Rescuing a Troubled Tolcapone with PEGylated PLGA Nanoparticles: Design, Characterization, and Hepatotoxicity Evaluation.

Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor used as adjuvant therapy in Parkinson's disease. However, it has a highly hepatotoxic profile, as recognized by the U.S. Food and Drug Administration. As a possible solution, nanoscience brought us several tools in the development of new functional nanomaterials with tunable physicochemical properties, which can be part of a solution to solve several drawbacks, including drug's short half-life and toxicity. This work aims to use PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a stable carrier with lower hydrodynamic size and polydispersity to encapsulate tolcapone in order to overcome its therapeutic drawbacks. Using the nanoprecipitation method, tolcapone-loaded nanoparticles with a DLC% of 5.7% were obtained (EE% of 47.0%) and subjected to a lyophilization optimization process to obtain a final shelf-stable formulation. Six different cryoprotectants in concentrations up to 10% (w/v) were tested. A formulation of PLGA nanoparticles with 3% hydroxypropyl-ß-cyclodextrin (HPßCD) as a cryoprotectant (PLGA-HP@Tolc), presenting sub-200 nm sizes and low polydispersity (PdI < 0.200) was selected. Cytotoxicity assays, namely, MTT and SRB, were used to study the metabolic activity and cell density of tolcapone and PLGA-HP@Tolc-treated cells. In both assays, a hepatocarcinoma cell line (HepG2) growing in glucose or glucose-free media (galactose-supplemented medium) was used. The results demonstrated that the treatment with the PLGA-HP@Tolc formulation led to a decrease in cytotoxicity in comparison to free tolcapone-treated cells in both media tested. Moreover, the elected formulation also counteracted ATP-depletion and excessive ROS production induced by tolcapone. The results suggest that HPßCD might have a dual function in the formulation: cryoprotectant and anticytotoxic agent, protecting cells from tolcapone-induced damage. Using an in vitro COMT inhibition assay, the PLGA-HP@Tolc formulation demonstrated to inhibit COMT as efficiently as free tolcapone. Overall, the results suggest that tolcapone-loaded PLGA NPs could be an interesting alternative to free tolcapone, demonstrating the same in vitro efficacy in inhibiting COMT but with a safer cytotoxic profile.

Morquio A Syndrome: Identification of Differential Patterns of Molecular Pathway Interactions in Bone Lesions.

Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disease (LSD) caused by deficiency of a hydrolase enzyme, N-acetylgalactosamine-6-sulfate sulfatase, and characterized clinically by mainly musculoskeletal manifestations. The mechanisms underlying bone involvement in humans are typically explored using invasive techniques such as bone biopsy, which complicates analysis in humans. We compared bone proteomes using DDA and SWATH-MS in wild-type and MPS IVA knockout mice (UNT) to obtain mechanistic information about the disease. Our findings reveal over 1000 dysregulated proteins in knockout mice, including those implicated in oxidative phosphorylation, oxidative stress (reactive oxygen species), DNA damage, and iron transport, and suggest that lactate dehydrogenase may constitute a useful prognostic and follow-up biomarker. Identifying biomarkers that reflect MPS IVA clinical course, severity, and progression have important implications for disease management.

The Effect of Systemic Parameters and Baseline Characteristics in Short-Term Response Analysis with Intravitreal Ranibizumab in Treatment-Naive Patients with Neovascular Age-Related Macular Degeneration.

Anti-vascular endothelial growth factor drugs keep being the main therapy for neovascular age-related macular degeneration (AMD). Possible predictive parameters (demographic, biochemical and/or inflammatory) could anticipate short-term treatment response with ranibizumab. 46 treatment-naive patients were included in a prospective observational study. They underwent three monthly injections of intravitreal ranibizumab for neovascular AMD and the clinical examination was made at baseline and one month after the third injection. Demographic characteristics, co-morbidities and concomitant treatments were recorded at the baseline visit. Biochemical parameters, complete blood count and inflammation biomarkers were also measured at these times. Uric Acid was found to be statistically significant with a one-point difference between good and poor responders in both basal and treated patients, but only in basal parameters was statistical significance reached (p = 0.007 vs. p = 0.071 in treated patients). Cholesterol and inflammatory parameters such as white blood cell count and neutrophils were significantly reduced over time when treated with intravitreal ranibizumab. On the other hand, women seemed to have a worse prognosis for short-term response to intravitreal ranibizumab treatment. Uric acid may help identify possible non-responders before initial treatment with ranibizumab, and cholesterol and white blood cells could be good candidates to monitor short-term response to ranibizumab treatment.

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems, Part II: Long-Term Stability and Clinical Ocular Biopermanence.

BACKGROUND: Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in several tissues and organs causing, among others, severe eye symptoms. The high instability of cysteamine eye drops makes it difficult to develop formulations with an acceptable shelf life to be prepared in hospital pharmacy departments. Previously, a new compounded formulation of cysteamine eye drops in hyaluronic acid (HA) packaged in innovative single-dose systems was developed. METHODS: Long-term stability at -20 °C of this formulation was studied considering the content of cysteamine, pH, osmolality, viscosity, and microbiological analysis. The oxygen permeability of single-dose containers was also studied and an ocular biopermanence study was conducted in healthy volunteers measuring lacrimal stability and volume parameters. RESULTS: Data confirm that cysteamine concentration remained above 90% for 120 days, all parameters remaining within the accepted range for ophthalmic formulations. The permeability of the containers was reduced over time, while ocular biopermanence was maintained despite the freezing process and storage time. CONCLUSIONS: 0.55% cysteamine hydrochloride formulation in HA and packaged in single-dose containers preserved at -20 °C is stable for 120 days protected from light, presenting high potential for its translation into clinical practice when commercial presentations are not available.

Intravitreal implants manufactured by supercritical foaming for treating retinal diseases.

Chronic retinal diseases, such as age-related macular degeneration (AMD), are a major cause of global visual impairment. However, current treatment methods involving repetitive intravitreal injections pose financial and health burdens for patients. The development of controlled drug release systems, particularly for biological drugs, is still an unmet need in prolonging drug release within the vitreous chamber. To address this, green supercritical carbon dioxide (scCO2) foaming technology was employed to manufacture porous poly(lactic-co-glycolic acid) (PLGA)-based intravitreal implants loaded with dexamethasone. The desired implant dimensions were achieved through 3D printing of customised moulds. By varying the depressurisation rates during the foaming process, implants with different porosities and dexamethasone release rates were successfully obtained. These implants demonstrated controlled drug release for up to four months, surpassing the performance of previously developed implants. In view of the positive results obtained, a pilot study was conducted using the monoclonal antibody bevacizumab to explore the feasibility of this technology for preparing intraocular implants loaded with biologic drug molecules. Overall, this study presents a greener and more sustainable alternative to conventional implant manufacturing techniques, particularly suited for drugs that are susceptible to degradation under harsh conditions.

Lipidic lyotropic liquid crystals: Insights on biomedical applications.

Liquid crystals (LCs) possess unique physicochemical properties, translatable into a wide range of applications. To date, lipidic lyotropic LCs (LLCs) have been extensively explored in drug delivery and imaging owing to the capability to encapsulate and release payloads with different characteristics. The current landscape of lipidic LLCs in biomedical applications is provided in this review. Initially, the main properties, types, methods of fabrication and applications of LCs are showcased. Then, a comprehensive discussion of the main biomedical applications of lipidic LLCs accordingly to the application (drug and biomacromolecule delivery, tissue engineering and molecular imaging) and route of administration is examined. Further discussion of the main limitations and perspectives of lipidic LLCs in biomedical applications are also provided. STATEMENT OF SIGNIFICANCE: Liquid crystals (LCs) are those systems between a solid and liquid state that possess unique morphological and physicochemical properties, translatable into a wide range of biomedical applications. A short description of the properties of LCs, their types and manufacturing procedures is given to serve as a background to the topic. Then, the latest and most innovative research in the field of biomedicine is examined, specifically the areas of drug and biomacromolecule delivery, tissue engineering and molecular imaging. Finally, prospects of LCs in biomedicine are discussed to show future trends and perspectives that might be utilized. This article is an ampliation, improvement and actualization of our previous short forum article "Bringing lipidic lyotropic liquid crystal technology into biomedicine" published in TIPS.

Monitoring dexamethasone skin biodistribution with ex vivo MALDI-TOF mass spectrometry imaging and confocal Raman microscopy.

Two of the most promising techniques in terms of ex vivo skin imaging and quantifying are confocal Raman microscopy and MALDI-TOF mass spectrometry imaging (MALDI-TOF MSI). Both techniques were set up, and the semiquantitative skin biodistribution of previously developed dexamethasone (DEX) loaded lipomers was compared using Benzalkonium chloride (BAK) as a tracer of the nanoparticles. In MALDI-TOF MSI, DEX was derivatised with GirT (DEX-GirT) and the semiquantitative biodistribution of both DEX-GirT and BAK was successfully obtained. The amount of DEX measured by confocal Raman microscopy was higher than that measured by MALDI-TOF MSI, but MALDI-TOF MSI proved to be a more suitable technique for tracing BAK. An absorption-promoting tendency of DEX loaded in lipomers versus a free-DEX solution was observed in confocal Raman microscopy. The higher spatial resolution of confocal Raman microscopy (350 nm) with respect to MALDI-TOF MSI (50 µm) allowed to observe specific skin structures like hair follicles. Nevertheless, the faster sampling rate of MALDI-TOF-MSI, permitted the analysis of larger tissue regions. In conclusion, both techniques allowed to simultaneously analyze semiquantitative data together with qualitative images of biodistribution, which is a very helpful tool when designing nanoparticles that accumulate in specific anatomical regions.

Biomedical Applications of Lactoferrin on the Ocular Surface.

Lactoferrin (LF) is a first-line defense protein with a pleiotropic functional pattern that includes anti-inflammatory, immunomodulatory, antiviral, antibacterial, and antitumoral properties. Remarkably, this iron-binding glycoprotein promotes iron retention, restricting free radical production and avoiding oxidative damage and inflammation. On the ocular surface, LF is released from corneal epithelial cells and lacrimal glands, representing a significant percentage of the total tear fluid proteins. Due to its multifunctionality, the availability of LF may be limited in several ocular disorders. Consequently, to reinforce the action of this highly beneficial glycoprotein on the ocular surface, LF has been proposed for the treatment of different conditions such as dry eye, keratoconus, conjunctivitis, and viral or bacterial ocular infections, among others. In this review, we outline the structure and the biological functions of LF, its relevant role at the ocular surface, its implication in LF-related ocular surface disorders, and its potential for biomedical applications.

Efficacy and Safety of Inhaled Ethanol in Early-Stage SARS-CoV-2 Infection in Older Adults: A Phase II Randomized Clinical Trial.

BACKGROUND: Inhaled ethanol in the early stages of SARS-CoV-2 infection may reduce the viral load, decreasing progression and improving prognosis. The ALCOVID-19 trial was designed to study the efficacy and safety of inhaled ethanol in older adults at initial phases of infection. METHODS: Randomized, triple-blind, placebo-controlled phase II clinical trial. Experimental group (n = 38) inhaled 65° ethanol through an oxygen flow, while in the control group (n = 37), water for injection was used. General endpoint was to evaluate disease progression according to the modified World Health Organization (WHO) Clinical Progression Scale. Specific effectiveness endpoints were body temperature, oxygen saturation, viral load assessed by cycle threshold (Ct) on real-time polymerase chain reaction (RT-PCR), analytical biomarkers and use of antibiotics or corticosteroids. Specific safety outcomes were the absence of ethanol in plasma, electrographic, analytical, or respiratory alterations. RESULTS: In the intention-to-treat population, no differences were found regarding disease progression. Mean Ct values increased over time in both groups, being numerically higher in the ethanol group, reaching a value above 33 only in the ethanol group on day 14, a value above which patients are considered non-infective. No differences were found in the other specific effectiveness endpoints. Inhaled ethanol was proven to be safe as no plasma ethanol was detected, and there were no electrocardiographic, analytical, or respiratory alterations. CONCLUSIONS: The efficacy of inhaled ethanol in terms of the progression of SARS-CoV-2 infection was not demonstrated in the present trial. However, it is positioned as a safe treatment for elderly patients with early-stage COVID-19.

Design and biopharmaceutical preclinical characterisation of a new thermosensitive hydrogel for the removal of gastric polyps.

BACKGROUND AND AIMS: Submucosal injection agents are widely used solutions in gastric polyp resection techniques. Currently, many different solutions are used in clinical practice, but most are not authorised for this use or are not biopharmaceutical characterised. The objective of this multidisciplinary work is to test the efficacy of a novel thermosensitive hydrogel designed specifically for this indication. METHODS: A mixture design of various components (Pluronic®, hyaluronic acid and sodium alginate) was carried out to select the combination with optimal properties for this use. Three final thermosensitive hydrogels were selected on which biopharmaceutical characterisation was performed and stability and biocompatibility were analysed. Efficacy in maintaining elevation was tested ex vivo on pig mucosa and in vivo in pigs RESULTS: The mixture design allowed selection of the ideal combinations of agents for the characteristics sought. The thermosensitive hydrogels studied showed high values of hardness and viscosity at 37 °C, maintaining good syringeability. One of them demonstrated superiority in maintaining polyp elevation in the ex vivo assay and non-inferiority in the in vivo assay. CONCLUSION: The thermosensitive hydrogel specifically designed for this use is promising both for its biopharmaceutical characteristics and for its demonstrated efficacy. This study lays the foundation for evaluating the hydrogel in humans.

Efficacy and safety of a new medicated nail hydrolacquer in the treatment of adults with toenail onychomycosis: A randomised clinical trial.

BACKGROUND: A new water-soluble formulation with ciclopirox has shown a higher penetration than other ciclopirox nail lacquers currently marketed, thus providing a higher concentration of ciclopirox into the nail. OBJECTIVE: To evaluate the efficacy and safety of a new ciclopirox nail hydrolacquer compared with its vehicle and an active comparator (hydroxypropyl chitosan-based 80 mg/g ciclopirox nail lacquer) for the treatment of toenail fungal infection. METHODS: Phase III, multicenter, randomised, double-blind, clinical trial in patients with distal mild to moderate toenail onychomycosis due to dermatophyte fungi. Patients were randomised to apply topically a ciclopirox nail hydrolacquer, its vehicle or a reference product once daily for 48 weeks with a follow-up period of 4 weeks up to week 52. RESULTS: A total of 381 patients were included. No statistically significant differences were observed between patient groups in the proportion of subjects achieving a complete cure. At week 52, a higher percentage of patients in the ciclopirox nail hydrolacquer group achieved a mycological cure (negative for culture and DTS/KOH test, with results: 32.0% ciclopirox nail hydrolacquer, 23.2% vehicle and 27% reference product, respectively), and similar results were found for improvement (mycological cure and reduction of diseased nail ≥20%, with results: 27.2% ciclopirox nail hydrolacquer, 21.6% vehicle and 20.6% reference product, respectively). Regarding mycological results, only ciclopirox nail hydrolacquer demonstrated significant statistical superiority versus vehicle negativizing dermatophyte culture (p = .039) with no recurrences, relapses or re-infections in a four-week follow-up patients with complete cure. The safety profile was comparable to the vehicle and reference product and consistent with the previously reported. CONCLUSIONS: A new water-soluble formulation for a ciclopirox nail lacquer showed similar efficacy to the reference product to eradicate toenail onychomycosis and superiority in the mycological cure defined by negative culture, thus preventing reinfections and recurrences. Efficacy and safety data demonstrate the positive benefit-risk profile of this new topical antifungal preparation. [Correction added on 13 April 2023, after first online publication: The results and conclusions in the Abstract contained incorrect information and were revised in this version.].

Bringing lipidic lyotropic liquid crystal technology into biomedicine.

Liquid crystals (LCs), discovered more than 130 years ago, are now emerging in the field of biomedicine. This article highlights the recent uses of lipid lyotropic LCs in therapeutics delivery, imaging, and tissue engineering and invites the scientific community to continue exploring the design of more complex LCs.

Stability of insulin eye drops in the treatment of refractory corneal ulcers.

OBJECTIVE: To determine and compare the physicochemical and microbiological stability of two 25 IU/mL insulin eye drop formulations made with normal saline and a balanced salt solution, respectively, stored for 120 days under various conditions. METHOD: Eye drops were compounded in triplicate with 100 IU/mL Actrapid®  insulin and either normal saline or a balanced salt solution as vehicles, and  they were stored alternatively at room temperature (25 °C), in a refrigerator  (2-8 °C) or in a freezer (-20 °C) for 120 days. Insulin concentrations were  determined by ultra-high resolution liquid chromatography, and osmolality and  pH values were measured at days 0, 3, 7, 15, 30, 60, 90 and 120. Likewise,  samples were extracted for microbiological studies on days 0, 30, 60, 90 and  120. RESULTS: The formulation made with normal saline maintained insulin concentrations above 90% of the baseline level after 120 days across all  temperature conditions. In the case of the balanced salt solution- based eye drops, insulin concentration when stored at room temperature or in the freezer remained stable after 120 days, although insulin concentration when stored in the refrigerator fell below 90% on day 90 of the  study. Osmolality and pH values remained constant in both formulations and across all storage conditions. No microbiological growth was observed in any of the samples. CONCLUSIONS: 25 IU/mL insulin eye drops made with normal saline remain  stable for 120 days whether they are stored at room temperature, in a  refrigerator or in a freezer, provided that they are protected from light. When  made with a balanced salt solution, they remain stable for 120 days at room  temperature and in a freezer, their shelf life being reduced to 90 days in the  case of storage in a refrigerator.

OBJETIVO: Determinar y comparar la estabilidad físico-química y microbiológica de dos colirios de insulina 25 UI/ml elaborados con suero fisiológico o balanced salt solution bajo diferentes condiciones de  conservación durante 120 días.Método: Los colirios se elaboraron por triplicado con insulina Actrapid® 100  Ul/ml y balanced salt solution o suero fisiológico como vehículo, y fueron  conservados a temperatura ambiente (25 °C), en nevera (2-8 °C) o congelador  (­20 °C) durante 120 días. Se determinó la concentración de  insulina mediante cromatografía liquida de ultra alta resolución, la osmolalidad  y el pH a días 0, 3, 7, 15, 30, 60, 90 y 120. Asimismo, se extrajeron muestras  para estudios microbiológicos en los días 0, 15, 30, 60, 90 y 120. RESULTADOS: La formulación elaborada con suero fisiológico mantuvo la  concentración de insulina por encima del 90% con respecto a la inicial tras 120  días de estudio en todas las condiciones de temperatura. En el caso del  colirio elaborado con balanced salt solution, la concentración se mantuvo  estable en ambiente y congelador tras 120 días, aunque en nevera descendió  por debajo del 90% a día 90 de estudio. Los valores de osmolalidad y pH se  mantuvieron constantes en ambas formulaciones y condiciones de  conservación. No se observó crecimiento microbiológico en ninguna de las  muestras retiradas. CONCLUSIONES: El colirio de insulina 25 UI/ml elaborado con suero fisiológico  es estable 120 días, conservado tanto a temperatura ambiente como en nevera  o congelador, protegido de la luz. Con balanced salt solution  permanece estable 120 días a temperatura ambiente y congelador, reduciéndose el periodo de validez a 90 días en el caso de la conservación en nevera.

PET study of intravitreal adalimumab pharmacokinetics in a uveitis rat model.

Adalimumab is an anti-TNFα drug approved for uveitis treatment by subcutaneous injection. This administration route exposes patients to systemic adverse effects and makes difficult to obtain therapeutic drug concentrations in the site of action due to the anatomical and physiological barriers of the eye. These inconveniences could be avoided by intravitreal injection. The aim of this study is to evaluate the pharmacokinetic profile and the biodistribution of the intravitreal administration of 89Zr-adalimumab in a uveitis rat model using PET imaging. Adalimumab was radiolabelled to 89Zr with a maximum specific activity of 10 MBq/mg. Four µL containing ≃1.74 MBq of 89Zr-labelled adalimumab were injected into the vitreous. A microPET acquisition was carried out immediately after the injection and at different time points through a 10-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration of 99.69 %. The antibody ocular pharmacokinetics followed a one-compartment model, showing an intraocular elimination half-life of 15.57 h for healthy rats and  33.64 h for rats with uveitis, implying that 89Zr-adalimumab remains around two times longer in rats with the disease compared to healthy ones. However, blood concentration half-life had similar values in both groups. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis of adalimumab in a uveitis model in rats.

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems: Stability and Ocular Biopermanence.

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs causing, among other symptoms, severe ocular manifestations. Cysteamine eye drops are prepared in hospital pharmacy departments to facilitate access to treatment, for which vehicles that provide adequate biopermanence, as well as adaptable containers that maintain its stability, are required. Difficulties related to cysteamine preparation, as well as its tendency to oxidize to cystamine, show the importance of conducting rigorous galenic characterization studies. This work aims to develop and characterize an ophthalmic compounded formulation of cysteamine prepared with hyaluronic acid and packaged in innovative single-dose systems. For this task, the effect of different storage temperatures and the presence/absence of nitrogen on the physicochemical stability of the formulation and its packaging was studied in a scaled manner, until reaching the optimal storage conditions. The results showed that 0.55% cysteamine, prepared with hyaluronic acid and packaged in single-dose containers, is stable for 30 days when stored at -20 °C. In addition, opening vials every 4 h at room temperature after 30 days of freezing maintains the stability of the cysteamine formulation for up to 16 h. Moreover, ocular biopermanence studies were conducted using molecular imaging, concluding that the biopermanence offered by the vehicle is not affected by the freezing process, where a half-life of 31.11 min for a hyaluronic acid formulation stored for 30 days at -20 °C was obtained, compared with 14.63 min for 0.9% sodium chloride eye drops.

Preparation and ex vivo investigation of an injectable microparticulate formulation for gastrointestinal mucosa polyp resection.

Endoscopic submucosal dissection (ESD) and endoscopic submucosal resection (EMR) are non-invasive endoscopic techniques. They allow an early excised gastrointestinal (GI) mucosal precancerous lessions. For their application is necessary to use a submucosal injection that lifts the area to excise. The main objective of this study was the preparation of a microparticulate-based fluid for injection in the GI submucosa. Alginate microparticles (MPs) were developed by the solvent displacement technique and characterized by particle size, surface electrical properties, swelling, degradation, rheology, adhesion, leakage, syringeablity and stability. Furthermore, their potential to form a submucosal cushion was assayed in porcine stomach mucosa and porcine colon mucosa. Results showed MPs sizes below 160 µm, negative surface charge around -50 mV at pH = 6, high rates of swelling and good adhesion. The microparticulate-based fluid exhibited pseudoplastic behavior following the Ostwald-de Waele rheological model. A brief force is sufficient for its injection through a syringe. Finally, formulations were able to provide a submucosa elevation of 1.70 cm for more than 90 min and 120 min in the porcine stomach and colon, respectively.

Mucoadhesive PLGA Nanospheres and Nanocapsules for Lactoferrin Controlled Ocular Delivery.

BACKGROUND: the present work describes the preparation, characterization and optimization of eight types of PLGA-based nanosystems (nanospheres and nanocapsules) as innovative mucoadhesive drug delivery systems of lactoferrin, in order to achieve a preclinical consistent base as an alternative pharmacological treatment to different ocular syndromes and diseases. METHODS: All different nanoparticles were prepared via two modified nanoprecipitation techniques, using a three-component mixture of drug/polymer/surfactant (Lf/PLGA/Poloxamer), as a way to overcome the inherent limitations of conventional PLGA NPs. These modified polymeric nanocarriers, intended for topical ophthalmic administration, were subjected to in vitro characterization, surface modification and in vitro and in vivo assessments. RESULTS: An appropriate size range, uniform size distribution and negative ζ potential values were obtained for all types of formulations. Lactoferrin could be effectively included into all types of nanoparticles with appropriate encapsulation efficiency and loading capacity values. A greater, extended, and controlled delivery of Lf from the polymeric matrix was observed through the in vitro release studies. No instability or cytotoxicity was proved for all the formulations by means of organotypic models. Additionally, mucoadhesive in vitro and in vivo experiments show a significant increase in the residence time of the nanoparticles in the eye surface. CONCLUSIONS: all types of prepared PLGA nanoparticles might be a potential alternative for the topical ophthalmic administration of lactoferrin.

Fighting type 2 diabetes: Formulation strategies for peptide-based therapeutics.

Diabetes mellitus is a major health problem with increasing prevalence at a global level. The discovery of insulin in the early 1900s represented a major breakthrough in diabetes management, with further milestones being subsequently achieved with the identification of glucagon-like peptide-1 (GLP-1) and the introduction of GLP-1 receptor agonists (GLP-1 RAs) in clinical practice. Moreover, the subcutaneous delivery of biotherapeutics is a well-established route of administration generally preferred over the intravenous route due to better patient compliance and prolonged drug absorption. However, current subcutaneous formulations of GLP-1 RAs present pharmacokinetic problems that lead to adverse reactions and treatment discontinuation. In this review, we discuss the current challenges of subcutaneous administration of peptide-based therapeutics and provide an overview of the formulations available for the different routes of administration with improved bioavailability and reduced frequency of administration.

Lactoferrin-loaded nanostructured lipid carriers (NLCs) as a new formulation for optimized ocular drug delivery.

Nanostructured lipid carriers (NLC) are novel lipidic nanosystems that provide significant improvements in terms of high drug loading capacity and controlled drug release. The purpose of the present work was based on the design, development, and physicochemical characterization of lactoferrin-loaded NLCs as a new therapeutic alternative for the keratoconus treatment. Lactoferrin-loaded NLCs were successfully prepared by a double emulsion/solvent evaporation method. The resultant NLC were assessed in terms of particle size, size distribution, surface charge, morphology, encapsulation efficiency (EE), loading capacity (LC), stability, cytotoxicity, in vitro release, and ocular surface retention. Resulting data showed a size of 119.45 ± 11.44 nm, a 0.151 ± 0.045 PDI value and a surface charge of -17.50 ± 2.53 mV. Besides, high EE and LC values were obtained (up to 75%). The in vitro release study demonstrated a lactoferrin controlled release pattern. NLCs were also stable, non-toxic and show mucoadhesive properties. Thus, a consistent preclinical base was obtained, where NLC may be considered as a potential controlled release novel drug delivery system of lactoferrin for the keratoconus treatment.