Recent trends in the delivery of RNA drugs: Beyond the liver, more than vaccine.

RNAs are known for versatile functions and therapeutic utility. They have gained significant interest since the approval of several RNA drugs, including COVID-19 mRNA vaccines and therapeutic agents targeting liver diseases. There are increasing expectations for a new class of RNA drugs for broader applications. Successful development of RNA drugs for new applications hinges on understanding their diverse functions and structures. In this review, we explore the last five years of literature to understand current approaches to formulate a spectrum of RNA drugs, focusing on new efforts to expand their applications beyond vaccines and liver diseases.

The promise of microneedle technologies for drug delivery.

Microneedle (MN) technologies offer the opportunity to improve patient access and target delivery of drugs and vaccines to specific tissues. When in the form of skin patches, MNs can be administered by personnel with minimal training, or could be self-administered by patients, which can improve access to medication, especially those usually requiring injection. Because MNs are small (usually sub-millimetre), they can be used for precise tissue targeting. MN patches have been extensively studied to administer vaccines and drugs in preclinical work as well as in multiple clinical trials. When formulated with biodegradable polymer, MNs can enable long-acting therapies by slowly releasing drug as the MNs biodegrade. Targeted drug delivery by hollow MNs has resulted in FDA-approved products that are able to inject vaccines to skin-resident immune cells to improve immune response and to target specific parts of the eye (e.g., suprachoroidal space) for increased efficacy and avoidance of side effects in other parts of the eye. Cosmetic products based on MN technologies are already in widespread use, mostly as anti-aging agents. With extensive research coupled with FDA-approved products, MN technology promises to continue is growth in research leading to products that can benefit patients.

"Regulatory Sandboxes" Could Solve the Regulatory Problems Encountered in Europe and Arising from Innovation in Biological Medicinal Products.

Pharmaceutical innovation can sometimes clash with existing regulations, creating challenges for pioneering medicinal products, especially biologics, as they transition from the research phase to product development and post-approval categorisation. For instance, vaccines and advanced therapy medicinal products must fall under the category of biological medicinal products. However, the ability to chemically synthesise both proteins or mRNA can rule out classifying them as vaccines or advanced therapy medicinal products. Consequently, many organic products face regulatory obstacles when attempting to reach the market owing to their inherent natures or involved technologies. The European Commission's proposal for a directive to overhaul the European Union pharmaceutical legislation brings in a new tool: the regulatory sandboxes. They could be a suitable solution to manufacture pioneering medicinal products. Regulatory sandboxes are a form of legal experimentation helping with the marketing of a medicinal product based on groundbreaking technology as they sidestep current regulations. In essence, a regulatory sandbox is a tailor-made, inherently flexible, and time-limited regulatory framework facilitating the development of a drug outside the standard regulatory framework.

Pharmaceutical Innovation in Latin America and the Caribbean.

This study assesses Latin America and Caribbean countries' capacity to innovate new pharmaceuticals, defined as developing new drugs and vaccines, repurposing existing drugs, and inventing around patents to produce new drug variations. Vaccine innovation includes reengineering existing vaccines, developing new manufacturing methods, and the clinical development of unapproved vaccine candidates initiated elsewhere.

Trust in pharmaceuticals and vaccine hesitancy: exploring factors influencing COVID-19 immunization among Lebanese children aged 1 to 11 years.

INTRODUCTION: The COVID-19 pandemic is a serious threat to everyone's health. Numerous studies have demonstrated that vaccines are very effective in preventing COVID-19-related severe illness, hospitalization, and death. Children's vaccination exerts its protecting effect by preventing the spread of the virus. The purpose of this study was to analyze the rate of COVID-19 immunization among Lebanese children aged 1 to 11 years and assess parental factors that affect immunization rates. METHODS: An online cross-sectional study was conducted between January and March 2023. The online survey was distributed across all social media channels, including the Ministry of Public Health website. RESULTS: A total of 390 parents filled the survey (mean age = 37.48 ± 8.39 years; 50.5% mothers; 70% with a university level of education). Mothers compared to fathers, having a history of bad reaction to a vaccine vs. not, and higher vaccine hesitancy were significantly associated with less willingness to administer the vaccine to the child. Trusting pharmaceutical companies was significantly associated with more willingness to administer the vaccine to the child. CONCLUSION: The results of this study show that the factors associated with parents' decisions to vaccinate their children may vary. Our findings conclude that vaccine acceptance is being highly associated with parental concerns, trust, and information regarding the vaccine safety and efficacy.

On the momentum toward vaccine self-sufficiency in the BRICS: an integrative review of the role of pharmaceutical entrepreneurship and innovation.

Background: With the perspicuous effect of COVID-19 on vaccine demand, academic and business interest in vaccine production in the BRICS nations (Brazil, the Russian Federation, India, China, and South Africa) has reached a crescendo. Aware of a "dark" past when the BRICS depended heavily on vaccines and pharmaceuticals from other parts of the world, academic curiosity on how the BRICS countries have leveraged vaccine self-sufficiency and become the hub of global vaccine production and supply is justifiable, especially in times of ineffable pandemics. Methods: The articles were searched from November 2020 to December 2022. Within this period, an electronic search of 13 reputable healthcare and public databases was conducted. The initial searches from the designated databases yielded a total of 3,928 articles. Then, duplicated studies were removed through a two-step process, articles without titles and abstracts were excluded, and the remaining 898 articles that met the qualification assessment criteria were evaluated for article quality. Results: The main entrepreneurial innovations that have quickened the pace of vaccine self-sufficiency in the BRICS include investment in artificial intelligence (AI), Big Data Analytics, and Blockchain technologies. These help to speed up the drug delivery process by enhancing patient identification or optimizing potential drug candidates for clinical trials and production. Conclusion: Over the past 20 years, the BRICS nations have achieved major strides in vaccine development, regulation, and production. The creation of the BRICS Vaccine Research and Development (R&D) Center will have a significant impact on vaccine cost and accessibility given the anticipated development of stronger research capability, production, and distribution technology, as well as stronger standardization to improve vaccine production quality in the near future. It is anticipated that the BRICS' contributions to vaccine development will alter the global vaccination market and hasten the availability of vaccinations in developing nations. The challenge is turning these hopes into concrete plans of action and outcomes.

Lyotropic liquid crystalline phases: Drug delivery and biomedical applications.

Liquid crystal (LC)-based nanoformulations may efficiently deliver drugs and therapeutics to targeted biological sites. Lyotropic liquid crystalline phases (LLCPs) have received much interest in recent years due to their unique structural characteristics of both isotropic liquids and crystalline solids. These LLCPs can be utilized as promising drug delivery systems to deliver drugs, proteins, peptides and vaccines because of their improved drug loading, stabilization, and controlled drug release. The effects of molecule shape, microsegregation, and chirality are very important in the formation of liquid crystalline phases (LCPs). Homogenization of self-assembled amphiphilic lipids, water and stabilizers produces LLCPs with different types of mesophases, bicontinuous cubic (cubosomes) and inverse hexagonal (hexosomes). Moreover, many studies have also shown higher bioadhesivity and biocompatibility of LCs due to their structural resemblance to biological membranes, thus making them more efficient for targeted drug delivery. In this review, an outline of the engineering aspects of LLCPs and polymer-based LLCPs is summarized. Moreover, it covers parenteral, oral, transdermal delivery and medical imaging of LC in targeting various tissues and is discussed with a scope to design more efficient next-generation novel nanosystems. In addition, a detailed overview of advanced liquid crystal-based drug delivery for vaccines and biomedical applications is reviewed.

Unraveling the potential of M13 phages in biomedicine: Advancing drug nanodelivery and gene therapy.

M13 phages possessing filamentous phage genomes offer the benefits of selective display of molecular moieties and delivery of therapeutic agent payloads with a tolerable safety profile. M13 phage-displayed technology for resembling antigen portions led to the discovery of mimetic epitopes that applied to antibody-based therapy and could be useful in the design of anticancer vaccines. To date, the excremental experiences have engaged the M13 phage in the development of innovative biosensors for detecting biospecies, biomolecules, and human cells with an acceptable limit of detection. Addressing the emergence of antibiotic-resistant bacteria, M13 phages are potent for packaging the programmed gene editing tools, such as CRISPR/Cas, to target multiple antimicrobial genes. Moreover, their display potential in combination with nanoparticles inspires new approaches for engineering targeted theragnostic platforms targeting multiple cellular biomarkers in vivo. In this review, we present the available data on optimizing the use of bacteriophages with a focus on the to date experiences with M13 phages, either as monoagent or as part of combination regimens in the practices of biosensors, vaccines, bactericidal, modeling of specific antigen epitopes, and phage-guided nanoparticles for drug delivery systems. Despite increasing research interest, a deep understanding of the underlying biological and genetic behaviors of M13 phages is needed to enable the full potential of these bioagents in biomedicine, as discussed here. We also discuss some of the challenges that have thus far limited the development and practical marketing of M13 phages.

Pharma - manufacturing: the unappreciated and overlooked indispensable skill.

The process of vaccine production, manufacturing, is time-intensive, complex, expensive, and highly technical, requiring close coordination and collaboration among multiple companies with different inputs, from active pharmaceutical ingredients to glass, and specializations, and with the supply chains spread across many countries. Covid-19 pandemic highlighted that neglecting and ignoring the need for a global effort in vaccine manufacturing and delivery can have alarming, and devastating, repercussions, especially when the world needs a robust healthcare ecosystem to make sure that all of us are safe. So, the natural question is: what does the world need to be well-prepared for the next virus; what does it take to have the manufacturing of vaccines become less concentrated in a few countries and centers and diversified to more countries so that distribution can be more universal, so that all of us are safe? First will need to be the political recognition, and the acceptance, that no country can do or supply everything alone in the pharmaceutical sector - no country can be an island -and that binding international agreements will need to be adopted to make access to medicine more equitable and secure around the world. Furthermore, and critically so, significant long-term sustained investment in human resources must be adopted to fill major gaps in expertise, starting with a robust educational system whose graduates have the knowledge, ability, and capacity to work in this technical industry. Only then, with a professional-educated labor force, can resilient pharma-manufacturing clusters be successfully built throughout the world, which can, and will, give life to the new health code: "No one is safe, until everyone is safe."

New role of bacteriophages in medical oncology.

Targeted treatment of cancer is one of the most paramount approaches in cancer treatment. Despite significant advances in cancer diagnosis and treatment methods, there are still significant limitations and disadvantages in the field, including high costs, toxicity, and unwanted damage to healthy cells. The phage display technique is an innovative method for designing carriers containing exogenic peptides with cancer diagnostic and therapeutic properties. Bacteriophages possess unique properties making them effective in cancer treatment. These characteristics include the small size enabling them to penetrate vessels; having no pathogenicity to mammals; easy manipulation of their genetic information and surface proteins to introduce vaccines and drugs to cancer tissues; lower cost of large-scale production; and greater stimulation of the immune system. Bacteriophages will certainly play a more effective role in the future of medical oncology; however, studies are in the early stages of conception and require more extensive research. We aimed in this review to provide some related examples and bring insights into the potential of phages as targeted vectors for use in cancer diagnosis and treatment, especially regarding their capability in gene and drug delivery to cancer target cells, determination of tumor markers, and vaccine design to stimulate anticancer immunity.

Public trust is earned: Historical discrimination, carceral violence, and the COVID-19 pandemic.

OBJECTIVE: To assess whether knowledge of Tuskegee, the U.S. Immigration and Customs Enforcement (ICE) agency's detainment of children, and satisfaction with the George Floyd death investigation were associated with trust in actors involved in the development and distribution of coronavirus vaccines. DATA SOURCES AND STUDY SETTING: National survey with a convenience sample of Black (n = 1019) and Hispanic (n = 994) adults between July 1 and 26, 2021. STUDY DESIGN: Observational study using stratified adjusted logistic regression models to measure the association between ratings of the trustworthiness of actors involved in the development and distribution of coronavirus vaccines. PRINCIPAL FINDINGS: Among Black respondents, lower satisfaction with the George Floyd death investigation was associated with lower trustworthiness ratings of pharmaceutical companies (ME: -0.09; CI: -0.15, 0.02), the FDA (ME: -0.07; CI: -0.14, -0.00), the Trump Administration (ME: -0.09; CI: -0.16, -0.02), the Biden Administration (ME: -0.07, CI: -0.10, 0.04), and elected officials (ME: -0.10, CI: -0.18, -0.03). Among Hispanic respondents, lower satisfaction was associated with lower trustworthiness ratings of the Trump Administration (ME: -0.14, CI: -0.22, -0.06) and elected officials (ME: -0.11; CI: -0.19, -0.02). Greater knowledge of ICE's detainment of children and families among Hispanic respondents was associated with lower trustworthiness ratings of state elected officials (ME: -0.09, CI: -0.16, 0.01). Greater knowledge of the US Public Health Service Study of Syphilis in Tuskegee was associated with higher trustworthiness ratings of their usual source of care (ME: 0.09; CI: 0.28, 0.15) among Black respondents (ME: 0.09; CI: 0.01, 0.16). CONCLUSIONS: Among Black respondents, lower satisfaction with the George Floyd death investigation was associated with lowered levels of trust in pharmaceutical companies, some government officials, and administrators; it was not associated with the erosion of trust in direct sources of health care delivery, information, or regulation. Among Hispanic respondents, greater knowledge of the ICE detainments was associated with lower trustworthiness ratings of elected state officials. Paradoxically, higher knowledge of the Study of Syphilis in Tuskegee was associated with higher trustworthiness ratings in usual sources of care.

Recent progress in PLGA-based microneedle-mediated transdermal drug and vaccine delivery.

Microneedles (MNs) have recently been found to have applications in drug, vitamin, protein and vaccine delivery. Polymeric MN arrays continue to attract increasing attention due to their capability to bypass the skin's stratum corneum (SC) barrier with minimal invasiveness. These carriers can achieve the targeted intradermal delivery of drugs and vaccines and improve their transdermal delivery level. As a nontoxic FDA-approved copolymer, polylactic glycolic acid (PLGA) has good biocompatibility and biodegradability. Currently, PLGA-based MNs have a noticeable tendency to be utilized as a delivery system. This study focuses on the most recent advances in PLGA-based MNs. Both PLGA nanoparticle-based MNs and PLGA matrix-based MNs, created for the delivery of vaccines, drugs, proteins and other therapeutic agents, are discussed. The paper also discusses the various types of MNs and their potential applications. Finally, the prospects and challenges of PLGA-based MNs are reviewed.

[Erythrocytes-camouflaged nanoparticles: a promising delivery system for drugs and vaccines].

Erythrocytes-camouflaged nanoparticles is an in vivo delivery system that uses erythrocytes or erythrocyte membrane nano vesicles as carriers for drugs, enzymes, peptides and antigens. This system has the advantages of good biocompatibility, long circulation cycle and efficient targeting. This review summarizes the type of carriers, their development history, the application of delivery strategies as well as their limitations and future challenges. Lastly, future directions and key issues in the development of this system are discussed.

The United States Food and Drug Administration (FDA) regulatory response to combat neglected tropical diseases (NTDs): A review.

The availability and accessibility of safe and effective drugs, vaccines, and diagnostics are essential to reducing the immense global burden of neglected tropical diseases (NTDs). National regulatory authorities, such as the United States Food and Drug Administration (FDA), play an essential role in this effort to ensure access to safe and effective medical products by working within a set of legal frameworks and regulatory functions. However, medical product development for NTDs remains neglected, as combating NTDs is not a viable commercial market for pharmaceutical companies. To spur research and development (R&D) of NTD products, the US government has authorized various programs and policies to engage pharmaceutical companies, many of which provide FDA with the legal authority to implement NTD programs and pathways. Thus, this review provides a clear overview of the various regulatory pathways and programs employed by the FDA to increase the availability of NTD drugs, vaccines, and diagnostics. The review assesses the available information on various regulatory considerations and their impact on NTD product development as a first step in estimating the importance of such programs. Next, findings related to currently approved NTD products through these programs are discussed. Lastly, gaps in NTD R&D are identified and suggestions on how to address these are presented. The available data shows that while such incentive programs are factored into companies' decisions to pursue NTD R&D, approved products for NTDs remains vastly insufficient. Most approved products that utilize these NTD regulatory pathways and programs are overwhelmingly for tuberculosis and malaria-both of which are not considered NTDs by the World Health Organization (WHO). Dedicated efforts are needed to facilitate and accelerate NTD product including employing multiple incentive programs, regular assessment of such programs, and leveraging on public-private partnerships.

Mechanical properties and immunotherapeutic effects of dissolving microneedles with different drug loadings based on hyaluronic acid

Abstract Improving vaccine immunity and reducing antigen usage are major challenges in the clinical application of vaccines. Microneedles have been proven to be painless, minimally invasive, highly efficient, and have good patient compliance. Compared with traditional transdermal drug delivery, it can effectively deliver a large-molecular-weight drug into the skin, resulting in a corresponding immune response. However, few studies have examined the relationship between microneedle loading dose and immune effects. In this study, the hyaluronic acid (HA) conical and pyramidal dissolving microneedles were prepared by the two-step vacuum drying method, respectively. The model drug ovalbumin (OVA) was added to HA to prepare dissolving microneedles with different loading amounts. The mass ratios of HA to OVA were 5:1, 5:3, and 5:5. The mechanical properties of the dissolving microneedles were characterized using nanoindentation and in vitro puncture studies. The immune effects of the matrix and drug content were studied in Sprague-Dawley (SD) rats. Finally, the diffusion behavior of OVA and the binding mode of HA and OVA in the microneedles were simulated using Materials Studio and Autodocking software. The experimental results showed that the conical microneedles exhibited better mechanical properties. When the mass ratio of HA to OVA was 5:3, the immune effect can be improved by 37.01% compared to subcutaneous injection, and achieved a better immune effect with relatively fewer drugs. This conclusion is consistent with molecular simulations. This study provides theoretical and experimental support for the drug loading and efficacy of microneedles with different drug loadings

Erythrocytes-camouflaged nanoparticles: a promising delivery system for drugs and vaccines / 生物工程学报

Erythrocytes-camouflaged nanoparticles is an in vivo delivery system that uses erythrocytes or erythrocyte membrane nano vesicles as carriers for drugs, enzymes, peptides and antigens. This system has the advantages of good biocompatibility, long circulation cycle and efficient targeting. This review summarizes the type of carriers, their development history, the application of delivery strategies as well as their limitations and future challenges. Lastly, future directions and key issues in the development of this system are discussed.

To Affinity and Beyond: A Personal Reflection on the Design and Discovery of Drugs.

Faced with new and as yet unmet medical need, the stark underperformance of the pharmaceutical discovery process is well described if not perfectly understood. Driven primarily by profit rather than societal need, the search for new pharmaceutical products-small molecule drugs, biologicals, and vaccines-is neither properly funded nor sufficiently systematic. Many innovative approaches remain significantly underused and severely underappreciated, while dominant methodologies are replete with problems and limitations. Design is a component of drug discovery that is much discussed but seldom realised. In and of itself, technical innovation alone is unlikely to fulfil all the possibilities of drug discovery if the necessary underlying infrastructure remains unaltered. A fundamental revision in attitudes, with greater reliance on design powered by computational approaches, as well as a move away from the commercial imperative, is thus essential to capitalise fully on the potential of pharmaceutical intervention in healthcare.

A Call to Action Against Persistent Lack of Transparency in Vaccine Pricing Practices During the COVID-19 Pandemic.

Lack of transparency in vaccine pricing practices is a problem that has been under discussion for a long time. To tackle this, the World Health Assembly adopted the resolution Improving the transparency of markets for medicines, vaccines, and other health products in 2019. However, despite the appalling effects of the current pandemic and the unequal global distribution of vaccines, the 2019 resolution has not been included as a fundamental pillar in the global health response to COVID-19. Governments and public health agencies have provided public funding to pharmaceutical companies for research and development of new vaccines. Yet, information on pricing strategies and methodologies is still inaccessible. Furthermore, these companies are profiting from publicly funded research and development. But secrecy and opacity prevails in the pharmaceutical industry, affecting low and middle income countries. Situating the demand for transparency, accountability and fair pricing of pharmaceutical products as a global health justice issue, I suggest an independent global observatory for accountability and transparency in the pharmaceutical global market should be created to help international organizations, governments and civil society in their quest for affordable and safe vaccines and therapeutics.