Nanoparticles Based on Linear and Star-Shaped Poly(Ethylene Glycol)-Poly(ε-Caprolactone) Copolymers for the Delivery of Antitubulin Drug.

PURPOSE: Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections. METHODS: Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations. RESULTS: Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC50 values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution. CONCLUSIONS: Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues. Graphical Abstract ᅟ.

Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Different Surface Characteristics and Sizes in Excised Porcine Olfactory Epithelium.

The ability to deliver therapeutically relevant amounts of drugs directly from the nasal cavity to the central nervous system to treat neurological diseases is dependent on the availability of efficient drug delivery systems. Increased delivery and/or therapeutic effect has been shown for drugs encapsulated in nanoparticles; however, the factors governing the transport of the drugs and/or the nanoparticles from the nasal cavity to the brain are not clear. The present study evaluates the potential transport of nanoparticles across the olfactory epithelium in relation to nanoparticle characteristics. Model systems, 20, 100, and 200 nm fluorescent carboxylated polystyrene (PS) nanoparticles that were nonmodified or surface modified with polysorbate 80 (P80-PS) or chitosan (C-PS), were assessed for transport across excised porcine olfactory epithelium mounted in a vertical Franz diffusion cell. Assessment of the nanoparticle content in the donor chamber of the diffusion cell, accompanied by fluorescence microscopy of dismounted tissues, revealed a loss of nanoparticle content from the donor suspension and their association with the excised tissue, depending on the surface properties and particle size. Chitosan surface modification of PS nanoparticles resulted in the highest tissue association among the tested systems, with the associated nanoparticles primarily located in the mucus, whereas the polysorbate 80-modified nanoparticles showed some penetration into the epithelial cell layer. Assessment of the bioelectrical properties, metabolic activity, and histology of the excised olfactory epithelium showed that C-PS nanoparticles applied in pH 6.0 buffer produced a damaging effect on the epithelial cell layer in a size-dependent manner, with fine 20 nm sized nanoparticles causing substantial tissue damage relative to that with the 100 and 200 nm counterparts. Although histology showed that the olfactory tissue was affected by the application of citrate buffer that was augmented by addition of chitosan in solution, this was not reflected in the bioelectrical parameters and the metabolic activity of the tissue. Regarding transport across the excised olfactory tissue, none of the nanoparticle systems tested, irrespective of particle size or surface modification, was transported across the epithelium to appear in measurable amounts in the receiver chamber.

Mechanism of mucosal permeability enhancement of CriticalSorb® (Solutol® HS15) investigated in vitro in cell cultures.

PURPOSE: CriticalSorb™, with the principal component Solutol® HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol® HS15. METHODS: Micelle size and CMC of Solutol® HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeability of a panel of biological drugs, and to assess changes in TEER, tight junction and F-actin morphology. The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2-10. RESULTS: This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a 'classical' tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton. CONCLUSION: Solutol® HS15 is the principle component of CriticalSorb™ that has shown an enhancement in permeability of medium sized biological drugs across epithelia. This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.

Surface characterisation of bioadhesive PLGA/chitosan microparticles produced by supercritical fluid technology.

PURPOSE: Novel biodegradable and mucoadhesive PLGA/chitosan microparticles with the potential for use as a controlled release gastroretentive system were manufactured using supercritical CO(2) (scCO(2)) by the Particle Gas Saturated System (PGSS) technique (also called CriticalMix(TM)). METHODS: Microparticles were produced from PLGA with the addition of mPEG and chitosan in the absence of organic solvents, surfactants and crosslinkers using the PGSS technique. Microparticle formulations were morphologically characterized by scanning electron microscope; particle size distribution was measured using laser diffraction. Microparticle surface was analyzed using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to evaluate the presence of chitosan on the surface. Mucoadhesiveness of the microparticles was evaluated in vitro using a mucin assay employing two different kinds of mucin (Mucin type III and I-S) with different degrees of sialic acid contents, 0.5-1.5% and 9-17%, respectively. RESULTS: The two analytical surface techniques (XPS and ToF-SIMS) demonstrated the presence of the chitosan on the surface of the particles (<100 µm), dependent on the polymer composition of the microparticles. The interaction between the mucin solutions and the PLGA/chitosan microparticles increased significantly with an increasing concentration of mucin and chitosan. CONCLUSIONS: The strong interaction of mucin with the chitosan present on the surface of the particles suggests a potential use of the mucoadhesive carriers for gastroretentive and oral controlled drug release.

Nasal vaccination against SARS-CoV-2: Synergistic or alternative to intramuscular vaccines?

It is striking that all marketed SARS-CoV-2 vaccines are developed for intramuscular administration designed to produce humoral and cell mediated immune responses, preventing viremia and the COVID-19 syndrome. They have a high degree of efficacy in humans (70-95%) depending on the type of vaccine. However, little protection is provided against viral replication and shedding in the upper airways due to the lack of a local sIgA immune response, indicating a risk of transmission of virus from vaccinated individuals. A range of novel nasal COVID-19 vaccines are in development and preclinical results in non-human primates have shown a promising prevention of replication and shedding of virus due to the induction of mucosal immune response (sIgA) in upper and lower respiratory tracts as well as robust systemic and humoral immune responses. Whether these results will translate to humans remains to be clarified. An IM prime followed by an IN booster vaccination would likely result in a better well-rounded immune response, including prevention (or strong reduction) in viral replication in the upper and lower respiratory tracts.

Effect of PEGylation on the toxicity and permeability enhancement of chitosan.

The aim of the present work is to investigate if conditions can be devised where PEGylation of chitosan would reduce its toxicity toward the nasal mucosa while maintaining its ability to open the cellular tight junctions and, consequently, produce an enhancement of macromolecular permeability. A series of mPEG-g-chitosan copolymers with varying levels of mPEG substitution, mPEG molecular weight, and chitosan molecular weight were synthesized by grafting carboxylic acid-terminated mPEGs (Mw 1.9 and 5.0 × 10(3) g mol(-1)) to chitosans (Mw 28.9 and 82.0 × 10(3) g mol(-1)) using a NHS/EDC coupling system. The synthesized mPEG-g-chitosans were fully characterized using a number of techniques, including FT-IR, (1)H NMR, and SEC-MALLS and their physicochemical properties were analyzed by TGA and DSC. Thereafter, the conjugates were tested for their cytotoxicity and tight junction modulating property in a relevant cell model, a mucus producing Calu-3 monolayer. mPEG-g-chitosan conjugates exhibited reduced toxicity toward cells, as compared to unmodified chitosan counterparts. Furthermore, the conjugates demonstrated a dramatic effect on cell monolayer transepithelial electrical resistance (TEER) and enhancement of permeability of model macromolecules. TEER and permeability-enhancing effects, as measurable indicators of tight junction modulation, were found to be pH-dependent and were notably more pronounced than those exhibited by unmodified chitosans. This work therefore demonstrates that conditions can be contrived where PEGylation improves the toxicity profile of chitosan, while preserving its effect on epithelial tight junctions in the nose.

Transmucosal Absorption Enhancers in the Drug Delivery Field.

Drug delivery systems that safely and consistently improve transport of poorly absorbed compounds across epithelial barriers are highly sought within the drug delivery field. The use of chemical permeation enhancers is one of the simplest and widely tested approaches to improve transmucosal permeability via oral, nasal, buccal, ocular and pulmonary routes. To date, only a small number of permeation enhancers have progressed to clinical trials, and only one product that includes a permeation enhancer has reached the pharmaceutical market. This editorial is an introduction to the special issue entitled Transmucosal Absorption Enhancers in the Drug Delivery Field (https://www.mdpi.com/journal/pharmaceutics/special_issues/transmucosal_absorption_enhancers). The guest editors outline the scope of the issue, reflect on the results and the conclusions of the 19 articles published in the issue and provide an outlook on the use of permeation enhancers in the drug delivery field.

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update.

The application of permeation enhancers (PEs) to improve transport of poorly absorbed active pharmaceutical ingredients across the intestinal epithelium is a widely tested approach. Several hundred compounds have been shown to alter the epithelial barrier, and although the research emphasis has broadened to encompass a role for nanoparticle approaches, PEs represent a key constituent of conventional oral formulations that have progressed to clinical testing. In this review, we highlight promising PEs in early development, summarize the current state of the art, and highlight challenges to the translation of PE-based delivery systems into safe and effective oral dosage forms for patients.

Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis.

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55-108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans.

A Tailored Thermosensitive PLGA-PEG-PLGA/Emulsomes Composite for Enhanced Oxcarbazepine Brain Delivery via the Nasal Route.

The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a corona of phospholipids (PC) and a coating of Tween 80, which combines the properties of both liposomes and emulsions. Oxcarbazepine (OX), an antiepileptic drug, was entrapped in emulsomes and then localized in a poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer thermogel. The incorporation of OX emulsomes in thermogels retarded drug release and increased its residence time (MRT) in rats. The OX-emulsome and the OX-emulsome-thermogel formulations showed in vitro sustained drug release of 81.1 and 53.5%, respectively, over a period of 24 h. The pharmacokinetic studies in rats showed transport of OX to the systemic circulation after nasal administration with a higher uptake in the brain tissue in case of OX-emulsomes and highest MRT for OX-emulsomal-thermogels as compared to the IN OX-emulsomes, OX-solution and Trileptal® suspension. Histopathological examination of nasal tissues showed a mild vascular congestion and moderate inflammatory changes around congested vessels compared to saline control, but lower toxic effect than that reported in case of the drug solution.

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis.

Osteoporosis treatment with PTH 1-34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1-34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1-34 nasal spray formulation bioactivity. The chemically synthesised PTH 1-34 had an EC50 of 0.76nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1-34 within an in vitro cell culture model (p >0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1-34 into the blood via intranasal delivery produced a Cmax of 2.1±0.5ng/ml compared to 13.7±1.6ng/ml with Solutol® HS15 enhancer (p=0.016) and a Cmax14.8±8ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol® HS15 formulation therefore demonstrated potential as a PTH 1-34 nasal spray formulation for the treatment of osteoporosis.

Evaluation of effect of ephedrine on the transport of drugs from the nasal cavity to the systemic circulation and the central nervous system.

It has been shown that vasoconstrictive drugs such as ephedrine derivatives are able to decrease systemic absorption of drugs administered by mucosal surfaces. The present paper set out to evaluate in the rat model the effect of co-administered nasal ephedrine on the absorption of GR138950 in a simple and in a pectin self-gelling formulation. It was hypothetised that a decrease in nasal systemic absorption would lead to an increase in direct nose-to-brain transport as demonstrated by the drug concentration in the olfactory lobes of the brain. It was found that ephedrine administered nasally with the drug in a simple aqueous solution resulted in a significant increase in nasal systemic absorption and also an increase in brain delivery; however, this trend was not observed with the pectin formulations. The pectin formulation with ephedrine resulted in lower systemic absorption of GR138950 and lower brain uptake compared to the simple solution formulation containing ephedrine.

Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems?

This review discusses the possible benefits of using nanoparticles for nasal delivery of drugs and vaccines. It considers the various factors affecting particle transport across the nasal tissue. The evidence for the improved transport of drugs, such as peptides and proteins, across the nasal epithelium when formulated in a nanoparticulate system, as compared to an optimal solution formulation, is not convincing. For instance it has been shown that a chitosan solution and especially a chitosan powder formulation was superior in enhancing the nasal absorption of insulin as compared to chitosan nanoparticles. On the other hand, the use of nanoparticles for vaccine delivery seems beneficial in that good immune responses are achieved. This could be due to the fact that small particles can be transported preferentially by the lymphoid tissue of the nasal cavity (NALT). However, apparently no studies have been published comparing directly other adjuvant nasal systems with nanoparticulate systems.

Intranasal delivery: physicochemical and therapeutic aspects.

Interest in intranasal (IN) administration as a non-invasive route for drug delivery continues to grow rapidly. The nasal mucosa offers numerous benefits as a target issue for drug delivery, such as a large surface area for delivery, rapid drug onset, potential for central nervous system delivery, and no first-pass metabolism. A wide variety of therapeutic compounds can be delivered IN, including relatively large molecules such as peptides and proteins, particularly in the presence of permeation enhancers. The current review provides an in-depth discussion of therapeutic aspects of IN delivery including consideration of the intended indication, regimen, and patient population, as well as physicochemical properties of the drug itself. Case examples are provided to illustrate the utility of IN dosing. It is anticipated that the present review will prove useful for formulation scientists considering IN delivery as a delivery route.

Chitosans inhibit the growth and the adhesion of Klebsiella pneumoniae and Escherichia coli clinical isolates on urinary catheters.

OBJECTIVE: The aim of this study was to determine the antimicrobial activity of different chitosans (CS) against typical colonizing pathogens of the urinary tract and to assess their efficacy against bacterial adhesion and the subsequent biofilm formation on urinary catheters. METHODS: The antimicrobial activity of high and low molecular weight CS (50 and 150 kDa) at pH 5.0 and 6.0 was tested against Klebsiella pneumoniae and Escherichia coli clinical isolates by time-kill studies. The anti-adhesion assays on Foley urinary catheters were performed in Artificial Urine Medium (AUM) with the addition of each CS (AUM-CS) at the same pH values. Finally, the efficacy over time of chitosan treatments on bacterial adhesion on urinary catheters was determined. RESULTS: A viability reduction of K. pneumoniae and E. coli isolates, regardless of pH value, was evidenced in time-kill studies, in particular in the presence of CS 50 kDa. As regards the anti-adhesion efficacy on urinary catheters, high and low molecular weight CS evidenced a higher efficacy to reduce bacterial adhesion at pH 5.0. A low number of viable K. pneumoniae and E. coli cells were recovered from catheters after CS treatments, highlighting a promising efficacy over time. CONCLUSION: Our data show the potential of chitosans to reduce or prevent not only the adhesion of well-known human uropathogens on urinary catheters but also the re-growth ability of the uropathogens.

Nasal clearance in health and disease.

This paper reviews the anatomical and physiological factors of importance for nasal drug delivery and discusses in particular the influence of the nasal mucociliary clearance mechanism on the nasal absorption of drugs. The effect of nasal pathological conditions on the mucociliary clearance mechanism and the possible effect of such disease states on nasal drug transport are also discussed. Strategies for the exploitation of bioadhesive drug delivery systems and especially nasal absorption enhancers for the improvement of nasal drug delivery are evaluated to include considerations of the mechanism of action and correlation between the degree of bioadhesion and absorption enhancement and transport of drugs across the nasal membrane. A range of studies involving bioadhesive/absorption enhancer systems are detailed. A selected bioadhesive material, chitosan, which has been shown to have excellent absorption enhancer properties for a variety of drugs is discussed in some detail.

Intranasal Human Growth Hormone (hGH) Induces IGF-1 Levels Comparable With Subcutaneous Injection With Lower Systemic Exposure to hGH in Healthy Volunteers.

CONTEXT: The development of an improved, efficacious human GH (hGH) product administered by a noninjectable route of delivery such as the nasal route is highly desirable. We have developed a novel nasal hGH product (CP024) that showed excellent nasal absorption in animal models; however, the translation of these results into the clinical setting is essential because past attempts to develop such formulations by other groups have been unable to induce IGF-1 in man. OBJECTIVE: The objective of the study was to assess the pharmacokinetics, pharmacodynamics, and tolerability of CP024 compared with a sc hGH injection. DESIGN: This was a single-center, nonrandomized placebo-controlled, open-label, five-way crossover study in eight healthy volunteers. SETTING: The study was carried out at a contract research organization, Quotient Bioresearch. VOLUNTEERS: Eight healthy male volunteers, given an iv infusion of octreotide to suppress the endogenous GH secretion during the study period, participated in the study. No volunteers were withdrawn due to side effects. MAIN OUTCOME MEASURES: Measurement of hGH and IGF-1 levels and tolerability of the drug product was performed. RESULTS: No serious adverse events were reported and no subjects withdrawn from study due to the treatment. After the nasal administration of CP024, 3-fold higher hGH blood levels were obtained as compared with hGH nasal control. The relative bioavailability was about 3%. CP024 (given twice daily) induced a significant increase in IGF-1 levels up to 19 hours after administration, with no significant difference to those obtained after the sc injection of hGH. CONCLUSIONS: The study indicates that CP024 is a promising candidate for an efficacious nasal product for the treatment of GH deficiency due to induction of IGF-1 similar to that after a sc injection, despite the lower plasma hGH concentration obtained. A dose-response study is needed to evaluate the optimal nasal dose.

Nasal drug delivery: new developments and strategies.

The use of the nasal route for the delivery of challenging drugs has created much interest in recent years in the pharmaceutical industry. Consequently, drug delivery companies are actively pursuing the development of novel nasal drug-delivery systems and the exploitation of these for administration of conventional generic drugs and peptides, both in-house and with partners in the pharmaceutical industry. This review sets out to discuss some new developments and strategies in nasal drug delivery. An exiting discovery that drugs can be transported directly from nose to brain via the olfactory pathway is discussed and examples of proof-of-concept in man are given.

Absorption enhancers for nasal drug delivery.

This paper describes the basic concepts for the transmucosal delivery of drugs, and in particular the use of the nasal route for delivery of challenging drugs such as polar low-molecular-weight drugs and peptides and proteins. Strategies for the exploitation of absorption enhancers for the improvement of nasal delivery are discussed, including consideration of mechanisms of action and the correlation between toxic effect and absorption enhancement. Selected enhancer systems, such as cyclodextrins, phospholipids, bioadhesive powder systems and chitosan, are discussed in detail. Examples of the use of these enhancers in preclinical and clinical studies are given. Methods for assessing irritancy and damage to the nasal membrane from the use of absorption enhancers are also described. Finally, the mucosal use of absorption enhancers (chitosan) for the improved nasal delivery of vaccines is reported with reference to recent phase I/II clinical studies.

Nasal drug delivery--possibilities, problems and solutions.

This paper discusses the problems associated with nasal drug delivery and how it is possible, sometimes by means of quite simple concepts, to improve transport across the nasal membrane. In this way it is feasible to deliver efficiently challenging drugs such as small polar molecules, peptides and proteins and even the large proteins and polysaccharides used in vaccines or DNA plasmids exploited for DNA vaccines. The transport of drugs from the nasal cavity directly to the brain is also described and examples of studies in man, where this has been shown to be feasible, are discussed. Recent results from Phase I/II studies in man with a novel nasal chitosan vaccine delivery system are also described. Finally, the author's thoughts about the future for nasal drug delivery are also depicted.