Critical View on the Qualification of Electronic Tongues Regarding Their Performance in the Development of Peroral Drug Formulations with Bitter Ingredients.

In this review, we aim to highlight the advantages, challenges, and limitations of electronic tongues (e-tongues) in pharmaceutical drug development. The authors, therefore, critically evaluated the performance of e-tongues regarding their qualification to assess peroral formulations containing bitter active pharmaceutical ingredients. A literature search using the keywords 'electronic', 'tongue', 'bitter', and 'drug' in a Web of Science search was therefore initially conducted. Reviewing the publications of the past decade, and further literature where necessary, allowed the authors to discuss whether and how e-tongues perform as expected and whether they have the potential to become a standard tool in drug development. Specifically highlighted are the expectations an e-tongue should meet. Further, a brief insight into the technologies of the utilized e-tongues is given. Reliable protocols were found that enable (i) the qualified performance of e-tongue instruments from an analytical perspective, (ii) proper taste-masking assessments, and (iii) under certain circumstances, the evaluation of bitterness.

A simple drug-delivery microneedling technique modality successfully improves linear atrophic scars.

BACKGROUND: Atrophic scars are white, dermal depressions, caused by the destruction of collagen fibers and decrease in epidermal cells, following inflammation after different types of trauma. They lead to significant physical, aesthetic and psychological barriers and their treatment remain a therapeutic challenge for dermatologists. Microneedling has been shown to improve scars by stimulating angiogenesis and neocolagenesis and the combination of anti-fibrotic drugs could potentialize the results. METHODS: We present 8 cases of patients with linear scars, successfully treated with two sessions of a new Microneedling technique, using a tattoo machine, associated with drug delivery of 5-FU. RESULTS: A marked improvement in scar pigmentation and texture were noted by patients and doctors, 6 months following the sessions of MMP and drug delivery with 5-FU, in different body sites. We also showed that the assessment scores of at least one of the professionals with those of the patient had significant correlations with each other, which shows consistency between the qualitative assessment instruments. We also showed that the cause of the injury can influence joint assessment scores (physicians plus patient) or those exclusive to professionals trained for the assessments, generating evidence that the cause of the injury can influence the treatment outcome itself. CONCLUSIONS: We present an inexpensive and promising approach that can be easily done as an in-office procedure. Larger, multicenter studies are needed to validate this technique among the first line therapies for acne scar treatment.

Preparation of Nanosized Pharmaceutical Formulations by Dual Centrifugation.

Dual centrifugation (DC) is an innovative in-vial homogenization and in-vial nanomilling technique that has been in use for the preparation of liposomes for more than one decade. Since then, DC has continuously been developed for preparing various liposomes and other lipid nanoparticles including emulsions and solid lipid nanoparticles (SLNs) as well as polymersomes and nanocrystals. Improvements in equipment technology have been achieved over the past decade, so that DC is now on its way to becoming the quasi-standard for the simple, fast, and aseptic production of lipid nanoparticles and nanocrystals in small and medium batch sizes, including the possibility of simple and fast formulation screening or bedside preparations of therapeutic nanoparticles. More than 68 publications in which DC was used to produce nanoparticles have appeared since then, justifying an initial review of the use of DC for pharmaceutical nanotechnology.

On the calculation of ³Jαß-coupling constants for side chains in proteins.

Structural knowledge about proteins is mainly derived from values of observables, measurable in NMR spectroscopic or X-ray diffraction experiments, i.e. absorbed or scattered intensities, through theoretically derived relationships between structural quantities such as atom positions or torsional angles on the one hand and observable quantities such as squared structure factor amplitudes, NOE intensities or (3) J-coupling constants on the other. The standardly used relation connecting (3) J-couplings to torsional angles is the Karplus relation, which is used in protein structure refinement as well as in the evaluation of simulated properties of proteins. The accuracy of the simple and generalised Karplus relations is investigated using side-chain structural and (3) J (αß)-coupling data for three different proteins, Plastocyanin, Lysozyme, and FKBP, for which such data are available. The results show that the widely used Karplus relations are only a rough estimate for the relation between (3) J (αß)-couplings and the corresponding χ(1)-angle in proteins.

Calculation of the relative free energy of oxidation of Azurin at pH 5 and pH 9.

Free energy calculations are described for the small copper-containing redox protein Azurin from Pseudomonas aeruginosa. A thermodynamic cycle connecting the reduced and oxidized states at pH 5 and pH 9 is considered, allowing for an assessment of convergence in terms of hysteresis and cycle closure. Previously published thermodynamic integration (TI) data is compared to Hamiltonian replica exchange TI (RE-TI) simulations using different simulation setups. The effects of varying simulation length, initial structure, position restraints on particular atoms, and the strength of temperature coupling are studied. Although the overall simulation times are too short to observe an experimentally described peptide plane rotation, it is found that RE-TI simulations do stimulate the distribution of conformational changes over the relevant values of the TI coupling parameter λ. This results in significantly improved values for hysteresis and cycle closure when compared to regular TI.

An improved structural characterisation of reduced French bean plastocyanin based on NMR data and local-elevation molecular dynamics simulation.

Deriving structural information about a protein from NMR experimental data is still a non-trivial challenge to computational biochemistry. This is because of the low ratio of the number of independent observables to the number of molecular degrees of freedom, the approximations involved in the different relationships between particular observable quantities and molecular conformation, and the averaged character of the experimental data. For example, protein (3)J-coupling data are seldom used for structure refinement because of the multiple-valuedness and limited accuracy of the Karplus relationship linking a (3)J-coupling to a torsional angle. Moreover, sampling of the large conformational space is still problematic. Using the 99-residue protein plastocyanin as an example we investigated whether use of a thermodynamically calibrated force field, inclusion of solvent degrees of freedom, and application of adaptive local-elevation sampling that accounts for conformational averaging produces a more realistic representation of the ensemble of protein conformations than standard single-structure refinement in a non-explicit solvent using restraints that do not account for averaging and are partly based on non-observed data. Yielding better agreement with observed experimental data, the protein conformational ensemble is less restricted than when using standard single-structure refinement techniques, which are likely to yield a picture of the protein which is too rigid.

Processing of Lipid Nanodispersions into Solid Powders by Spray Drying.

Spray drying is a promising technology for drying lipid nanodispersions. These formulations can serve as carrier systems for poorly water-soluble active pharmaceutical ingredients (APIs) that are loaded into the lipid matrix to improve their bioavailability. Once the API-loaded nanocarriers have been further processed into solid dosage forms, they could be administered orally, which is usually preferred by patients. Various solid lipids as well as oils were used in this study to prepare lipid nanodispersions, and it was shown that their nanoparticulate properties could be maintained when lactose in combination with SDS was used as matrix material in the spray-drying process. In addition, for lipid nanoemulsions loaded with fenofibrate, a good redispersibility with particle sizes below 300 nm at a lipid content of 26.8 wt.% in the powders was observed. More detailed investigations on the influence of the drying temperature yielded good results when the inlet temperature of the drying air was set at 110 °C or above, enabling the lactose to form an amorphous matrix around the embedded lipid particles. A tristearin suspension was developed as a probe to measure the temperature exposure of the lipid particles during the drying process. The results with this approach indicate that the actual temperature the particles were exposed to during the drying process could be higher than the outlet temperature.

Embedding of Poorly Water-Soluble Drugs in Orodispersible Films-Comparison of Five Formulation Strategies.

The poor bioavailability of many newly developed active pharmaceutical ingredients (APIs) poses a major challenge in formulation development. To overcome this issue, strategies such as the preparation of amorphous solid dispersions (ASDs), and the application of the APIs in lipid nanocarriers or the wet-milling of the substances into nanoparticles have been introduced. In addition to an efficient formulation strategy, a dosage form that is accepted by all patients is also of great importance. To enable a simple application of the oral dosage form for all patients, orodispersible films (ODFs) are a very promising delivery platform for the APIs because the films directly disintegrate in the mouth. In this study, two poorly water-soluble APIs, fenofibrate and naproxen, were formulated using five different formulation strategies and then embedded in ODFs. It was found that the deliverable amount of API with one ODF highly depends on the formulation strategy as well as the physicochemical properties of the formulated API. The most promising film formulations were ASD-ODFs as well as films with API-loaded lipid nanoemulsions. Both showed a reduction of the dissolution time of the APIs from the ODF compared to an ODF with unformulated API micro particles. In addition, short disintegration times were achieved, although the mechanical film properties were slightly worse compared to the API-free film formulation.

Calculation of binding free energies of inhibitors to plasmepsin II.

An understanding at the atomic level of the driving forces of inhibitor binding to the protein plasmepsin (PM) II would be of interest to the development of drugs against malaria. To this end, three state of the art computational techniques to compute relative free energies-thermodynamic integration (TI), Hamiltonian replica-exchange (H-RE) TI, and comparison of bound versus unbound ligand energy and entropy-were applied to a protein-ligand system of PM II and several exo-3-amino-7-azabicyclo[2.2.1]heptanes and the resulting relative free energies were compared with values derived from experimental IC(50) values. For this large and flexible protein-ligand system, the simulations could not properly sample the relevant parts of the conformational space of the bound ligand, resulting in failure to reproduce the experimental data. Yet, the use of Hamiltonian replica exchange in conjunction with thermodynamic integration resulted in enhanced convergence and computational efficiency compared to standard thermodynamic integration calculations. The more approximate method of calculating only energetic and entropic contributions of the ligand in its bound and unbound states from conventional molecular dynamics (MD) simulations reproduced the major trends in the experimental binding free energies, which could be rationalized in terms of energetic and entropic characteristics of the different structural and physico-chemical properties of the protein and ligands.

Influence of process and formulation parameters on the preparation of solid lipid nanoparticles by dual centrifugation.

A promising strategy to formulate poorly water-soluble active pharmaceutical ingredients (APIs) is the application of these substances in solid lipid nanoparticles. These drug carrier systems are commonly prepared by high-pressure homogenization above the melting temperature of the utilized lipid. While being very useful for large-scale production this method is quite resource-consuming and does not allow simultaneous processing of multiple samples, e.g. for screening purposes. For this reason, an alternative manufacturing process, dual centrifugation, is introduced to prepare solid lipid nanoparticles. The ingredients of the dispersions were directly weighed into 2 mL vessels at room temperature without the need to prepare a pre-mix emulsion. Due to an additional rotation of the samples in the heated centrifuge as well as the addition of grinding media an intensive stressing of the samples was achieved. The emulsification process was finished within 10 min with sample temperatures of up to 90 °C being obtained. Dependent on the process set-up like grinding media size, filling ratio or process temperature and the composition of the lipid formulation, the achieved particles sizes were below 200 nm and had a narrow, monomodal size distribution.

Orodispersible Films: A Delivery Platform for Solid Lipid Nanoparticles?

To overcome the poor bioavailability observed for many newly developed active pharmaceutical ingredients (APIs), an appropriate formulation strategy is necessary. One approach is the formulation of these substances in solid lipid nanoparticles and their further processing into solid dosage forms. A promising and innovative oral delivery platform could be orodispersible films (ODFs). ODFs were already investigated more closely, e.g., for the administration of API nanoparticles, and proved their suitability for this formulation approach. The current study was aimed at investigating if the HPMC (hydroxypropyl methyl cellulose) film matrix is also suitable to serve as an appropriate delivery platform for solid lipid nanoparticles. Dependent on the type of triglyceride nanoparticles embedded in the film matrix and the formulation of the lipid particles, lipid contents of up to 54 wt.% could be realized in the film matrix without the loss of the nanoparticulate state. Good mechanical properties were confirmed for these films by determining the tensile strength as well as the elongation before breakage. Interestingly, processing of a lipid suspension into this solid dosage form led to a significantly reduced transformation of the lipid particles from the metastable α- into the stable ß-polymorph. This could prove very beneficial when the lipid particles are loaded with APIs.

Treatment of Male-Pattern Alopecia with Platelet-Rich Plasma.

BACKGROUND: Androgenetic alopecia (AGA) affects up to 80% of men and 50% of women throughout their lifetime, causing significant discomfort. Minoxidil, finasteride, and low-level laser light therapy are the only Food and Drug Administration-approved treatments for AGA, and they have shown positive results in randomized controlled trials and meta-analyses. However, their efficacy is limited, and new therapies are needed. Injection of platelet-rich plasma (PRP), a minimally invasive technique, has been described by several authors as a promising treatment for AGA. Although many studies report beneficial effects of PRP on AGA, there is no standardized practice for PRP preparation and administration or a standard method to evaluate results. OBJECTIVE: The aim of this study was to evaluate the efficacy of manually prepared PRP in the treatment of male AGA. MATERIALS AND METHODS: We treated 20 male patients with AGA with 3 monthly injections of PRP and analyzed results by TrichoScan®. RESULTS: In this study, there was no statistically significant improvement in hair count or proportion of anagen hairs. CONCLUSIONS: This lack of response could be related to any of the variables during PRP preparation described above and also to the limited number of patients in the study.

SOFTs - Structured orodispersible film templates.

Orodispersible films (ODFs) have a high potential to accelerate the individualized medication. The films can be produced as drug-free templates and subsequently printed with an API (active pharmaceutical ingredient) solution or suspension according to the needs of the patient. While the printing technology already enables a precise dosing of fluids, there is still a high need of suitable, edible templates with elevated loading capacity. The structured orodispersible film templates (SOFTs) developed in this study should overcome this void. The SOFTs are pervaded with pores to realize a high API load into the film structure and possess a closed bottom side to prevent the printed fluids to pass through the film. They consist of a water-soluble cellulose derivative and are produced with the solvent casting method. This study focused on the influence of the formulation of the film casting mass on the film properties, like porosity and disintegration time due to changed pore sizes and numbers. Due to the porous film structure a mass load of up to 6.1 mg cm-2 could be realized already in SOFTs, but, higher loads are feasible. The mechanical film properties could further be improved by additional matrix material in the suspension formulation, also inhibiting particle agglomeration and aggregation during the drying process, and positively influencing the dissolution behavior of the applied nanoparticles. An application of a protection layer on top of the loaded SOFTs improves the handling safety by inhibiting contact to the API and it prevents a removal of the particles from the film surface.

Model-based description of disintegration time and dissolution rate of nanoparticle-loaded orodispersible films.

The embedding of nanoparticles in orodispersible films (ODFs) is an innovative strategy to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (API). As the films are supposed to disintegrate within seconds when placed in the mouth, the disintegration time of the ODFs as well as the dissolution behavior of the API are of great interest. This study introduces a new possibility for a model-based description of these film properties to enable a prediction for the process layout for the manufacturing of the nanoparticle-loaded ODFs. Furthermore, this fundamental understanding can provide information on process robustness as a tool applied in future Quality by Design (QbD) approaches. The disintegration times of the nanoparticle-containing ODFs were measured with the SFaB method (slide frame and ball) and could be mathematically described considering the impact of the particle load and the dry film thickness on the disintegration behavior. Furthermore, it is considered if the films are disintegrated at the calculated time with a probability of 50% or any other probability. Besides the disintegration time, a clear influence of film parameters like the particle load, size of the embedded particles, film thickness and sample sizes was shown which affect the dissolution rate of the API from the ODF. The second model developed in the study identified a clear correlation between the total surface area of API particles in the film and the dissolution rate of the API, to predict the time period needed to release the API embedded in the ODFs.

Evaluation of oral tranexamic acid in the treatment of melasma.

BACKGROUND: Melasma is an acquired, chronic, recurrent hypermelanosis that occurs exclusively in areas exposed to the sun. Its treatment can be very challenging. Tranexamic acid (TA) is an inhibitor of plasmin, and it is a synthetic derivative of the amino acid lysine that reversibly blocks binding sites on the plasminogen molecule, inhibiting the plasminogen activator from converting plasminogen to plasmin. AIMS: This study evaluated the efficacy of oral TA in the treatment of melasma in patients from a philanthropic dermatological clinic. PATIENTS/METHODS: This was a monocentric, randomized, double-blind, controlled clinical trial. Patients with facial melasma were randomly divided into the following two groups: A (TA 250 mg orally twice daily) or B (oral placebo twice daily). Evaluations were performed before and after 12 weeks of treatment with photographs, colorimetry, MELASQoL, and MASI. All patients were instructed to use tinted sunscreen (SPF 50). RESULTS: Of the 47 patients selected, 37 completed the study, with 20 in group A and 17 in group B; the patients consisted of one male and 36 females, and the mean age was 43.97 years old. Based on the four methods of evaluation, the melasma in 50% of patients in group A improved versus only 5.9% of patients in group B (P < 0.005). There was an improvement according to all evaluation methods in the treatment group. No patient had severe side effects. CONCLUSIONS: We conclude that tranexamic acid was effective in 50% of patients according to four methods of evaluation when compared to the placebo.

Quality of life before and after cosmetic procedures on the face: A cross-sectional study in a public service.

BACKGROUND: Quality of life can be impaired by health conditions that modify body appearance. AIMS: The objective of this cross-sectional study was to evaluate the quality of life of patients before and after free-of-charge esthetic dermatological treatments offered in a philanthropic Dermatological Clinic for nonpathological conditions, such as anti-aging procedures. METHODS: All consecutive patients admitted between March and November 2016 were recruited. All esthetic treatments in this study were simple procedures applied in one session only, on the face, neck, arms, and upper chest, with a consult visit scheduled four weeks later for clinical evaluation. The WHOQOL-BREF instrument was used before and one month after the procedure. RESULTS: WHOQOL-BREF scores increased significantly after treatment (P < 0.001) in all the domains. CONCLUSION: Patients undergoing simple dermatological treatments applied by specialists report overall and specific domain improvements in quality of life, according to the World Health Organization instrument, regardless of the type of procedure.

Instant ODFs - Development of an intermediate, nanoparticle-based product platform for individualized medication.

The individualization of solid dosage forms to realize a flexible therapy for all patient groups is a topic which increasingly gains importance in pharmaceutical research. The goal of this study was to develop a nanoparticulate, instant orodispersible film (iODF) powder which can easily be reconstituted in water to cast ODFs containing an individualized concentration of an active pharmaceutical ingredient (API). It was shown that the processing of the film casing mass to iODF powders by spray drying provides the same advantageous film properties, particles sizes redispersed from the ODF and dissolution profiles as compared to the common production route. Due to the realization of nanoparticle loads up to 50wt.% in the iODF powders, high API loads (11.8mgcm-2) are achieved in final ODFs. The powders are well storable at different temperatures for at least three months and do not change their crystalline state during storage. Furthermore, dissolution of a defined amount of API from ODFs was found to be the fastest with the highest drug loads in the films.

Comparative study on disintegration methods for oral film preparations.

Orodispersible films (ODFs) provide high application comfort due to rapid disintegration in the oral cavity. They increasingly found the approval of pharmaceutical research and development and were added to the European Pharmacopeia in 2012. The European Pharmacopeia explicitly demands disintegration testing for ODFs, but does not refer to a suitable method. The aim of this study was to collect and evaluate existing disintegration methods regarding their suitability to investigate different ODF formulations. Therefore, 21 ODF formulations produced at different gap heights and/or different amounts of suspended microcrystalline cellulose (MCC) particles were manufactured by solvent casting technique, using hypromellose (HPMC) as film-forming polymer. Four disintegration methods described in literature were applied to characterize the disintegration behavior of these formulations. They were the petri dish, the slide frame, slide frame and ball (SFaB) method as well as the PharmaTest® disintegration tester equipped with a film sample holder. All methods show similar tendencies, at which the disintegration time proportionally increases with increasing dry film thicknesses. Reduced disintegration times were observed for ODFs containing insoluble MCC particles compared to their corresponding particle-free formulations. However, the suitability to investigate varying types of ODFs applying the four different test methods highly depends on the intended purpose. Therefore, the slide frame and SFaB method seems to be particularly applicable for research and development purposes, whereas the PharmaTest® disintegration tester and the SFaB method fulfil the demands required for testing methods within the quality control.