OphthalMimic: A new alternative apparatus without animal tissue for the evaluation of topical ophthalmic drug products.

The necessity of animal-free performance tests for novel ophthalmic formulation screening is challenging. For this, we developed and validated a new device to simulate the dynamics and physical-chemical barriers of the eye for in vitro performance tests of topic ophthalmic formulations. The OphthalMimic is a 3D-printed device with an artificial lacrimal flow, a cul-de-sac area, a support base, and a simulated cornea comprised of a polymeric membrane containing poly-vinyl alcohol 10 % (w/v), gelatin 2.5 % (w/v), and different proportions of mucin and poloxamer, i.e., 1:1 (M1), 1:2 (M2), and 2:1 (M3) w/v, respectively. The support base is designed to move between 0° and 50° to replicate the movement of an eyelid. We challenged the model by testing the residence performance of poloxamer®407 16 % and poloxamer®407 16 % + chitosan 1 % (PLX16CS10) gels containing fluconazole. The test was conducted with a simulated tear flow of 1.0 mL.min-1 for 5 min. The OphthalMimic successfully distinguished PLX16 and PLX16C10 formulations based on their fluconazole drainage (M1: 65 ± 14 % and 27 ± 10 %; M2: 58 ± 6 % and 38 ± 9 %; M3: 56 ± 5 % and 38 ± 18 %). In conclusion, the OphthalMimic is a promising tool for comparing the animal-free performance of ophthalmic formulations.

Polymeric nanocapsules: A review on design and production methods for pharmaceutical purpose.

Polymeric nanocapsules have extensive application potential in medical, biological, and pharmaceutical fields, and, therefore, much research has been dedicated to their production. Indeed, production protocols and the materials used are decisive for obtaining the desired nanocapsules characteristics and biological performance. In addition to that, several technological strategies have been developed in the last decade to improve processing techniques and form more valuable nanocapsules. This review provides a guide to current methods for developing polymeric nanocapsules, reporting aspects to be considered when choosing appropriate materials, and discussing different ways to produce nanocapsules for superior performances.

Pouteria macrophylla Fruit Extract Microemulsion for Cutaneous Depigmentation: Evaluation Using a 3D Pigmented Skin Model.

Here, we verify the depigmenting action of Pouteria macrophylla fruit extract (EXT), incorporate it into a safe topical microemulsion and assess its effectiveness in a 3D pigmented skin model. Melanocytes-B16F10- were used to assess the EXT effects on cell viability, melanin synthesis, and melanin synthesis-related gene transcription factor expression, which demonstrated a 32% and 50% reduction of intra and extracellular melanin content, respectively. The developed microemulsion was composed of Cremophor EL®/Span 80 4:1 (w/w), ethyl oleate, and pH 4.5 HEPES buffer and had an average droplet size of 40 nm (PdI 0.40 ± 0.07). Skin irritation test with reconstituted epidermis (Skin Ethic RHETM) showed that the formulation is non-irritating. Tyrosinase inhibition was maintained after skin permeation in vitro, in which microemulsion showed twice the inhibition of the conventional emulsion (20.7 ± 2.2% and 10.7 ± 2.4%, respectively). The depigmenting effect of the microemulsion was finally confirmed in a 3D culture model of pigmented skin, in which histological analysis showed a more pronounced effect than a commercial depigmenting formulation. In conclusion, the developed microemulsion is a promising safe formulation for the administration of cutite fruit extract, which showed remarkable depigmenting potential compared to a commercial formulation.

Preformulation Studies to Guide the Production of Medicines by Fused Deposition Modeling 3D Printing.

Fused deposition modeling (FDM) 3D printing has demonstrated high potential for the production of personalized medicines. However, the heating at high temperatures inherent to this process causes unknown risks to the drug product's stability. The present study aimed to assess the use of a tailored preformulation protocol involving physicochemical assessments, including the rheological profiles of the samples, to guide the development of medicines by FDM 3D printing. For this, polymers commonly used in FDM printing, i.e., high impact polystyrene (HIPS), polylactic acid (PLA), and polyvinyl alcohol (PVA), and their common plasticizers (mineral oil, triethyl citrate, and glycerol, respectively) were evaluated using the thermolabile model drug isoniazid (INH). Samples were analyzed by chemical and physical assays. The results showed that although the drug could produce polymorphs under thermal processing, the polymeric matrix can be a protective element, and no polymorphic transformation was observed. However, incompatibilities between materials might impact their chemical, thermal, and rheological performances. In fact, ternary mixtures of INH, PLA, and TEC showed a major alteration in their viscoelastic behavior besides the chemical changes. On the other hand, the use of plasticizers for HIPS and PVA exhibited positive consequences in drug solubility and rheologic behavior, probably improving sample printability. Thus, the optimization of the FDM 3D printing based on preformulation studies can assist the choice of compatible components and seek suitable processing conditions to obtain pharmaceutical products.

Latanoprost Loaded in Polymeric Nanocapsules for Effective Topical Treatment of Alopecia.

Latanoprost has recently been used to treat alopecia as it causes an increase in the capillary density of patients. This work presents for the first time the development of polymeric nanocapsules containing latanoprost for the topical treatment of alopecia. Poly-ε-caprolactone nanocapsules loading latanoprost were developed by nanoprecipitation of the polymer on the surface of drug oily nanodroplets. The method encapsulated 93.9 ± 0.4% of the drug into nanocapsules of 197.8 (± 1.2) nm (PdI = 0.15 ± 0.01). The nanosystem presented a zeta potential equal to - 30.1 ± 1.8 mV and was stable for at least 90 days when stored at 6°C. The colloidal aqueous dispersion was non-irritating, according to the in vitro HET-CAM test. The nanocapsules improved latanoprost accumulation into the hair follicles when topically applied on porcine skin, delivering 30% more drug to these skin structures relative to the control solution (P < 0.05). Also, with a simple manual massage, latanoprost accumulation was increased by twofold (P < 0.05). In conclusion, in addition to being a stable and safe formulation, nanocapsules enhanced latanoprost accumulation into the hair follicles, being a nanosystem with high potential for use as a topical formulation for the treatment of androgenic alopecia.

Stability-indicating analytical method of quantifying spironolactone and canrenone in dermatological formulations and iontophoretic skin permeation experiments.

A simple, stability-indicating, chromatographic method of quantifying spironolactone (SPI) and its metabolite, canrenone (CAN), in the presence of excipients typical in dermatological formulations and skin matrices in studies of passive and iontophoretic permeation was proposed and validated here. SPI and CAN were separated using a reversed-phase column with a mobile phase of methanol-water (60:40, v/v) at a flow rate of 1.0 mL/min. Data were collected with a UV detector at 238 and 280 nm, with retention times of 6.2 and 7.9 min for SPI and CAN, respectively. The method was precise, accurate and linear (r2 > 0.99) in a concentration range of 1-30 µg/mL, and recovery rates of SPI and CAN from the different skin layers exceeded 85%. The method was not only sensitive (LOD of 0.05 and 0.375 µg/mL and LOQ of 0.157 and 1.139 µg/mL for SPI and CAN, respectively) but also selective against skin matrices and highly representative components of topical formulations. The method moreover demonstrated SPI's degradation in iontophoresis by applying Pt-AgCl electrodes and its continued drug stability using Ag-AgCl electrodes. Altogether, the method proved valuable for quantifying SPI and CAN and may be applied in developing and controlling the quality of dermatological products.

The Influence of Matrix Technology on the Subdivision of Sustained Release Matrix Tablets.

The subdivision of sustained release tablets is a controversial issue, especially concerning its impact on dissolution profiles. The purpose of this study was to elucidate the behavior upon subdivision of this class of tablets. For this, three common sustained release matrices containing different technologies were selected, e.g., a tablet comprised of a multiple-unit particulate system (MUPS), a lipid matrix tablet, and a polymeric inert matrix tablet. These tablets were studied concerning their physicochemical performance, dissolution rate, and kinetic profile before and after their subdivision. When subdivision occurred in the scoreline, mass variation and mass loss were below the mean values described in the literature. The dissolution of tablets with inert matrices and some lipid tablets that had their matrices preserved along the dissolution was influenced directly by tablet surface area, which increased after the subdivision. Such a result implies possible clinical consequences, especially in the case of drugs with a narrow therapeutic window, such as clomipramine. Conversely, the subdivision of MUPS tablets did not interfere in the dissolution profile since the drug was released from the granules that resulted from tablet disintegration. Hence, MUPS technology is the most recommended to produce sustained release matrix tablets intended for dose adjustment upon subdivision.

Chromatographic method for clobetasol propionate determination in hair follicles and in different skin layers.

Clobetasol propionate (CLO) is a potent steroid used for the treatment of several dermatological diseases. Recent studies suggest its additional use in alopecia topical treatment, generating a demand for novel formulations with specific delivery into hair follicles. Hence, a selective analytical method for drug quantification in follicular structures and skin layers is required. For this, a simple HPLC-UV method was developed. Quantification was performed using a RP-C18 column (4.6 mm × 15 cm, 5 µm), with a mixture of methanol-acetonitrile-water (50:15:35 v/v) as mobile phase, a flow rate of 1.2 mL/min, oven temperature of 30°C, injection volume of 50 µL and detection at 240 nm. The optimized conditions enabled a 12 min running with CLO elution at 10.1 min and resolution of 2.424 from skin matrix interferences. Validation was performed in accordance with International Conference on Harmonization guidelines and fulfilled the criteria of selectivity, linearity (0.5-15.0 µg/mL), robustness, precision, accuracy and limits of detection and quantification (0.02 and 0.07 µg/mL, respectively). The validated method was successfully applied for CLO quantification following in vitro skin permeation experiments and differential tape-stripping for hair follicle deposition determination, demonstrating its suitability.

Preparation of benznidazole pellets for immediate drug delivery using the extrusion spheronization technique.

Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.

Key Technical Aspects Influencing the Accuracy of Tablet Subdivision.

Tablet subdivision is a common practice used mainly for dose adjustment. The aim of this study was to investigate how the technical aspects of production as well as the method of tablets subdivision (employing a tablet splitter or a kitchen knife) influence the accuracy of this practice. Five drugs commonly used as subdivided tablets were selected. For each drug, the innovator drug product, a scored-generic and a non-scored generic were investigated totalizing fifteen drug products. Mechanical and physical tests, including image analysis, were performed. Additionally, comparisons were made between tablet subdivision method, score, shape, diluent composition and coating. Image analysis based on surface area was a useful tool as an alternative assay to evaluate the accuracy of tablet subdivision. The tablet splitter demonstrates an advantage relative to a knife as it showed better results in weight loss and friability tests. Oblong, coated and scored tablets had better results after subdivision than round, uncoated and non-scored tablets. The presence of elastic diluents such as starch and dibasic phosphate dehydrate conferred a more appropriate behaviour for the subdivision process than plastic materials such as microcrystalline cellulose and lactose. Finally, differences were observed between generics and their innovator products in all selected drugs with regard the quality control assays in divided tablet, which highlights the necessity of health regulations to consider subdivision performance at least in marketing authorization of generic products.

Iontophoresis use for increasing drug penetration into root canals and dentinal tubules: A proof-of-concept study.

INTRODUCTION: The success of endodontic treatment depends on the significant disinfection of the root canal system, its irregularities, and dentinal tubules. However, achieving complete disinfection remains challenging, with frequent failures and occurrence of secondary infections. Here, we propose using iontophoresis to increase the penetration and distribution of disinfecting agents into root canals, using methylene blue for proof-of-concept. METHODS: The marker was applied in bovine root canals, and the radial distribution of the dye in the dentinal tubules was evaluated by optical microscopy. Iontophoresis was applied at 0.5 and 1.5 mA for 5 and 15 min. RESULTS: A significant statistical difference (p < 0.05) was observed in the marker penetration between passive and iontophoretic applications. Both current density and application time had an important effect on methylene blue distribution, with a greater efficacy delivery to the apical region achieved after 1.5 mA for 5 min or 0.5 mA for 15 min, showing longer application time can compensate for lower application current. CONCLUSION: Iontophoresis increases the penetration and distribution of methylene blue into bovine root canals and dentinal tubules, including its innermost portions. CLINICAL SIGNIFICANCE: Iontophoresis has shown to be a promising technique for root canal and dentinal tubule disinfection.

Melt crystallization and thermal degradation profile of the antichagasic drug nifurtimox.

Despite nifurtimox (NFX) being a traditional drug for treating Chagas disease, some of its physicochemical properties are still unknown, especially its thermal behavior, which brings important outcomes regarding stability and compatibility. In this work, a comprehensive study of NFX's thermal properties was conducted to assist incremental innovations that can improve the efficacy of this drug in novel pharmaceutical products. For this purpose, thermal analyses associated with spectroscopy and spectrometry techniques were used. DSC analyses revealed that the melt crystallization of the NFX led to its amorphous form with the possible formation of a minor fraction of a different crystalline phase. Coats-Redfern method using TGA results indicated the activation energy of NFX non-isothermal degradation as 348.8 ± 8.2 kJ mol-1, which coincides with the C-NO2 bond dissociation energy of the 2-nitrofuran. Investigation of the isothermal degradation kinetics using FTIR 2D COS showed the possible detachment of radical NO2 and ethylene from the NFX structure, which could affect its mechanism of action. A preliminary mechanism for the thermal degradation of this drug was also proposed. The results enhanced the understanding of NFX's thermal properties, providing valuable insights, especially for developing NFX-based pharmaceutical products that involve thermal processing.

Conformational analysis and spectroscopic properties of antichagasic nifurtimox.

Considering the health relevance of Chagas' disease, recent research efforts have focused on developing more efficient drug delivery systems containing nifurtimox (NFX). This paper comprehensively investigates NFX through conformational analysis and spectroscopic characterization. Using a conformer-rotamer ensemble sampling tool (CREST-xtb), five distinct conformers of NFX were sampled within a 3.0 kcal mol-1 relative energy window. Subsequently, such structures were used as inputs for geometry optimization by density functional theory (DFT) at B3LYP-def2-TZVP level of theory. Notably, harmonic vibrational frequencies were calculated to establish an in-depth comparison with experimental results and existing literature for the NFX or similar molecules and functional groups, thereby achieving a widely reasoned assignment of the mid-infrared band absorptions for the first time. Moreover, UV-VIS spectra of NFX were obtained in several solvents, enabling the determination of the molar absorptivity coefficient for the two electronic transitions observed for NFX. Among the aprotic solvents, a bathochromic effect was observed in the function of the dielectric constants. Furthermore, a hypochromic effect was observed when the drug was dissolved in protic solvents. These findings offer crucial support for new drug delivery systems containing NFX while demonstrating the potential of spectrophotometric studies in establishing quality control assays for NFX drug products.

Customizable Three-Dimensional Printed Earring Tap for Treating Affections Caused by Aesthetic Perforations.

This work aimed to develop a three-dimensional (3D) wearable drug-loaded earring tap to treat affections caused by aesthetic perforations. The initial phase involved a combination of polymers to prepare filaments for fused deposition modeling (FDM) 3D printing using a centroid mixture design. Optimized filament compositions were used in the second phase to produce 3D printed earring taps containing the anti-inflammatory naringenin. Next, samples were assessed via physicochemical assays followed by in vitro skin permeation studies with porcine ear skin. Two filament compositions were selected for the study's second phase: one to accelerate drug release and another with slow drug dissolution. Both filaments demonstrated chemical compatibility and amorphous behavior. The use of the polymer blend to enhance printability has been confirmed by rheological analysis. The 3D devices facilitated naringenin skin penetration, improving drug recovery from the skin's most superficial layer (3D device A) or inner layers (3D device B). Furthermore, the devices significantly decreased transdermal drug delivery compared to the control containing the free drug. Thus, the resulting systems are promising for producing 3D printed earring taps with topical drug delivery and reinforcing the feasibility of patient-centered drug administration through wearable devices.

Ibrutinib topical delivery for melanoma treatment: The effect of nanostructured lipid carriers' composition on the controlled drug skin deposition.

Melanoma is responsible for more than 80% of deaths related to skin diseases. Ibrutinib (IBR), a Bruton's tyrosine kinase inhibitor, has been proposed to treat this type of tumor. However, its low solubility, extensive first-pass effect, and severe adverse reactions with systemic administration affect therapeutic success. This study proposes developing and comparing the performance of two compositions of nanostructured lipid carriers (NLCs) to load IBR for the topical management of melanomas in their early stages. Initially, the effectiveness of IBR on melanoma proliferation was evaluated in vitro, and the results confirmed that the drug reduces the viability of human melanoma cells by inducing apoptosis at a dose that does not compromise dermal cells. Preformulation tests were then conducted to characterize the physical compatibility between the drug and the selected components used in NLCs preparation. Sequentially, two lipid compositions were used to develop the NLCs. Formulations were then characterized and subjected to in vitro release and permeation tests on porcine skin. The NLCs containing oleic acid effectively controlled IBR release over 24 h compared to the NLCs composed of pomegranate seed oil. Furthermore, the nanoparticles acted as permeation enhancers, increasing the fluidity of the lipids in the stratum corneum, as determined by EPR spectroscopy, which stimulated the IBR penetration more profoundly into the skin. However, the NLCs composition also influenced the permeation promotion factor. Thus, these findings emphasize the importance of the composition of NLCs in controlling and increasing the skin penetration of IBR and pave the way for future advances in melanoma therapy.

Curcumin quantification in skin and mucosa: Optimization of extraction and chromatographic method validation.

Curcumin is a natural phenol found in the rhizome of Curcuma longa. It has been studied to treat several human carcinomas, such as melanomas and breast, head and neck, prostate, and ovary cancers. Here, we develop and validate a method for recovering curcumin from the skin layers and mucosa and selectively quantifying it, aiming to support permeation studies in developing topical formulations containing the natural compound. Recovery of curcumin from the stratum corneum, remaining skin, and mucosa was performed using ethanol, DMSO/ethanol, and DMSO, respectively, under mild stirring for specific periods. The separation of curcumin from the other curcuminoids, skin, and mucosa interferents was obtained using a C18 column as a stationary phase. The mobile phase was composed of pH 3.0 phosphoric acid at 1.0 mmol/L and acetonitrile (47:53, v/v), which flowed at 1 mL min-1. UV-Vis detection of curcumin was at 424 nm. The chromatographic method was selective, linear (r > 0.999), with a regression curve in the concentration range from 1.0 to 30.0 µg mL-1, robust, precise, and accurate, with curcumin recovery rates higher than 95 ± 7 % from the mucosa, 82 ± 2 % from the stratum corneum, and 65 ± 10 % from the remaining skin. Finally, the method was successfully used in a skin permeation test performed with porcine skin and mucosa. The validated method is, therefore, suitable for the recovery and quantification of curcumin from the skin layers and mucosa, favoring the development of new topical formulations destined for these sites of administration.

Iontophoresis for the cutaneous delivery of nanoentraped drugs.

INTRODUCTION: The skin is an attractive route for drug delivery. However, the stratum corneum is a critical limiting barrier for drug permeation. Nanoentrapment is a way to enhance cutaneous drug delivery, by diverse mechanisms, with a notable trend of nanoparticles accumulating into the hair follicles when topically applied. Iontophoresis is yet another way of increasing drug transport by applying a mild electrical field that preferentially passes through the hair follicles, for being the pathway of lower resistance. So, iontophoresis application to nanocarriers could further increase actives accumulation into the hair follicles, impacting cutaneous drug delivery. AREAS COVERED: In this review, the authors aimed to discuss the main factors impacting iontophoretic skin transport when combining nanocarriers with iontophoresis. We further provide an overview of the conditions in which this combination has been studied, the characteristics of nanosystems employed, and hypothesize why the association has succeeded or failed to enhance drug permeation. EXPERT OPINION: Nanocarriers and iontophoresis association can be promising to enhance cutaneous drug delivery. For better results, the electroosmotic contribution to the iontophoretic transport, mainly of negatively charged nanocarriers, charge density, formulation pH, and skin models should be considered. Moreover, the transfollicular pathway should be considered, especially when designing the nanocarriers.

Methodologies to Evaluate the Hair Follicle-Targeted Drug Delivery Provided by Nanoparticles.

Nanotechnology has been investigated for treatments of hair follicle disorders mainly because of the natural accumulation of solid nanoparticles in the follicular openings following a topical application, which provides a drug "targeting effect". Despite the promising results regarding the therapeutic efficacy of topically applied nanoparticles, the literature has often presented controversial results regarding the targeting of hair follicle potential of nanoformulations. A closer look at the published works shows that study parameters such as the type of skin model, skin sections analyzed, employed controls, or even the extraction methodologies differ to a great extent among the studies, producing either unreliable results or precluding comparisons altogether. Hence, the present study proposes to review different skin models and methods for quantitative and qualitative analysis of follicular penetration of nano-entrapped drugs and their influence on the obtained results, as a way of providing more coherent study protocols for the intended application.

Chromatographic method for dacarbazine quantification in skin permeation experiments.

Dacarbazine (DTIC) is a chemotherapeutic drug currently used for the systemic treatment of melanomas. Considering the easy access to these tumors, a topical route of drug administration could provide a more comfortable and less toxic treatment. However, DTIC quantification aiming at the design of topical formulations is challenging, pondering all the interferents present in the drug samples recovered from the skin. Hence, this work intended to validate a selective chromatographic method for DTIC determination in skin permeation studies. A reversed-phase C18 column was used as a stationary phase, and gradient elution of a mobile phase consisting of methanol and pH 6.5 sodium phosphate monohydrate buffer (0.01 mol/L) at a flow rate of 1.0 mL/min was implemented. DTIC was detected at 364 nm. The method was selective against skin interferents, linear (r = 0.9995) in a concentration range of 1.0-15.0 µg/mL, precise with an overall variation coefficient lower than 3.8%, accurate achieving recovery from the skin layers within 91-112%, and sensitive for the proposed application (detection limit = 0.10 µg/ mL, quantification limit = 0.30 µg/mL). Furthermore, the analytical method was successfully tested in in vitro skin permeation studies. In conclusion, the developed method is appropriate for DTIC analysis from the skin sample matrix.

Novel technologies to improve the treatment of endodontic microbial infections: Inputs from a drug delivery perspective.

Endodontic microbial infections are still a challenge for an effective treatment for being biofilm-mediated and very refractory to conventional therapies. Biomechanical preparation and chemical irrigants cannot fully eradicate biofilms due to the anatomic structure of the root canal system. Instruments employed in biomechanical preparation and irrigants solution cannot reach the narrow and deepest portion of root canals, especially the apical thirds. In addition, aside from the dentin surface, biofilms can also infiltrate dentine tubules and periapical tissues, compromising treatment success. Therefore, different technologies have been investigated to achieve a more effective outcome in the control of endodontic infections. However, these technologies continue to face great difficulties in reaching the apical region and eradicating biofilms to avoid the recurrence of infection. Here, we present an overview of the fundamentals of endodontics infections and review technologies currently available for root canal treatment. We discuss them from a drug delivery perspective, highlighting each technology's strength to envision the best use of these technologies.