Ivermectin: recent approaches in the design of novel veterinary and human medicines.

Ivermectin (IVM) is a drug widely used in veterinary and human medicine for the management of parasitic diseases. Its repositioning potential has been recently considered for the treatment of different diseases, such as cancer and viral infections. However, IVM faces some limitations to its formulations due to its low water solubility and bioavailability, along with reports of drug resistance. In this sense, novel technological approaches have been explored to optimize its formulations and/or to develop innovative medicines. Therefore, this review discusses the strategies proposed in the last decade to improve the safety and efficacy of IVM and to explore its novel therapeutic applications. Among these technologies, the use of micro/nano-drug delivery systems is the most used approach, followed by long-acting formulations. In general, the development of these novel formulations seems to run side by side in veterinary and human health, showing a shared interface between the two areas. Although the technologies proposed indicate a promising future in the development of innovative dosage forms containing IVM, its safety and therapeutic targets must be further evaluated. Overall, these approaches comprise tailoring drug delivery profiles, decreasing the risks of developing drug resistance, and supporting the application of IVM for reaching different therapeutic targets.

A liquid chromatography coupled to quadrupole-time-of-flight-mass spectrometry (LC-QTOF-MS) method for identification analysis of saponins from Quillaja saponaria bark extracts in foot-and-mouth disease vaccines: Development, validation and applicability.

Saponins from Quillaja saponaria have been commonly used as immunomodulatory adjuvants in foot-and-mouth disease vaccines (FMDVs). However, due to the lack of consensus over the possible exacerbation of local inflammatory responses in cattle and its economic impacts, their use has been discouraged by Brazilian authorities. A qualitative method intended to determine the presence of saponins from Q. saponaria bark extracts in FMDVs was developed and validated. Instrumental analysis was performed using an liquid chromatography (LC) coupled to a quadrupole-time-of-flight-mass spectrometry (TOF-MS) system. The method was validated according to the International Conference on Harmonization Harmonized Tripartite Guideline Q2 (R1) and Brazilian Ministry of Agriculture, Livestock and Food Supply Analytical Quality Assurance Guidelines. Validation parameters were determined and considered suitable to the established criteria. The validated method has been applied in routine analysis in the National Agricultural Laboratory at Rio Grande do Sul (LANAGRO-RS). All results obtained were in agreement with the vaccine's composition described by the manufacturer. The method is easy and adequate for analysis in routine laboratories. To the best of the authors' knowledge, this is the first report of a method which intends to investigate the presence of saponins from Q. saponaria bark extracts in veterinary vaccines.

Redispersible Spray-Dried Powder Containing Nanoencapsulated Curcumin: the Drying Process Does Not Affect Neuroprotection In vitro.

A redispersible spray-dried formulation containing curcumin-loaded, lipid-core nanocapsules (LNC-C) was developed for oral administration. The neuroprotective activity of curcumin after the spray-drying process was evaluated in vitro. The spray-dried powder (SD-LNC-C) was produced using a drying adjuvant composed of a blend of maltodextrin and L-leucine (90:10 w/w). Acceptable process yield (~ 70%) and drug content (6.5 ± 0.2 mg g-1) were obtained. SD-LNC-C was formed by smooth, spherical-shaped particles, and confocal Raman analysis indicated the distribution of the LNC-C on the surface of the leucine/maltodextrin agglomerates. The surface of the agglomerates was formed by a combination of LNC-C and adjuvants, and laser diffraction showed that SD-LNC-C had adequate aqueous redispersion, with no loss of controlled drug release behaviour of LNC-C. The in vitro curcumin activity against the lipopolysaccharide (LPS)-induced proinflammatory response in organotypic hippocampal slice cultures was evaluated. Both formulations (LNC-C and SD-LNC-C) reduced TNF-α to similar levels. Therefore, neuroprotection of curcumin in vitro may be improved by nanoencapsulation followed by spray-drying, with no loss of this superior performance. Hence, the redispersible spray-dried powder proposed here represents a suitable approach for the development of innovative nanomedicines containing curcumin for the prevention/treatment of neurodegenerative diseases.

Free and nanoencapsulated vitamin D3 : effects on E-NTPDase and E-ADA activities in an animal model with induced arthritis.

UNLABELLED: The effect of vitamin D3 in oral solution (VD3 ) and vitamin D3 -loaded nanocapsules (NC-VD3 ) was analysed in animals with complete Freund's adjuvant (CFA) induced arthritis (AR). For this purpose, we evaluated scores for arthritis, thermal hyperalgesia and paw oedema, as well as histological analyses and measurements of the activity of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) enzymes in rat lymphocytes. Haematological and biochemical parameters were also determined. The doses administered were 120 UI/day of VD3 and 15.84 UI/day of NC-VD3 . Fifteen days after the induction of AR, the groups were treated for 15 days with vitamin D3 . The results demonstrated that VD3 was able to reduce arthritis scores, thermal hyperalgesia and paw oedema in rats with CFA-induced arthritis. However, treatment with NC-VD3 did not reduce arthritis scores. The histological analyses showed that both formulations were able to reduce the inflammatory changes induced by CFA. The activity of E-NTPDase in rat lymphocytes was higher in the AR compared with the control group, while the activity of E-ADA was lower. This effect was reversed after the 15-day treatment. Data from this study indicates that both forms of vitamin D3 seem to contribute to decreasing the inflammatory process induced by CFA, possibly altering the activities of ectoenzymes. Copyright © 2016 John Wiley & Sons, Ltd. SIGNIFICANCE OF THE STUDY: The effects promoted by both formulations of vitamin D3 , either in oral solution or nanoencapsulated form, strongly suggests the softening of the inflammatory process induced by complete Freund's adjuvant (CFA), possibly altering the E-NTPDase and E-ADA activities. However, it is known that vitamin D has a beneficial effect on the modulation of the immune system components responsible for the inflammatory process. Moreover, the establishment of responses to treatment with vitamin D3 may provide an alternative for inhibiting the proinflammatory response, assisting in our understanding of the immunopathology of this disease and possibly improving the signs and symptoms that hinder the quality of life of patients with rheumatoid arthritis. HIGHLIGHTS: Evaluation of the effects on the E-NTPDase and E-ADA activities in an animal model of induced arthritis. Two formulations of vitamin D3 were used: form oral solution and nanoencapsulated. Vitamin D3 seems to contribute to the inflammatory process induced by CFA. Vitamin D3 possibly alters the E-NTPDase and E-ADA activities. Vitamin D3 may be an alternative supplementary treatment for chronic arthritis.

Cationic Polymeric Nanocapsules as a Strategy to Target Dexamethasone to Viable Epidermis: Skin Penetration and Permeation Studies.

The present work aimed to evaluate the behavior of dexamethasone-loaded cationic polymericnanocapsules in hydrogels, regarding their in vitro drug release and skin drug retention and per- meation. Cationic polymeric nanocapsules prepared with Eudragit RS 100 as the polymeric wall had mean particle size of 139 +/- 3.6 nm, positive zeta potential (+11.38 +/- 1.7 mV), and high encapsulation efficiency (81 +/- 2%). After preparation, they were formulated as hydrogels, which showed non-Newtonian, plastic behavior, and acidic pH. Photon correlation spectroscopy analysis of these hydrogels demonstrated the presence of particles with mean particle size close to that of the original colloidal suspensions. The presence of dexamethasone-loaded nanocapsules in hydrogels promoted controlled drug release and an increase in the amount of drug delivered into viable epidermis, the main target tissue to topical glucocorticoid action. Moreover, the formulation did not increase the risk of drug penetration to dermis and permeation to the receptor compartment.

Nanoencapsulation of Clobetasol Propionate Decreases Its Penetration to Skin Layers Without Changing Its Relative Skin Distribution.

An immunosuppressive effect with drug release control and higher NTPDase activity in the treatment of contact dermatitis was previously reported for a hydrogel containing 0.05% clobetasol propionate-loaded lipid-core nanocapsules (HG-LNC-CP) compared to a hydrogel containing the non-encapsulated drug (HG-CP). In order to investigate the factors underlying this different performance, we evaluated the in vitro skin permeation/penetration of CP from both formulations (HG-LNC-CP and HG-CP). CP did not permeate to the receptor medium during the experiment (24 h), but penetrated into the stratum corneum and viable skin (epidermis and dermis) in significant amounts after 24 h, regardless the type of the formulation. Comparing both formulations, although the relative amount of CP in each skin layer was not affected by the nanoencapsulation, HG-LNC-CP was able to reduce in 5.8, 6.9 and 3.7 times the amount of CP released into the stratum corneum, epidermis and dermis respectively. In this way, the higher effect of HG-LNC-CP previously observed could be due to the controlled drug penetration rate into the skin layers. Moreover, HG-LNC-CP reduces the chances of the corticosteroid to be absorbed systemically as the amount of CP reaching the dermis was reduced. The study reinforces the HG-LNC-CP as a promising dermatological nanomedicine for the treatment of skin disorders.

Assessing the In Vitro Drug Release from Lipid-Core Nanocapsules: a New Strategy Combining Dialysis Sac and a Continuous-Flow System.

The in vitro assessment of drug release from polymeric nanocapsules suspensions is one of the most studied parameters in the development of drug-loaded nanoparticles. Nevertheless, official methods for the evaluation of drug release from submicrometric carriers are not available. In this work, a new approach to assess the in vitro drug release profile from drug-loaded lipid-core nanocapsules (LNC) was proposed. A continuous-flow system (open system) was designed to evaluate the in vitro drug release profiles from different LNC formulations containing prednisolone or clobetasol propionate (LNC-CP) as drug model (LNC-PD) using a homemade apparatus. The release medium was constantly renewed throughout the experiment. A dialysis bag containing 5 mL of formulation (0.5 mg mL(-1)) was maintained inside the apparatus, under magnetic stirring and controlled temperature (37°C). In parallel, studies based on the conventional dialysis sac technique (closed system) were performed. It was possible to discriminate the in vitro drug release profile of different formulations using the open system. The proposed strategy improved the sink condition, by constantly renewing the release medium, thus maintaining the drug concentration farther from the saturated concentration in the release medium. Moreover, problems due to sampling errors can be easily overcome using this semi-automated system, since the collection is done automatically without interference from the analyst. The system proposed in this paper brings important methodological and analytical advantages, becoming a promising prototype semi-automated apparatus for performing in vitro drug release studies from drug-loaded lipid-core nanocapsules and other related nanoparticle drug delivery systems.

Pimobendan controlled release guar gum printlets: Tailoring drug doses for personalised veterinary medicines.

Treating chronic heart diseases in dogs is challenging due to variations in mass within and between species. Pimobendan (PBD), a veterinary drug only, is prescribed in specific cases of chronic heart disease in dogs and is available on the market in only a few different doses. Furthermore, the therapy itself is challenging due to the large size of the chewable tablets and the requirement for twice-daily administration. The development of customised and on-demand PBD medicines by three-dimensional (3D) printing has been proposed to circumvent these disadvantages. In this study, we designed controlled-release flavoured printlets containing PBD. We evaluated the use of two natural polymers, guar or xanthan gums, as the main component of the printing inks. Guar gum showed the better rheological behavior and printability by semisolid extrusion. The printlets were produced in three different shapes and sizes to allow dose customisation. Guar gum printlets showed a PBD controlled release profile, regardless of their shape or size. Therefore, we have demonstrated a novel approach for controlling PBD drug release and tailoring the dose by employing a natural polymer to produce 3D-printed tablets. This study represents a significant step towards the development of 3D-printed guar gum controlled-release formulations for veterinary applications.

A critical review of traditional and advanced characterisation tools to drive formulators towards the rational development of 3D printed oral dosage forms.

The high degree of precision and control of 3D printing has given formulators the autonomy to engineer sophisticated and personalised medicines, starting a revolution in pharmaceutics. In addition, dosage forms with tailored drug release profile can be produced by changing some parameters of the 3D printing processes. Therefore, 3D printed medicines must be characterised in an orthogonal approach, to establish their physicochemical and biopharmaceutical features, and consequently to understand how these characteristics can be customised by changing the formulation and process parameters to ensure medicines' safety and efficacy. Given the recent regulation and commercialisation of 3D printed medicines, several methods and techniques have been transposed from official compendia; however, formulators must still make a critical assessment of their practical implications. A comprehensive review of the findings obtained by the characterisation of 3D printed oral dosage forms using traditional and advanced techniques is therefore presented here, to drive formulators towards a rational pharmaceutical development pathway. The characterisation methods have been classified in terms of their physicochemical or biopharmaceutical character. Interestingly, beyond the rise of modern characterisation techniques, the reassessment of data obtained by traditional methods has provided knowledge and a solid foundation to support the evolution of 3D printing techniques in pharmaceutics.

Safety and Efficacy of the Therapeutic Use of Cannabis-Based Products in the Treatment of Dogs: An Integrative Review.

The use of cannabis-based products for therapeutic purposes is a reality in the field of animal health. However, although cannabis is considered safe when appropriately used by human patients, cannabis-based products can pose a risk to companion animals such as dogs, depending on their composition or route of administration. Thus, this article discusses aspects of the safety and efficacy of different cannabis-based products in dogs' treatment through an integrative review. The review was systematically performed in Medline (via Pubmed®) and Latin American and Caribbean Health Sciences Literature (LILACS) databases, with period restriction (between 1990 and 2021). The qualified articles (n=19), which met the previously established inclusion criteria, were critically evaluated. Based on the literature review, it is possible to infer safety in the administration of cannabis-based products for the treatment of dogs, especially products rich in cannabidiol (CBD), free or with low concentrations of tetrahydrocannabinol, under the conditions evaluated. In addition, CBD products potentially promote improved quality of life and reduce pain perception in animals affected by canine osteoarthritis. Finally, owing to the lack of large-scale and robust clinical research studies, the performance of clinical trials, considering the individual characteristics of each cannabis-based product (composition, concentration, nature of adjuvants, dosage form, route of administration), is strongly encouraged.

Liquid chromatography method to assay tretinoin in skin layers: validation and application in skin penetration/retention studies.

A liquid chromatography (LC) method for the quantification of tretinoin (TTN) in different matrices (adhesive tape, cotton and porcine skin layers, stratum corneum, viable epidermis, and dermis) was validated and applied in in vitro porcine skin penetration/retention studies. This study proposes, for the first time, a method for assaying TTN in separated porcine skin layers (stratum corneum, viable epidermis, and dermis). The skin studies were carried out using tape stripping and cutaneous retention techniques. The procedures for the extraction of TTN from dermatological formulations (creams and gels) and biological and non-biological matrices used with the tape stripping and retention techniques were also evaluated. The LC method consisted of a mobile phase composed of a mixture of methanol, water, and glacial acetic acid (85:15:1, v/v); a C18 column used as the stationary phase; a flow rate of 1.0 mL min-1; an injection volume of 100 µL; and TTN detection at 342 nm. The method was linear in the range of 0.05-15.00 µg mL-1 (r = 0.9999), and it was precise and accurate. The limit of detection (LOD) and limit of quantification (LOQ) were 0.0165 µg mL-1 and 0.0495 µg mL-1, respectively. TTN was extracted from different matrices, showing good precision [relative standard deviation (RSD) of <5%] and accuracy (89.4-113.9%). This method was successfully applied in the evaluation of TTN skin retention/permeation from dermatological formulations (cream and gel). A higher penetration of TTN through the skin was achieved with the gel rather than the cream, showing the influence of the dosage form. Therefore, the developed method can easily be applied in porcine skin penetration/retention studies of dermatological formulations containing TTN, and it is able to discriminate the behaviours of the different formulations.