHODS: Literature searches were conducted in MEDLINE, Embase and the Cochrane Library on 16 November 2017 to identify publications investigating chemotherapy compounding workflow software solutions used in a hospital pharmacy for the preparation of chemotherapy. RESULTS: 5175 publications were screened by title and abstract and 18 of 72 full publications screened were included. Grey literature searching identified an additional seven publications. The SR identified 25 publications relating to commercial technologies for compounding (Robotic compounding systems: APOTECAchemo (n=12), CytoCare (n=5) and RIVA (n=1); Workflow software: Cato (n=6) and Diana (n=1)). The studies demonstrate that compounding technologies improved accuracy in dose preparations and reduced dose errors compared with manual compounding. Comparable levels of contamination were reported for technologies compared with manual compounding. The compounding technologies were associated with reductions in annual costs compared with manual compounding, but the impact on compounding times was not consistent and was dependent on the type of compounding technology. CONCLUSIONS: The published evidence suggests that the implementation of chemotherapy compounding automation solutions may reduce compounding errors and reduce costs; however, this is highly variable depending on the form of automation. In addition, the available evidence is heterogeneous, sparse and inconsistently reported. A key finding from the current SR is a 'call to action' to encourage pharmacists to publish data following implementation of chemotherapy compounding technologies in their hospital, which would allow for evidence-based recommendations on the benefits of chemotherapy compounding technologies.

Retrospective survey of compounded medications for children in Japan.

Compounding of medications, such as crushing tablets and dispersing the contents of capsules, is a common practice in pharmacies and hospitals worldwide and is often done to provide age-appropriate formulations for oral use in pediatric patients. In the present study, a retrospective, descriptive, questionnaire-based survey was conducted to clarify the current status of drug compounding for pediatric patients in Japan. An electronic questionnaire was distributed to 740 hospitals in Japan with pediatric beds, and 208 (28.1%) of these hospitals responded. The total instances of compounding numbered 14,864 (9.6% of the total pediatric oral prescriptions) and comprised 266 active pharmaceutical ingredients (APIs), one-third of which (98 APIs) were compounded even though flexible dosage forms were available. The three most frequently compounded drugs were dantrolene sodium capsules (1152 prescriptions), ramelteon tablets (726 prescriptions), and hydrocortisone tablets (652 prescriptions), all of which were prescribed and administered in powder form. Although compounding of medications frequently varied by the patients' age, steroids such as prednisolone, dexamethasone, and hydrocortisone were commonly compounded in all age groups. To ensure the quality and safety of these compounded medications, developing a standard protocol for compounding methods is urgently needed in Japan.

Liquisolid Technology: A State-of-the-Art Review on the Current State, Challenges, New and Emerging Technologies for Next Generation.

Nowadays, the focus has been shifted to new technologies for improving drug solubility, permeability, and bioavailability, amid unprecedentedly increasing the number of newly discovered Active Pharmaceutical Ingredients (APIs), which are mostly categorized under Biopharmaceutical Classification System (BCS) as class-II and class IV. Traditional technologies and classical formulation strategies often fail to address most of the formulation problems associated with new APIs, particularly solubility and bioavailability. Therefore, exploring new and innovative technologies on an industrial scale is a prerequisite and requires modernization of manufacturing processes, as well as more advanced research and development. Liquisolid technology is a new, innovative industrial technology, particularly designed for either improving the release rates of poorly absorbed drugs or controlling their release pattern by achieving sustained-release profiles with zero-order release kinetics. Besides, it is a promising photoprotective system for photosensitive drugs and can further be used for modulating the drug microenvironmental pH. The next generation of liquisolid systems stems from a set of emerging technologies, such as liqui-pellet technology, which originates from combining liquisolid technology with pelletization technique, particularly extrusion-spheronization technique. This review article highlights the current state of liquisolid technology, ongoing challenges, characterization and applications, possible future prospects, the advent of new and emerging technologies, and the revolution of the next generation of liquisolid technology.

Recent Advances in Nanoencapsulation of Phytochemicals to Combat Obesity and Its Comorbidities.

An increasing epidemic of obesity has become a serious public health concern primarily because it contributes to pathogenesis of many chronic diseases including type 2 diabetes, cardiovascular disease, hepatobiliary disease, obstructive sleep apnea, kidney disease, some types of cancer, among others. Consumption of a variety of phytochemicals has emerged as a promising potential for combating obesity and its comorbidities. However, the generally low aqueous solubility, stability, bioavailability, and target specificity of phytochemicals, along with their side-effects and toxicity seen when used at high doses, have restricted their clinical applications. As a solution, phytochemicals can be encapsulated into nanoparticles to increase their stability and solubility, enhance their bioavailability, protect them from premature degradation in the body, prolong their circulation time, and thus enhance their antiobesity activity. In this perspective, we summarize the problems and limitations of the prominent phytochemicals (epigallocatechin gallate, trans-resveratrol, curcumin, and quercetin), the major biocompatible and biodegradable nanoparticles, and the efficacy of nanoencapsulated forms of these phytochemicals in combating obesity and its comorbidities.

Towards effective COVID­19 vaccines: Updates, perspectives and challenges (Review).

In the current context of the pandemic triggered by SARS-COV-2, the immunization of the population through vaccination is recognized as a public health priority. In the case of SARS­COV­2, the genetic sequencing was done quickly, in one month. Since then, worldwide research has focused on obtaining a vaccine. This has a major economic impact because new technological platforms and advanced genetic engineering procedures are required to obtain a COVID­19 vaccine. The most difficult scientific challenge for this future vaccine obtained in the laboratory is the proof of clinical safety and efficacy. The biggest challenge of manufacturing is the construction and validation of production platforms capable of making the vaccine on a large scale.