Poloxamer 188-Coated Ammonium Methacrylate Copolymer Nanocarriers Enhance Loperamide Permeability across Pgp-Expressing Epithelia.

Loperamide is a µ-opioid agonist with poor gastrointestinal absorption, mainly because of its modest aqueous solubility and being a P-glycoprotein (Pgp) efflux substrate. Nevertheless, studies associated with therapeutic effects strongly suggest that loperamide holds potential pharmacological advantages over traditional µ-opioid agonists commonly used for analgesia. Thus, in this Communication, we assessed in MDCK-hMDR1 cell lines the effects over loperamide uptake and efflux ratio, when loaded into Eudragit RS (ERS) nanocarriers coated with poloxamer 188 (P188). ERS was chosen for enhancing loperamide aqueous dispersibility and P188 as a potential negative Pgp modulator. In uptake assays, it was observed that Pgp limited the accumulation of loperamide into cells and that preincubation with P188, but not coincubation, led to increasing loperamide uptake at a similar extent of Pgp pharmacological inhibition. On the other hand, the efflux ratio displayed no alterations when Pgp was pharmacologically inhibited, whereas ERS/P188 nanocarriers effectively enhanced loperamide uptake and absorptive transepithelial transport. The latter suggests that loperamide transport across cells is significantly influenced by the presence of the unstirred water layer (UWL), which could hinder the visualization of Pgp-efflux effects during transport assays. Thus, results in this work highlight that formulating loperamide into this nanocarrier enhances its uptake and transport permeability.

The Effect of Inkjet Printing over Polymeric Films as Potential Buccal Biologics Delivery Systems.

The buccal mucosa appears as a promissory route for biologic drug administration, and pharmaceutical films are flexible dosage forms that can be used in the buccal mucosa as drug delivery systems for either a local or systemic effect. Recently, thin films have been used as printing substrates to manufacture these dosage forms by inkjet printing. As such, it is necessary to investigate the effects of printing biologics on films as substrates in terms of their physical and mucoadhesive properties. Here, we explored solvent casting as a conventional method with two biocompatible polymers, hydroxypropyl methylcellulose, and chitosan, and we used electrospinning process as an electrospun film fabrication of polycaprolactone fibers due to its potential to elicit mucoadhesion. Lysozyme was used as biologic drug model and was formulated as a solution for printing by thermal inkjet printing. Films were characterized before and after printing by mechanical and mucoadhesive properties, surface, and ultrastructure morphology through scanning electron microscopy and solid state properties by thermal analysis. Although minor differences were detected in micrographs and thermograms in all polymeric films tested, neither mechanical nor mucoadhesive properties were affected by these differences. Thus, biologic drug printing on films was successful without affecting their mechanical or mucoadhesive properties. These results open way to explore biologics loading on buccal films by inkjet printing, and future efforts will include further in vitro and in vivo evaluations.

Overview and Future Potential of Buccal Mucoadhesive Films as Drug Delivery Systems for Biologics.

The main route of administration for drug products is the oral route, yet biologics are initially developed as injectables due to their limited stability through the gastrointestinal tract and solubility issues. In order to avoid injections, a myriad of investigations on alternative administration routes that can bypass enzymatic degradation and the first-pass effect are found in the literature. As an alternative site for biologics absorption, the buccal route presents with a number of advantages. The buccal mucosa is a barrier, providing protection to underlying tissue, but is more permeable than other alternative routes such as the skin. Buccal films are polymeric matrices designed to be mucoadhesive properties and usually formulated with permeability enhancers to improve bioavailability. Conventionally, buccal films for biologics are manufactured by solvent casting, yet recent developments have shown the potential of hot melt extrusion, and most recently ink jet printing as promising strategies. This review aims at depicting the field of biologics-loaded mucoadhesive films as buccal drug delivery systems. In light of the literature available, the buccal epithelium is a promising route for biologics administration, which is reflected in clinical trials currently in progress, looking forward to register and commercialize the first biologic product formulated as a buccal film.

Buccal Dosage Forms: General Considerations for Pediatric Patients.

The development of an appropriate dosage form for pediatric patients needs to take into account several aspects, since adult drug biodistribution differs from that of pediatrics. In recent years, buccal administration has become an attractive route, having different dosage forms under development including tablets, lozenges, films, and solutions among others. Furthermore, the buccal epithelium can allow quick access to systemic circulation, which could be used for a rapid onset of action. For pediatric patients, dosage forms to be placed in the oral cavity have higher requirements for palatability to increase acceptance and therapy compliance. Therefore, an understanding of the excipients required and their functions and properties needs to be particularly addressed. This review is focused on the differences and requirements relevant to buccal administration for pediatric patients (compared to adults) and how novel dosage forms can be less invasive and more acceptable alternatives.

Novel strategies for the buccal delivery of macromolecules.

For years now, the delivery of small molecules through the buccal mucosal route has been described in the literature, but it has only been over the past decade that investigations into macromolecule delivery via the buccal route have sharply increased. The administration of macromolecules such as proteins and peptides, antibodies, or nucleic acids by buccal administration would be greatly enhanced due to the avoidance of the gastrointestinal conditions, rapid uptake into systemic circulation, as well as the potential for controlled drug delivery. Since macromolecules are faced with a number of specific challenges related to permeation through the epithelium, several strategies have been employed historically to improve their buccal absorption and subsequent bioavailability. Several conventional strategies to improve macromolecule penetration include the use of chemical permeation enhancers, enzyme inhibitors and the use of mucoadhesive materials acting as carriers. More recent approaches include the incorporation of the macromolecule as part of nanostructured delivery systems to further enhance targeting and delivery. This review focuses on the different permeation enhancing strategies as well as formulation design that are tailored to meet the challenges of active macromolecule delivery using the buccal mucosal route of administration.

Exploring paediatric oral suspension development: Challenges, requirements, and formulation advancements.

Oral suspension is the most preferred dosage form for the paediatric population because of the difficulties related to solid medications, such as the swallowing limitations, bitter taste, and poor oral bioavailability, which can cause serious impairment to attain a successful treatment. Given the importance of successful therapies, there is a need for safe and effective commercially-available paediatric oral suspension and their characterization. For the latter, it is important to identify safe excipients and preservatives. The paediatric group is a diverse category which includes infants and teenagers, with major pharmacokinetics and pharmacodynamics differences, mainly because of physiological and behavioral variations. Therefore, finding a single formulation for paediatric population remains a challenge, as well asthe formulation of stable-in-time suspension. In addition, drug's dissolving characteristic and permeation, are the main determinants for oral absorption, which are closely related to drug release kinetics from the pharmaceutical form. In this context, drug release profile is an important and limiting step in oral bioavailability, particularly for BCS class II drugs; thus, it is possible to increase bioavailability and minimize adverse effects by changing the release rate of such drugs. This review covers all the aspects for paediatric oral suspension development, and analyses the considerations for excipients selection as a crucial task for effectively choosing a safe and effective pharmaceutical form and correctly dosing paediatric patients.

A design of experiments to optimize a new manufacturing process for high activity protein-containing submicron particles.

A novel method for the manufacture of protein/peptide-containing submicron particles was developed in an attempt to provide particles with increased activity while using high energy input technologies. The method consists of antisolvent co-precipitation from an aqueous solution containing both an amino acid core material (e.g. D,L-valine), and either bovine serum albumin (BSA) or lysozyme (Lys) as model proteins. The aqueous solution was added to the organic phase by means of a nebulizer to increase the total surface area of interaction for the precipitation process. Sonication proved to be an effective method to produce small particle sizes while maintaining high activity of Lys. The use of a polysorbate or sorbitan ester derivatives as stabilizers proved to be necessary to yield submicron particles. Particles with very high yields (approximately 100%) and very high activity after manufacture (approximately 100%) could be obtained. A particle size of 439.0 nm, with a yield of 48.8% and with final remaining activity of 98.7% was obtained. By studying various factors using a design of experiments strategy (DoE) we were able to establish the critical controlling factors for this new method of manufacture.

The influence of recrystallized caffeine on water-swellable polymethacrylate mucoadhesive buccal films.

The aim of this work was to investigate the influence of particles on the properties of polymethacrylate films intended for buccal delivery. A solvent casting method was used with Eudragit RS and RL (ERS and ERL, respectively) as film-forming rate-controlling polymers, with caffeine as a water-soluble model drug. The physicochemical properties of the model films for a series of formulations with increasing concentrations of caffeine were determined in terms of morphology, mechanical and mucoadhesive properties, drug content uniformity, and drug release and associated kinetics. Typically regarded as non-mucoadhesive polymers, ERS and mainly ERL, were found to be good mucoadhesives, with ERL01 exhibiting a work of mucoadhesion (WoA) of 118.9 µJ, which was about five to six times higher than that observed for commonly used mucoadhesives such as Carbopol(®) 974P (C974P, 23.9 µJ) and polycarbophil (PCP, 17.4 µJ). The mucoadhesive force for ERL01 was found to be significantly lower yet comparable to C974P and PCP films (211.1 vs. 329.7 and 301.1 mN, respectively). Inspection of cross-sections of the films indicated that increasing the concentration of caffeine was correlated with the appearance of recrystallized agglomerates. In conclusion, caffeine agglomerates had detrimental effects in terms of mucoadhesion, mechanical properties, uniformity, and drug release at large particle sizes. ERL series of films exhibited very rapid release of caffeine while ERS series showed controlled release. Analysis of release profiles revealed that kinetics changed from a diffusion controlled to a first-order release mechanism.

Buccal delivery of small molecules and biologics: Of mucoadhesive polymers, films, and nanoparticles - An update.

Buccal delivery of small and large molecules is an attractive route of administration that has been studied extensively over the past few decades. This route bypasses first-pass metabolism and can be used to deliver therapeutics directly to systemic circulation. Moreover, buccal films are efficient dosage forms for drug delivery due to their simplicity, portability, and patient comfort. Films have traditionally been formulated using conventional techniques, including hot-melt extrusion and solvent casting. However, newer methods are now being exploited to improve the delivery of small molecules and biologics. This review discusses recent advances in buccal film manufacturing, using the latest technologies, such as 2D and 3D printing, electrospraying, and electrospinning. This review also focuses on the excipients used in the preparation of these films, with emphasis on mucoadhesive polymers and plasticizers. Along with advances in manufacturing technology, newer analytical tools have also been used for the assessment of permeation of the active agents across the buccal mucosa, the most critical biological barrier and limiting factor of this route. Additionally, preclinical and clinical trial challenges are discussed, and some small molecule products already on the market are explored.

Gold-, silver- and magnesium-doped zinc oxide nanoparticles prevents the formation of and eradicates bacterial biofilms.

Aim: This work aimed to synthesize magnesium-doped zinc oxide, silver and gold nanoparticles (Nps) and to evaluate their potential to prevent and eradicate Escherichia coli, Proteus mirabilis, Staphylococcus aureus, Acinetobacter baumannii and Pseudomonas aeruginosa biofilms. Materials & methods: The Nps were synthesized by precipitation and metallic reduction techniques. Physicochemical and biological characterization of Nps was performed. Results: All the Nps tested were able to inhibit the formation of E. coli, P. mirabilis, S. aureus and A. baumannii biofilms. The effects on the eradication of preformed biofilms were variable, although all the Nps tested were able to eradicate A. baumannii biofilms. Conclusion: The observed effects make the Nps suitable for coating surfaces and/or antibiotic carriers with medical interest.

Experimental design and optimization of a novel dual-release drug delivery system with therapeutic potential against infection with Helicobacter pylori.

The objective of this study was to develop clarithromycin-loaded lipid nanocarriers and incorporate them into microcapsules for pH-specific localized release of clarithromycin in the Helicobacter pylori microenvironment in order to obtain a gastro-retentive and pH-sensitive formulation. A Plackett-Burman design was applied to identify the effect of 5 factors on 3 responses. Then, a central composite design was applied to estimate the most important factors leading to the best compromise between lower particle size, polydispersity index and particle size changes. The optimized clarithromycin-loaded nanocapsules were employed to generate microcapsules by different methodologies. Nanocarriers and microcapsules were characterized in vitro. Experimental design and conditions were optimized to obtain nanocapsules of around 100 nm by a modified phase inversion-based process. High particle size homogeneity and high stability were achieved. At 4 °C both optimized lipid nanocapsules were stable during at least 365 days, confirming stability under those conditions. Clarithromycin incorporation in the nanocarrier was effective. Both types of microcoating were evaluated regarding their pH sensitivity. Spray drying microcapsules exhibited similar and uncontrolled release profiles at pH 2 and 7.4. Alternatively, when microcoatings were generated using an Encapsulator, release was insignificant at pH 2, while at pH 7.4 release was triggered, and appeared more appropriate to formulate microcapsules that release nanocarriers under pH neutral Helicobacter pylori microenvironment conditions, thereby permitting effective drug delivery in infected locations. The release of clarithromycin from lipid nanocarrier loaded microcapsules was pH-sensitive suggesting that this could be an effective strategy for clarithromycin delivery to the Helicobacter pylori microenvironment. Clarithromycin nanocapsules with and without microcoating showed a high anti-Helicobacter pylori activity in vitro.

Buccal and Sublingual Vaccines: A Review on Oral Mucosal Immunization and Delivery Systems.

Currently, most vaccines available on the market are for parental use; however, this may not be the best option on several occasions. Mucosal routes of administration such as intranasal, sublingual, and buccal generate great interest due to the benefits they offer. These range from increasing patient compliance to inducing a more effective immune response than that achieved through conventional routes. Due to the activation of the common mucosal immune system, it is possible to generate an effective systemic and local immune response, which is not achieved through parenteral administration. Protection against pathogens that use mucosal entry routes is provided by an effective induction of mucosal immunity. Mucosal delivery systems are being developed, such as films and microneedles, which have proven to be effective, safe, and easy to administer. These systems have multiple advantages over commonly used injections, which are simple to manufacture, stable at room temperature, painless for the patient since they do not require puncture. Therefore, these delivery systems do not require to be administered by medical personnel; in fact, they could be self-administered.

Screening of critical variables in fabricating polycaprolactone nanoparticles using Neuro Fuzzy Logic.

In this work, we used the artificial intelligence tool known as neurofuzzy logic (NFL) for fabricating uniform nanoparticles of polycaprolactone by the nanoprecipitation method with a focus on stabilizer selection. The adaptability of NFL assisted the decision-making on different manufacturing and formulation conditions. The nanoprecipitation method can be summarized as mixing a poorly water-soluble polymer solution with water and its consequent precipitation. Although nanoprecipitation seems simple, the process is highly variable to even slight modifications, leading to polydispersity and nanoparticle aggregation. Here, the NFL model established relationships between mixing conditions, different stabilizers and solvents, among other parameters. Seven parameters measured by dynamic light scattering and laser doppler electrophoresis were modelized with high predictability using NFL tool, as a function of the raw materials and operation conditions. The model allowed the principal component analysis to be carried out, showing that the selection of a stabilizer is the most critical parameter for avoiding nanoparticle aggregation. Then, inputs related to fluid dynamics were relevant to tune the characteristics of the stabilized nanoparticles even further. NFL model showed great potential to support pharmaceutical research by finding subtle relationships between several variables, even from incomplete or fragmented data, which is common in pharmaceutical development.

Inkjet printing of small molecules, biologics, and nanoparticles.

During the last decades, inkjet printing has emerged as a novel technology and attracted the attention of the pharmaceutical industry, as a potential method for manufacturing personalized and customizable dosage forms to deliver drugs. Commonly, the desired drug is dissolved or dispersed within the ink and then dispensed in various dosage forms. Using this approach, several studies have been conducted to load hydrophilic or poorly water-soluble small molecules onto the surface of different solid substrates, including films, tablets, microneedles, and smart data-enriched edible pharmaceuticals, using two-dimensional and three-dimensional inkjet printing methods, with high dose accuracy and reproducibility. Furthermore, biological drugs, such as peptides, proteins, growth factors, and plasmids, have also been evaluated with positive results, eliciting the expected biological response; nonetheless, minor changes in the structure of these compounds with significant impaired activity cannot be dismissed. Another strategy using inkjet printing is to disperse drug-loaded nanoscale particles in the ink liquid, such as nanosuspension, nanocomplexes, or nanoparticles, which have been explored with promising results. Although these favorable outcomes, the proper selection of ink constituents and the inkjet printer, the correlation of printing cycles and effectively printed doses, the stability studies of drugs within the ink and the optimal analysis of samples before and after the printing process are the main challenges for inkjet printing, and therefore, this review analyzes these aspects to assess the body of current literature and help to guide future investigations on this field.

Development of a Nanostructured Lipid Carrier (NLC) by a Low-Energy Method, Comparison of Release Kinetics and Molecular Dynamics Simulation.

Lipid nanocarriers have a great potential for improving the physicochemical characteristics and behavior of poorly water-soluble drugs, such as aqueous dispersibility and oral bioavailability. This investigation presents a novel nanostructured lipid carrier (NLC) based on a mixture of solid lipid glycerides, fatty acid esters of PEG 1500 (Gelucire® 44/14), and an oil mix composed of capric and caprylic triglycerides (Miglyol® 812). These NLCs were developed by a simple low-energy method based on melt emulsification to yield highly encapsulating and narrowly distributed nanoparticles (~100 nm, PdI = 0.1, and zeta potential = ~-10 mV). Rhodamine 123 was selected as a poorly water-soluble drug model and owing to its spectroscopic properties. The novel NLCs were characterized by dynamic light scattering (DLS), zeta potential, nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and colloidal stability. The drug release was determined through a dialysis bag and vertical Franzs' cells to provide insights about the methods' suitability, revealing similar performance regardless of their different fluid dynamics. Rhodamine 123 followed a characteristic biphasic release profile owing to the swelling of the hydrophilic polymer coating and diffusion process from the lipid core as revealed by the Korsmeyers-Peppas kinetic modeling. Moreover, to elucidate the formation and incorporation of Rhodamine 123 into the NLC core, several molecular dynamics simulations were conducted. The temperature was shown to be an important condition to improve the formation of the nanoparticles. In addition, the liquid lipid incorporation to the formulation forms nanoparticles with imperfect centers, in contrast to nanoparticles without it. Moreover, Miglyol® 812 improves hydrophobic molecule solubility. These results suggest the potential of novel NLC as a drug delivery system for poorly water-soluble drugs.

Nanoparticles as Potential Novel Therapies for Urinary Tract Infections.

Urinary tract infection (UTI) is one of the most common reasons for antibiotic treatment. Nevertheless, uropathogens are steadily becoming resistant to currently available therapies. In this context, nanotechnology emerges as an innovative and promising approach among diverse strategies currently under development. In this review we deeply discuss different nanoparticles (NPs) used in UTI treatment, including organic NPs, nanodiamonds, chemical and green synthesized inorganic NPs, and NPs made of composite materials. In addition, we compare the effects of different NPs against uropathogens in vivo and in vitro and discuss their potential impact the in the near future.

Nanoparticle-Mediated Angiotensin-(1-9) Drug Delivery for the Treatment of Cardiac Hypertrophy.

Ang-(1-9) peptide is a bioactive vasodilator peptide that prevents cardiomyocyte hypertrophy in vitro and in vivo as well as lowers blood pressure and pathological cardiovascular remodeling; however, it has a reduced half-life in circulation, requiring a suitable carrier for its delivery. In this work, hybrid nanoparticles composed of polymeric nanoparticles (pNPs) based on Eudragit® E/Alginate (EE/Alg), and gold nanospheres (AuNS), were developed to evaluate their encapsulation capacity and release of Ang-(1-9) under different experimental conditions. Hybrid pNPs were characterized by dynamic light scattering, zeta potential, transmission and scanning electron microscopy, size distribution, and concentration by nanoparticle tracking analysis. Nanometric pNPs, with good polydispersity index and colloidally stable, produced high association efficiency of Ang-(1-9) and controlled release. Finally, the treatment of neonatal cardiomyocytes in culture with EE/Alg/AuNS 2% + Ang-(1-9) 20% pNPs decreased the area and perimeter, demonstrating efficacy in preventing norepinephrine-induced cardiomyocyte hypertrophy. On the other hand, the incorporation of AuNS did not cause negative effects either on the cytotoxicity or on the association capacity of Ang-(1-9), suggesting that the hybrid carrier EE/Alg/AuNS pNPs could be used for the delivery of Ang-(1-9) in the treatment of cardiovascular hypertrophy.

Drug-Loaded Lipid-Core Micelles in Mucoadhesive Films as a Novel Dosage Form for Buccal Administration of Poorly Water-Soluble and Biological Drugs.

The aim of the study was to develop a novel buccal dosage form to transport rhodamine 123 and human insulin as models for poorly water-soluble and biological drugs, using lipid-core micelles (LCMs)-loaded mucoadhesive films. LCMs were synthesized by a low-energy hot emulsification process, yielding spherically shaped, small-sized, monodispersed and negatively charged carriers with high entrapment efficiency. In vitro release studies demonstrated a higher release of insulin rather than rhodamine from LCMs in simulated physiological conditions, due to an initial burst release effect; however, both release profiles are mainly explained by a diffusion mechanism. Furthermore, LCMs-loaded mucoadhesive films were manufactured and preserved with similar mechanical properties and optimal mucoadhesive behavior compared to nonloaded films. Ex vivo permeation experiments using excised porcine buccal epithelium reveal that both rhodamine and insulin-loaded LCM films elicited a significantly enhanced permeation effect compared to LCMs in suspension and free drugs in solution as controls. Hence, LCMs-loaded mucoadhesive films are suitable as buccal dosage form for the transport and delivery of rhodamine 123 and insulin, as models for poorly water-soluble and biological drugs, respectively.

Delivery of ionizable hydrophilic drugs based on pharmaceutical formulation of ion pairs and ionic liquids.

New therapeutics such as antisense oligonucleotides, small interfering RNA and peptide-drug conjugates are taking great relevance in the pharmaceutical industry due to their specificity of action and their improved safety profile. However, they could present bioavailability issues due to their hydrophilic nature, such as BCS class III drugs. Therefore, the formation of ion pairs of these type of molecules allows modifying their physicochemical characteristics such as polarity and lipophilicity leading to improved permeability. By carrying out a tailored synthesis, it is possible to obtain complexes with greater stability and better performance in vitro and in vivo, where their correlation with physicochemical properties continues to be a growing field of research. Moreover, ionic liquids (IL), which are substances that melt below 100 °C, have enabled modifying various drug properties, showing promising results in vitro-in vivo, especially when they are included in suitable drug delivery systems, such as nanoparticles, microparticles, self-emulsifying drug delivery systems, and transdermal patches, among others. The drug-IL is formed from the therapeutic agent and a counterion, mainly by ionic interactions, and resulting in a wide variety of derivatives with different properties. However, the pharmaceutical field is limited to the use of some excipients or GRAS (generally recognized as safe) substances, so the search for new counterions is of great interest. In this article, we have compiled key indexes that can be obtained from databases to guide the search for suitable counterions, together with different drug delivery system strategies to choose the most appropriate formulation according to the non-parenteral route of administration selected. Intellectual property advancements in the field are also presented and analyzed.