Formulation Strategies Research Articles

Application of polyethylene glycol 8000 as plasticizer for the development of ellagic acid and Eudragit® EPO based solid dispersions using hot melt extrusion.

Solid dispersion formation by Hot melt extrusion (HME) is a widely used formulation strategy to improve the solubility and bioavailability of poorly water-soluble drugs. Despite this, they are limited by various factors such as drug-excipient miscibility, poor stability, limited drug loading and extrudability of physical drug-excipient mixtures. In this work, polyethylene glycol 8000 (PEG 8000) was used as a plasticizer for the manufacture of ellagic acid solid dispersions (EASD) with high drug loading. Indeed, EA is a polyphenolic active compound with antimalarial and other promising therapeutic activities. However, its low solubility and low permeability limit its therapeutic use. Solid dispersions formation may overcome this challenge, but its high melting point negatively influences the extrudability of its binary physical mixtures with a high drug loading rate, hence the need to use a plasticizer. Thus, five formulations consisting of EA, Eudragit® EPO and PEG 8000 in the ratio of 15:75:10 (F1), 20:70:10 (F2), 25:65:10 (F3), 15:80:5 (F4) and 20:85:5 (F5) % w/w, respectively, have been extruded, four of which were successful. The extrudates were evaluated by X-ray powder diffraction, FTIR spectroscopy and in vitro dissolution tests. Based on the results of these tests, the F5 formulation was identified as the most promising. Indeed, after 15 min of dissolution test, the dissolution rate of ellagic acid from the formulations was 62.67±3.10%, 58.74±7.23 %, 88.75±3.02% and 83.47±4.40% respectively for formulation F1, F2, F4 and F5. Moreover, the results of the FTIR spectroscopy analyses showed stronger interactions between the different constituents in the F4 and 5 formulations compared to the F1 and 2 formulations. Extruded materials of the F5 formulation, characterized by solid state nuclear magnetic resonance (ssNMR) spectroscopy and subjected to stability studies, showed good physical stability for twelve months under real-time stability study conditions and for six months under accelerated conditions.

Benefits of combining supersaturating and solubilizing formulations – Is two better than one?

A variety of enabling formulations has been developed to address poor oral drug absorption caused by insufficient dissolution in the gastrointestinal tract. As the in vivo performance of these formulations is a result of a complex interplay between dissolution, digestion and permeation, development of suitable in vitro assays that captures these phenomena are called for. The enabling-absorption (ENA) device, consisting of a donor and receiver chamber separated by a semipermeable membrane, has successfully been used to study the performance of lipid-based formulations. In this work, the ENA device was prepared with two different setups (a Caco-2 cell monolayer and an artificial lipid membrane) to study the performance of a lipid-based formulation (LBF), an amorphous solid dispersion (ASD) and the potential benefit of combining the two formulation strategies. An in vivo pharmacokinetic study in rats was performed to evaluate the in vitro-in vivo correlation. In the ENA, high drug concentrations in the donor chamber did not translate to a high mass transfer, which was particularly evident for the ASD as compared to the LBF. The solubility of the polymer used in the ASD was strongly affected by pH-shifts in vitro, and the ph_dependence resulted in poor in vivo performance of the formulation. The dissolution was however increased in vitro when the ASD was combined with a blank lipid-based formulation. This beneficial effect was also observed in vivo, where the drug exposure of the ASD increased significantly when the ASD was co-administered with the blank LBF. To conclude, the in vitro model managed to capture solubility limitations and strategies to overcome these for one of the formulations studied. The correlation between the in vivo exposure of the drug exposure and AUC in the ENA was good for the non pH-sensitive formulations. The deconvoluted pharmacokinetic data indicated that the receiver chamber was a better predictor for the in vivo performance of the drug, however both chambers provided valuable insights to the observed outcome in vivo. This shows that the advanced in vitro setting used herein successfully could explain absorption differences of highly complex formulations.

Enzyme‐Responsive Polyion Complex Nanoparticles of Cationic Antimicrobials for Activatable Antibacterial Therapy

AbstractA self‐assembled “caging” strategy is presented for the safe delivery of potent cationic antimicrobials that suffer from non‐specific toxicity for the effective treatment of in vivo systemic bacterial infection. The key development here is a new block copolymer consisting of a poly(ethylene glycol) (PEG) stealth block and an anionic and lipase‐degradable block of poly(ɛ‐caprolactone) (PCL) and phosphonic acid‐bearing methacrylate copolymer, synthesized by hybrid copolymerization of methacrylate and cyclic esters. The anionic blocks electrostatically interact with cationic antimicrobials to form neutrally charged polyion complexes with the PEG blocks on the surface. The PCL component imparts the nanocomplex with biodegradability by bacterial secretory lipase. In the proof‐of‐concept study, cationic polyimidazolium that shows excellent antibacterial activity but severe toxicity is packaged by the block copolymer into nanocomplexes, which are stable in complex environments of high salt and protein concentrations and released the antimicrobials upon degradation of the copolymer by bacteria‐secreted lipase. The “caging” formulation of polyimidazolium eliminated its toxicity and led to highly effective bactericidal performance comparable to free polyimidazolium. This caging strategy does not require sophisticated chemical modification of cationic antimicrobials, offering a broadly applicable formulation strategy to overcome their common toxicity issue that has become a primary translational barrier.

Etiopathology, Epidemiology, Diagnosis, and Treatment of Fungal Keratitis.

Fungal keratitis (FK) is a severe ocular condition resulting from corneal infection that is prevalent in tropical countries, particularly in developing regions of Asia and Africa. Factors like corneal lens misuse, inappropriate steroid use, and diagnostic challenges have provoked the epidemic. FK causes significant vision impairment, scarring, and ocular deformities. Accurate pathological diagnosis is crucial for effective therapeutic intervention. Topical antifungal therapy with surface healing medications proves effective in preventing fungal-borne ulcers. Managing FK requires a comprehensive understanding of fungal pathogenesis, guiding formulation strategies and preventive measures to curb global ocular blindness. This review provides in-depth insights into FK, covering etiology, epidemiology, pathogenesis, therapeutic interventions, antifungal resistance, limitations, prevention, and future perspectives on ocular surface disease management.

Cyclodextrin inclusion complex and amorphous solid dispersions as formulation approaches for enhancement of curcumin’s solubility and nasal epithelial membrane permeation

BackgroundCurcumin is a compound that occurs in the rhizomes of the turmeric plant (Curcuma longa) and has shown potential for the treatment of illnesses including certain neurodegenerative diseases. The bioavailability of curcumin is hindered by its extremely poor aqueous solubility.ResultsThis study aimed to apply formulation strategies such as inclusion complex formation with hydroxypropyl-β-cyclodextrin (HPβCD), as well as amorphous solid dispersion (ASD) formation with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) and hydroxypropyl methylcellulose (HPMC) to increase curcumin’s solubility and thereby its nasal epithelial membrane permeation. The curcumin formulations were evaluated by means of DSC, TGA, FT-IR, XRPD, microscopic imaging, aqueous solubility and membrane permeation across nasal respiratory and olfactory epithelial membranes. The solubility of curcumin was substantially increased by the formulations from 8.4 µg/ml for the curcumin raw material to 79.0 µg/ml for the HPβCD inclusion complex, 256.4 µg/ml for the HPMC ASD and 314.9 µg/ml for the PVP VA64 ASD. The HPMC ASD only slightly changed the membrane permeation of curcumin, while the PVP VA64 ASD decreased the membrane permeation of curcumin. The HPβCD inclusion complex enhanced the nasal epithelial membrane permeation of curcumin statistically significantly across the olfactory epithelial tissue and extensively across the respiratory epithelial tissue.ConclusionComplexation of curcumin with HPβCD enhanced the solubility of curcumin and thereby also increased its permeation across excised nasal respiratory and olfactory epithelial tissue. This indicated high potential of the curcumin-HPβCD complex for nose-to-brain delivery of curcumin for treatment of neurodegenerative diseases by means of intranasal administration.Graphical abstract

Symphytum genus—from traditional medicine to modern uses: an update on phytochemistry, pharmacological activity, and safety

AbstractWith around 34 recognized species, Symphytum genus (comfrey) has a noteworthy position within the Boraginaceae family. Comfrey species have been empirically used since ancient times as wound-healing and skin-regenerating agents in ulcers, wounds, bone fractures, and rheumatic complaints. This review aims to provide a thorough examination of recent scientific advances and challenges within the Symphytum genus, covering data published between 2013 and 2023. It delivers an updated overview of the taxonomy, ethnopharmacological uses, chemical composition, and pharmacological activities of the genus. Special emphasis is put on molecular identification methods for species taxonomy, emerging extraction technologies for comfrey phytochemicals, metabolomics techniques for mapping chemical complexity, modern bioassay platforms revealing its poly-pharmacology, formulation strategies, and remediation approaches for removal of toxic pyrrolizidine alkaloids (PAs). For instance, recent metabolomic studies employing advanced spectro-chromatographic techniques have revealed a diverse chemical composition of comfrey plants, including polysaccharides, allantoin, benzoic and cinnamic acid derivatives, flavonoids, fatty acids, and unsaturated necine-structure-based PAs. The mechanisms underlying their anti-inflammatory, analgesic, wound-healing, anti-irritant, and osteo-regenerative properties were targeted in modern pharmacological setups. Thus, key compounds like allantoin, rosmarinic acid, globoidnans A and B, rabdosiin, and comfreyn A, have been identified as significant contributors to the anti-inflammatory and wound-healing effects of Symphytum-derived preparations. Despite their well-established clinical use, concerns about PAs-induced toxicity have prompted the development of novel PA remediation strategies, enabling the production of comfrey extracts with enhanced safety profiles that can meet the regulatory standards imposed by authorities.

Fast and reliable method for analysis of derivatized plasma amino acids by liquid chromatography-single quadrupole-mass spectrometry

The pool of free, genetically encoded AA in plasma plays an essential role not only as substrate for every protein synthesized in the body but also as signaling molecules that regulate a wide range of physiological processes. Here we present a method for the analysis of 19 of the 20 encoded AA (except Cys) in dairy cow plasma. Isolated plasma or standards for the 19 AA were gravimetrically mixed with an internal standard mix consisting of 13C isotopes of each AA. Plasma proteins were precipitated on acetonitrile and supernatants transferred to glass vials. For pre-column derivatization, plasma supernatants were buffered with sodium borate (pH 9.5 −10), and AA were derivatized with 9-fluorenylmethoxycarbonyl (Fmoc) chloride. Analytes were isolated by solid-phase extraction using a strong-anionic ion exchange column and dry eluates were reconstituted in mobile phase consisting of 70% water solution of ammonium formate and 30% acetonitrile. Amino acid derivatives were separated by reverse phase liquid chromatography over 17.5 min with a C18 column in which acetonitrile increased to 80% over the first 11 min of the method, before returning to initial levels. Electrospray ionization on negative mode was used for most AA, except Arg and Pro, for which positive mode yielded superior results. Single or double (only Lys) derivatives were measured by single quadrupole mass spectrometry. We hypothesized that pre-column Fmoc derivatization would yield optimal resolution for quantitative analysis of the 19 targeted AA and their respective 13C internal standards, with limits of quantitation beyond physiological ranges. All the 19 AA were detected with minimal background noise. An 11-point standard curve was developed for each AA. Limits of quantitation were beyond concentrations observed in plasma samples of lactating dairy cows, except for Gly that upper curve points had to be removed to maintain linearity, limiting quantitation to the upper range of physiological concentration. After removing the 4 highest concentrations from the Gly standard curve, coefficients of determination were greater than 0.999 for all the AA. Recovery of spiked AA from plasma samples ranged from 89.9% for Phe to 100.3% for Trp. Instrument repeatability averaged 0.91 and ranged from 0.33 for Val to 2.29 for Arg. Meanwhile, sample preparation method repeatability averaged 2.02 and ranged from 1.14 for Tyr to 3.34 for Arg. While robust methods have been developed, they depend on either availability of sophisticated instruments, mostly limited to core facilities (i.e., tandem MS methods), long and expensive chromatography without specific internal standards for each AA (i.e., HPLC-UV and HPLC-FLD), or unstable derivatization (GC-MS). Here we describe a method with high throughput, stable derivatization, high precision and recovery, and potentially more affordable than most existing methods. This method could help dairy nutritionists to consider plasma AA information for diet formulation strategies, potentially reducing feeding costs and N emissions.

CLIMATE CHANGE AND EXTREME EVENTS: EXPLORING THE INTERFACE

This review paper delves into "Resilience to Climate Crisis in the Anthropocene" within the broader context of "Climate Change: Conflict and Resilience in the Age of Anthropocene." It highlights that the issues resulting from climate change are both environmental and societal, intricately woven into the fabric of communities. Emphasizing the proactive cultivation of community resilience as essential for sustainable development, the chapter aims to deliver an in-depth understanding of this dynamic. The significance of this chapter lies in its holistic approach to how communities, as frontline responders, can develop resilience strategies to mitigate vulnerabilities and enhance adaptive capacities. By elucidating the interplay between climate change and community resilience, it seeks to empower policymakers, practitioners, and researchers with interdisciplinary insights. The methodology involves a comprehensive literature review that explores the interrelationship of climate change and community resilience. The paper aims to offer actionable insights and practical implications for policy formulation, governance, and community-based adaptation strategies, thereby serving as a roadmap for stakeholders. It aspires to guide informed decision-making and inspire collaborative efforts to cultivate resilient communities that pave the way for sustainable development in the Anthropocene.

Kebijakan Penta Helix dalam Pengembangan Parawisata Musik di Kota Ambon

Ambon City is known as the World Music City. As a music city, Ambon has a tourism appeal related to music. This research aims to understand the implementation of the Pentahelix policy by the Ambon City Government for the development of Ambon City as a World Music City, and to formulate and recommend strategies for collaboration among the Pentahelix actors in the implementation of the policy for the development of Ambon City as a World Music City. This research utilizes qualitative descriptive methods. The results of this study indicate that the Pentahelix policy model needs further optimization because the integrity among stakeholders is still low. Furthermore, there are several formulated recommendations and strategies that can be applied, including establishing a collaborative forum for Ambon music tourism, promoting communication among stakeholders, strengthening the AMO as a data hub and coordination center, making AMO an independent institution, stimulating communication and business initiatives, conducting research related to music tourism, developing an appropriate tourism calendar, educating and raising public awareness, conducting promotional campaigns through media, periodic monitoring and evaluation, as well as human resource development.

Changes in the Trade Pattern in China Under the RCEP: An Analysis of Trade Creation and Diversion Using the SMART-WITS Model

The Regional Comprehensive Economic Partnership (RCEP), one of the globe's most expansive free trade agreements (FTAs), has profoundly influenced its member countries' trading patterns. This fact is especially critical for a major economic powerhouse such as China. Understanding its trade creation and trade diversion within the RCEP context can facilitate successful formulation strategies and result in effective economic policies. In this study, we utilize the World Integrated Trade Solution Software for Market Analysis and Restrictions on Trade (WITS-SMART), a partial equilibrium modeling tool, on both state-level and industrial-tier tariff reductions under two distinct scenarios. Our findings confirm that China will benefit from impactful trade results across all RCEP members. Looking from industry point of view: machinery, chemicals, metals sector together with plastics and rubber production are projected to enjoy maximum rewards through increased trade creation and diversion opportunities from Japan and Korea. On the contrary, Australia and ASEAN have the greatest influence on the animal and vegetable sector. This crucial understanding creates strategic indicators that aid in evaluating the most appropriate alignments to harness the untapped potential in the RECP domain.

Stability of Protein Pharmaceuticals: Recent Advances.

There have been significant advances in the formulation and stabilization of proteins in the liquid state over the past years since our previous review. Our mechanistic understanding of protein-excipient interactions has increased, allowing one to develop formulations in a more rational fashion. The field has moved towards more complex and challenging formulations, such as high concentration formulations to allow for subcutaneous administration and co-formulation. While much of the published work has focused on mAbs, the principles appear to apply to any therapeutic protein, although mAbs clearly have some distinctive features. In this review, we first discuss chemical degradation reactions. This is followed by a section on physical instability issues. Then, more specific topics are addressed: instability induced by interactions with interfaces, predictive methods for physical stability and interplay between chemical and physical instability. The final parts are devoted to discussions how all the above impacts (co-)formulation strategies, in particular for high protein concentration solutions.'

A Lipophilic Salt Form to Enhance the Lipid Solubility and Certain Biopharmaceutical Properties of Lapatinib.

Lapatinib (LTP) commercially available as lapatinib ditosylate (LTP-DTS) salt is the only drug approved for the treatment of HER-positive metastatic breast cancer. A low and pH-dependent solubility results in poor and variable oral bioavailability, thus driving significant interest in molecular modification and formulation strategies of the drug. Furthermore, due to very high crystallinity, LTP and LTP-DTS have low solubility in lipid excipients, making it difficult to be delivered by lipid-based carrier systems. Thus, the present work reports a new salt form of LTP with a docusate counterion to enhance the pharmaceutical properties of the drug (LTP-DOC). NMR spectra showed a downfield shift of the methylene singlet proton from 3.83 and 4.41 ppm, indicating a lowering of electron density on the adjacent nitrogen atom and confirming the formation of amine-sulfonyl salt through the specified basic nitrogen center located adjacent to the furan ring. PXRD diffractograms of LTP-DOC indicated a reduced crystallinity of the prepared salt. The dissolution, equilibrium solubility, lipid excipient solubility, partitioning coefficient, distribution coefficient, tabletability, and in vitro cytotoxicity of the lipophilic salt of LTP were investigated. The equilibrium solubility data showed that LTP-DOC possesses a pH-independent solubility profile in the pH range of 3.5 to 7.4 with a 3.14 times higher permeability coefficient than commercial ditosylate salt. Furthermore, the prepared LTP-DOC salts showed twice higher log P than the free base and 8 times higher than LTP-DTS. The prepared LTP-DOC was found to have 4- to 9-fold higher solubility in lipid excipients like Capmul MCM C8 and Maisine CC compared to the ditosylate salt. The LTP-DOC salt was tabletable and showed approximately 1.2 times lower dissolution than commercial ditosylate salt, indicating extended-release behavior. A cytotoxicity study of LTP-DOC salt showed an approximately 2.5 times lower IC50 value than the LTP-free base and 1.7 times lower than commercial ditosylate salt with an approximately 3 times higher selectivity index. The investigations strongly indicate a high translational potential of the prepared salt form in maintaining solubility-lipophilicity interplay, enhancing the drug's bioavailability, and developing lipidic formulations.

Current status and future directions for the development of human papillomavirus vaccines.

The development of human papillomavirus (HPV) vaccines has made substantive progress, as represented by the approval of five prophylactic vaccines since 2006. Generally, the deployment of prophylactic HPV vaccines is effective in preventing newly acquired infections and incidences of HPV-related malignancies. However, there is still a long way to go regarding the prevention of all HPV infections and the eradication of established HPV infections, as well as the subsequent progression to cancer. Optimizing prophylactic HPV vaccines by incorporating L1 proteins from more HPV subtypes, exploring adjuvants that reinforce cellular immune responses to eradicate HPV-infected cells, and developing therapeutic HPV vaccines used either alone or in combination with other cancer therapeutic modalities might bring about a new era getting closer to the vision to get rid of HPV infection and related diseases. Herein, we summarize strategies for the development of HPV vaccines, both prophylactic and therapeutic, with an emphasis on the selection of antigens and adjuvants, as well as implications for vaccine efficacy based on preclinical studies and clinical trials. Additionally, we outline current cutting-edge insights on formulation strategies, dosing schedules, and age expansion among HPV vaccine recipients, which might play important roles in addressing barriers to vaccine uptake, such as vaccine hesitancy and vaccine availability.

Learning Goal Formulation Strategies in the Teaching-learning-assessment Alignment

Learning Goal Formulation Strategies in the Teaching-learning-assessment Alignment

Cutting-Edge Developments in Microemulsion Technology: Diverse Applications, Formulation Innovations, and Future Horizons

Microemulsion technology has emerged as a versatile and dynamic solution with widespread applications across various industries. This review delves into the diverse applications, formulation innovations, and anticipated future trends in microemulsion technology. From pharmaceuticals and food to cosmetics and enhanced oil recovery, the unique properties of microemulsions have paved the way for numerous breakthroughs. We explore the formulation strategies that contribute to their stability and efficiency, shedding light on the key factors influencing their success. Additionally, the article highlights the current landscape of microemulsion applications and discusses how ongoing research is shaping the future of this promising technology.

Pre-oxidation and coagulation-flocculation as a pretreatment to UF-RO applied for surface water treatment and arsenic removal

In this paper, the effects of applying pre-oxidation, coagulation, and flocculation (C/F) as pretreatment of an ultrafiltration (UF) - reverse osmosis (RO) system treating water containing arsenic were assessed. For this, the performance of a pilot scale – with a maximum treatment capacity of 2.25 m3/h - UF-RO system with and without pretreatment was evaluated. The membranes were able to generate high-quality permeates, even when the feed presented a remarkable increase in color (>2100 uH) and turbidity (>300 NTU) due to the beginning of the rainy season. UF was not efficient for arsenic removal, so RO was essential to guarantee safe water, generating permeates with concentrations below 0.5 μg/L of arsenic. The effective removal of iron and manganese, among other ions, was verified using membranes. Given the high quality of the permeates, blend formulation strategies were carried out, mixing filtered water from the conventional water treatment plant and RO permeate (Strategy I) and mixing filtered water, UF permeate, and RO permeate (strategy II). Strategy II was viable for arsenic concentrations in filtered water of 13 and 15 μg/L. Pretreatment was important in maintaining a higher membrane permeability and ensured a more stable performance in the face of variations in feed quality, which may be seasonal in some places, as in the present case, where feed quality is significantly altered by the rainy season. Overall, although UF and RO membranes are effective processes for treating surface water containing arsenic, the results suggested that pretreatment, which is already part of the treatment of several water treatment plants, guarantees more robustness to the treatment concerning a higher and more stable membrane permeability, directly impacting operational expenses with membranes operation.

Predictions of biorelevant solubility change during dispersion and digestion of lipid-based formulations

Computational approaches are increasingly explored in development of drug products, including the development of lipid-based formulations (LBFs), to assess their feasibility for achieving adequate oral absorption at an early stage. This study investigated the use of computational pharmaceutics approaches to predict solubility changes of poorly soluble drugs during dispersion and digestion in biorelevant media. Concentrations of 30 poorly water-soluble drugs were determined pre- and post-digestion with in-line UV probes using the MicroDISS Profiler™. Generally, cationic drugs displayed higher drug concentrations post-digestion, whereas for non-ionized drugs there was no discernible trend between drug concentration in dispersed and digested phase. In the case of anionic drugs there tended to be a decrease or no change in the drug concentration post-digestion. Partial least squares modelling was used to identify the molecular descriptors and drug properties which predict changes in solubility ratio in long-chain LBF pre-digestion (R2 of calibration = 0.80, Q2 of validation = 0.64) and post-digestion (R2 of calibration = 0.76, Q2 of validation = 0.72). Furthermore, multiple linear regression equations were developed to facilitate prediction of the solubility ratio pre- and post-digestion. Applying three molecular descriptors (melting point, LogD, and number of aromatic rings) these equations showed good predictivity (pre-digestion R2 = 0.70, and post-digestion R2 = 0.68). The model developed will support a computationally guided LBF strategy for emerging poorly water-soluble drugs by predicting biorelevant solubility changes during dispersion and digestion. This facilitates a more data-informed developability decision making and subsequently facilitates a more efficient use of formulation screening resources.

Production of nano-protein particles in living cells

The escalating demand for therapeutic proteins calls for advanced biomanufacturing and formulation strategies to ensure efficient production and timely supply. Productions of therapeutic proteins, as well as many other proteins, require high purity and stability. However, the manufacturing process is bottlenecked by the purification process. We have established a novel platform leveraging the capabilities of living E. coli cells as cell factory, for efficient synthesis (protein expression) and easy separation (protein particle formation) of a model protein, Red Fluorescent Protein (mRFP). With the designed plasmid, the target protein (mRFP) was heterologously expressed inside cells, and directed to form protein particles, and the red fluorescence of these particles proved their correct folding and bioavailability. Target protein production was validated through SDS-PAGE and fluorescent microscopy. The cells with protein particles and the isolated protein particles were characterized by SEM, optical and fluorescent microscopic. The new cell factory technology developed for mRFP production has exhibited broad potential in advancing biomanufacturing, which can be further developed to enable the efficient bioproduction of other therapeutic proteins and peptides.

Stochastic control with distributionally robust constraints for cyber–physical systems vulnerable to attacks

In this paper, we investigate the control of a cyber–physical system (CPS) while accounting for its vulnerability to external attacks. We formulate a constrained stochastic problem with a robust constraint to ensure robust operation against potential attacks. We seek to minimize the expected cost subject to a constraint limiting the worst-case expected damage an attacker can impose on the CPS. We present a dynamic programming decomposition to compute the optimal control strategy in this robust-constrained formulation and prove its recursive feasibility. We also illustrate the utility of our results by applying them to a numerical simulation.

Nanotechnology Enabled Advances in Oral Delivery of Therapeutic Peptides: Mechanistic Insights for Translation to Clinic

Abstract: Peptides represent a rapidly expanding class of novel treatments with distinct pharmacokinetic properties when compared to macromolecular proteins or small-molecule medications. Peptides are polymers with a molecular mass of less than 10 kDa. Protein-protein interactions have been the primary goal of oral delivery of peptide drugs for the last two decades. Recent trends suggest the possibility of mechanistically targeting challenging binding interfaces with the right binding affinity and specificity for molecules like peptides that bring conformational flexibility. Over 80 peptide medications have received regulatory approval to treat a range of conditions, from human immunodeficiency infection caused by viruses to fatal diseases like cancer. This review covers the need for peptide delivery via the oral route and offers insights to overcome the challenges. For successful translation to the clinic, oral delivery of therapeutic peptides coupled with nano formulation strategies has gained increased attention in recent years. The role of permeation boosters, and digestive enzyme inhibitors to overcome major hurdles such as degradation in the gastrointestinal tract and low intestinal permeability are presented here. Alteration of physicochemical characteristics of peptide molecules, the addition of functional excipients to specifically designed drug delivery systems, nanoformulation approaches, amongst other recent methodologies, to increase the oral bioavailability of peptide medications, are also presented herein. Numerous peptide candidates, both approved and under clinical trials, are included in this review.