Revisiting the Effect of Aging on the Transport of Molecules through the Skin.

Both intrinsic and extrinsic aging lead to a series of morphological changes in the skin including the flattening of the dermal-epidermal junction, increased stratum corneum dryness, reduction in sebaceous gland activity and enzyme activity as well as atrophy of blood vessels. In this study, the impact of these changes on the transport of molecules through the skin was revised. The increase in the number of transdermal formulations on the market in recent decades and life expectancy represent the main reasons for an in-depth discussion of this topic. Furthermore, elderly subjects have often been excluded from clinical trials due to polypharmacy, raising concerns in terms of efficacy and safety. In this way, ex vivo and in vivo studies comparing the transport of molecules through the mature and young skin were analyzed in detail. The reduced water content in mature skin had a significant impact on the transport rate of hydrophilic molecules. The lower enzymatic activity in aged skin, in turn, would explain changes in the activation of prodrugs. Interestingly, greater deposition of nanoparticles was also found in mature skin. In vivo models should be prioritized in future experimental studies as they allow to evaluate both absorption and metabolism simultaneously, providing more realistic information.

Advanced Solid Formulations For Vulvovaginal Candidiasis.

Vulvovaginal candidiasis (VVC) is an opportunistic and endogenous infection caused by a fungus of the Candida genus, which can cause pruritus, dysuria, vulvar edema, fissures and maceration of the vulva. The treatment of vaginal candidiasis is carried out mainly by antifungal agents of azole and polyene classes; however, fungal resistance cases have been often observed. For this reason, new therapeutic agents such as essential oils, probiotics and antimicrobial peptides are being investigated, which can be combined with conventional drugs. Local administration of antimicrobials has also been considered to allow greater control of drug delivery and reduce or avoid undesirable systemic adverse effects. Conventional dosage forms such as creams and ointments result in reduced residence time in the mucosa and non-sustained and variable drug delivery. Therefore, advanced solid formulations such as intravaginal rings, vaginal films, sponges and nanofibers have been purposed. In these systems, polymers in different ratios are combined aiming to achieve a specific drug release profile and high mucoadhesion. Overall, a more porous matrix structure leads to a higher rate of drug release and mucoadhesion. The advantages, limitations and technological aspects of each dosage form are discussed in detail in this review.

A Comparative Analysis of Biological and Synthetic Skin Models for Drug Transport Studies.

Ethical restrictions as well as practical or economic issues related to use of animal and human skin has been the main reason the growth in the number of investigations with alternative models. Reconstructed skin models, for example, have been useful to evaluate the in vitro toxicity of compounds; however, these models usually overestimate the amount of drug permeated due to impaired barrier properties. In this review, the performance of synthetic and biological skin models in transport studies was compared by considering two compounds with different physicochemical properties. The advantages and limitations of each skin model are discussed in detail. Although synthetic and reconstructed skin models have shown to be useful in the formulation optimization step, they present many limitations: (1) impaired barrier properties; (2) lack of follicular transport; (3) no metabolism in synthetic membranes; (4) differences in terms of lipid organization; (5) more affected by formulation constituents. Therefore, animal and human tissues should still be prioritized in drug transport studies until new advances in alternative models are achieved. Investigations of the impact of cell-culture conditions on skin formation, in turn, bring perspectives related to the development of unhealthy/injured skin models (an aspect that still deserves attention).

Effect of Vehicle Composition on the Preparation of Different Types of Dapsone Crystals for Topical Drug Delivery.

Topical formulations composed of API-pure crystals have been increasingly studied, especially in regards to the impact of particle size in penetration efficiency. Less attention, however, has been devoted to the solid-state properties of drugs delivered to the skin. In this study, we address the effect of formulation composition on the crystal form existing in topical products. Dapsone (DAP) gel formulations were prepared by mixing an organic solution containing DAP with an aqueous solution containing polymers and preservatives. The organic solvent was chosen as ethoxydiglycol (DEGEE), polyethylene glycol (PEG), or 1-methyl-2-pirrolidone (MPR) to assess the impact of composition on DAP crystal form. Such solvent variations resulted in different particulate matter. In terms of crystalline nature, the presence of DEGEE in formulations induced the crystallization of DAP hydrate, while PEG cocrystal and a mixture of hydrate and MPR solvate crystallized from the same amounts of PEG and MPR, respectively. Microscopic analysis of the gels showed heterogeneous particles with different characteristics. The behavior of gels after application to the skin was also tested. Interestingly, the different formulations seemed to accumulate in different regions of the skin. This could be the result of the effect of vehicle composition/excipients on the characteristics of the skin, such as hydration. The site-specific accumulation, however, was more pronounced in crystal-loaded gels as opposed to blank formulations. These results indicate that future studies should consider the effect of formulation composition on the API crystal form landscape as part of the strategies used to successfully target drug delivery to the skin.

A New Saquinavir Mesylate-Sodium Decyl Sulfate Salt Discovered by Serendipity during an Anomalous Dissolution Test.

PURPOSE: To understand the anomalous behavior of Saquinavir Mesylate (SQVM) in sodium decyl sulfate (SDS) medium during a dissolution test through a crystallographic analysis of the crystal obtained. As a result, it will be possible to elucidate its crystal structure and carry out a complete solid-state characterization of the API. METHODS: The solid form obtained was characterized by a structural analysis through X-ray single crystal and powder diffraction. The crystallographic structures of the new salt and the SQVM were compared. In addition, a complete solid-state characterization of SQVM raw material was carried out by techniques such as diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), Raman spectroscopy, scanning electron microscopy and a dissolution method. RESULTS: A new salt consisting of SQVM and SDS was crystallized and its crystal structure was elucidated and reported herein for the first time. The anionic part of SDS interacts with the cationic segment of SQVM to obtain a new salt designated as SQV-DS, which precipitates. The main difference between the two structures occurs in the c-axis expansion, which increases from 15.966 (5) to 21.1924 (14), respectively. CONCLUSIONS: Some of the strategies to enhance the dissolution rate of poorly aqueous soluble APIs include the use of surfactants such as SDS in the dissolution medium, as well as in the formulated products. However, there have been constant reports of a dissolution rate slowdown by some surfactants. The interaction mechanisms between the APIs and the dissolution medium containing surfactants need to be carefully investigated in current pharmaceutical formulations. Graphical Abstract.

Emerging Technologies to Target Drug Delivery to the Skin - the Role of Crystals and Carrier-Based Systems in the Case Study of Dapsone.

Dapsone (DAP) is a long-established molecule that remains a promising therapeutic agent for various diseases mainly because it combines antimicrobial and anti-inflammatory activities. Its oral application, however, is limited by the dose-dependent hematological side effects that may rise from systemic exposure. As an alternative to overcome this limitation, the administration of DAP to the skin has witnessed prominent interest in the past 20 years, particularly when applied to the treatment of dermatological disorders. In this review, all technological strategies proposed to the topical delivery of DAP are presented. Most of the reported studies have been devoted to the clinical use and safety of a gel formulation containing both solubilized and microcrystalline drug, however, the technological characteristics of such preparation are still missing. In parallel, the incorporation of DAP into vesicular and particulate carriers (e.g. nano- and microemulsions, niosomes, invasomes, bilosomes, cubosomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocapsules and polymer-lipid-polymer hybrid nanoparticles) appears to be an alternative to provide greater drug release control, enhanced drug solubilization and follicular targeting. Indeed, the main application of DAP topical formulations reported in the literature was the treatment of acne vulgaris, a disease located in the hair follicle. Other diseases affecting different regions of the skin (e.g. cutaneous lupus erythematosus and cutaneous leishmaniasis), however, may also benefit from a topical therapeutic regimen containing DAP. Therefore, the investigation of appendageal route in comparison to passive transmembrane diffusion as a function of targeted disease, as well as pharmacokinetic studies, are perspectives highlighted herein. Such studies may drive future efforts towards the rational development of safe and effective technologies to deliver DAP to the skin. Graphical abstract.

Transbuccal Delivery of Isoniazid: Ex Vivo Permeability and Drug-Surfactant Interaction Studies.

The oral administration of isoniazid (INH) may lead to discontinuation of tuberculosis treatment due to drug-related hepatotoxicity events, and thus, the transbuccal delivery of this drug was investigated, for the first time, as an alternative administration route. Ex vivo permeability assays were performed in Franz-type diffusion chambers, applying INH alone and in combination with sodium dodecyl sulfate (SDS) and sodium taurocholate (ST). After confirming the formation of micelle structures by dynamic light scattering analysis, UV-visible spectroscopy and zeta potential analyses were used to investigate drug-micelle interactions. In zeta potential analyses, no electrostatical interactions were identified for both surfactants in saliva buffer pH 6.8. Spectrophotometric analyses, in turn, indicated chemical interactions between INH and SDS in both pH values (2.0 and 6.8) whereas no interaction between the drug and ST was observed. Despite the interaction between SDS and drug, this surfactant increased the buccal transport rate of INH by approximately 11 times when compared with the control. In contrast, ST did not increase the drug permeability. The INH retention in SDS-treated mucosa was significantly higher when compared with the control and an effect on intercellular lipids was suggested. In vivo studies are needed to confirm the high INH absorption found here. Grapical abstract.

Effect of extrusion temperature and screw speed on properties of oat and rice flour extrudates.

BACKGROUND: Whole oat and rice flours were mixed to develop instant flours by a high pressure and low mechanical shear extrusion process. The screw profile was designed aiming to obtain an infant food with gelatinized starch and high hydration ability. Response surface methodology was selected to study the impact of operating parameters such as temperature and screw speed (73-186 °C; 109-391 rpm) on physicochemical and pasting properties of the final extruded product. The main challenge of this study was to process high oats content, since they are characterized by high lipid and fiber content, which impact on material processing. RESULTS: The optimal response was achieved at 170 °C and 350 rpm. The optimal expansion ratio, bulk density, water absorption index, and water solubility index were 2.24, 289.65 kg m-3 , 6.42 g g-1 , and 4.75 g g-1 respectively. Overall, both temperature and screw speed affected the responses studied, except for water absorption index (only screw speed affected this response). Although lipids from oats reduce the expansion ratio of extrudates compared with samples containing higher starch proportions, their lipids protect the starch granules from mechanical degradation when higher screw speed values are used. As a result, both ungelatinized and gelatinized starches may be found in extrudates, which was confirmed by pasting property analyses. CONCLUSION: High oat content may be efficiently processed by optimizing the extruder conditions (temperature, screw speed, and profile), improving the nutritional properties of the final product. © 2017 Society of Chemical Industry.

Chitosan microencapsulation of the dispersed phase of an O/W nanoemulsion to hydrochlorothiazide delivery.

In view of biopharmaceutical limitations of hydrochlorothiazide (HCTZ), Trojan-type mucoadhesive systems were proposed, aiming to improve HCTZ pharmacological properties by modulating its release. Nanoemulsions were formed spontaneously by combining medium-chain triglycerides (Lipoid® S75 and Pluronic® F68) and high encapsulation efficiency was obtained. The mucoadhesive properties were provided by chitosan and microencapsulation of nanoemulsions in spray-dryer was successfully achieved by using Aerosil® as wall material. The rapid redispersion of nanoemulsion in simulated fluids led to a fast and complete release of HCTZ in gastric medium. The pharmacodynamics of HCTZ was improved, extending the diuretic activity. Once a simple and low-energy method contributed to obtain stable mucoadhesive nanoemulsions, advantages in terms of production could also be achieved, allowing easy scaling up. This novel mucoadhesive Trojan particulate system of HCTZ showed to be a promising approach to overcome limitations in terms of absorption and consequently improve the therapeutic efficacy.

Lipid- and Polymer-Based Nanostructures for Cutaneous Delivery of Curcumin.

It is well-known that nanoencapsulation may overcome biopharmaceutical limitations of curcumin (CUR), but studies regarding the contribution of the vesicular nature of CUR-loaded nanoparticles on skin permeation are still scarce. Therefore, the effect of three colloidal systems (solid lipid nanoparticles (SLN), nanoemulsion (NE), and polymeric nanoparticles (NP)) on the control of cutaneous permeation of CUR was investigated in porcine ear skin/Franz diffusion cells. Colloidal suspensions were designed to present a similar particle size (±170 nm), narrow size distribution (PdI < 0.2), and high entrapment efficiency (>99%). Zeta potential values were -0.13, -9.68 and -36.7 mV for the CUR-loaded NP, SLN and NE, respectively. Nanoencapsulation resulted in a cumulative amount of CUR in the more superficial layers of the skin. NP significantly enhanced the compound retention in the epidermis, which was approximately 2.49- and 3.32-fold more than SLN and NE, respectively. The CUR levels into the dermis were significantly increased after treatment with NE, which may be associated with repulsion phenomena in surface skin. Therefore, a more superficial or deeper action of CUR on the skin may be obtained depending on nanostructure type. While NPs are more effective in upper skin layers, NE should be prioritized when a dermal action for the CUR is required.

Self-Nanoemulsified Drug Delivery System of Hydrochlorothiazide for Increasing Dissolution Rate and Diuretic Activity.

Hydrochlorothiazide (HCTZ) is a class IV drug according to the Biopharmaceutical Classification System. This study aimed the development of self-nanoemulsifying drug delivery system (SNEDDS) for HCTZ as an approach to overcome the biopharmaceutical limitations. Pre-formulation screening and ternary phase diagrams were carried out to select the oil phase, the surfactant, and the co-surfactant as the amount of each constituent. The optimized formulations, with reduced amount of surfactant, and composed of medium chain triglycerides, Cremophor EL and Transcutol P did not affect the pH or show drug incompatibilities. The SNEDDS were stabilized by the nanoscale globules and high negative zeta potential. All the physicochemical characterization assays were performed in biorelevant media to better predict the in vivo performance. The enhanced dissolution rate of the SNEDDS reflected in the in vivo diuretic activity, presenting a natriuresis, kaliuresis, and chloriuresis at early stages and an increased volume of total urine compared with HCTZ alone. The designed SNEDDS produced an improvement in the pharmacodynamics due to high dissolution and probable inhibition of intestinal efflux protein by Cremophor EL. The use of SNEDDS demonstrated to be an efficient approach to modulate the absorption of HCTZ and drug therapeutics.

Adipose-Derived Stem Cells Decrease Bone Morphogenetic Protein Type 2-Induced Inflammation In Vivo.

PURPOSE: Recombinant human bone morphogenetic protein type 2 (rhBMP-2) has been used to promote bone regeneration. In contrast, some reports have suggested rhBMP-2 does not provide advantages over autogenous bone grafting owing to the undesirable postoperative symptoms of this growth factor. Because the undesirable symptoms of rhBMP-2 are usually promoted by inflammation, this study evaluated the in vivo effect of human adipose-derived stem cells (ASCs) incorporated into polylactic co-glycolic acid (PLGA) scaffolds in decreasing the inflammatory response induced by a low dose of rhBMP-2. MATERIALS AND METHODS: PLGA scaffolds were characterized and loaded with rhBMP-2 1, 2.5, or 5 µg per scaffold (n = 6) and the in vitro released protein amounts were quantified at 7 hours and 1, 7, and 21 days after loading (n = 3). The muscle tissue of 6 beagles received the following treatments: PLGA, PLGA plus rhBMP-2 (2.5 µg), and PLGA plus rhBMP-2 plus ASCs (1 × 10(6) ASCs). The samples were evaluated 45 days after surgery. Statistical analyses were performed and the P value was set at .05. RESULTS: PLGA plus rhBMP-2 plus ASCs yielded the smallest number of inflammatory foci (P < .001) and giant cells (P < .001) and the largest number of angiogenesis sites (P < .001). CONCLUSIONS: Human ASCs administered in vivo into PLGA scaffolds with a low dose of rhBMP-2 decrease tissue inflammation and increase angiogenesis in muscular sites.

Enhancing the buccal mucosal delivery of peptide and protein therapeutics.

With continuing advances in biotechnology and genetic engineering, there has been a dramatic increase in the availability of new biomacromolecules, such as peptides and proteins that have the potential to ameliorate the symptoms of many poorly-treated diseases. Although most of these macromolecular therapeutics exhibit high potency, their large molecular mass, susceptibility to enzymatic degradation, immunogenicity and tendency to undergo aggregation, adsorption, and denaturation have limited their ability to be administered via the traditional oral route. As a result, alternative noninvasive routes have been investigated for the systemic delivery of these macromolecules, one of which is the buccal mucosa. The buccal mucosa offers a number of advantages over the oral route, making it attractive for the delivery of peptides and proteins. However, the buccal mucosa still exhibits some permeability-limiting properties, and therefore various methods have been explored to enhance the delivery of macromolecules via this route, including the use of chemical penetration enhancers, physical methods, particulate systems and mucoadhesive formulations. The incorporation of anti-aggregating agents in buccal formulations also appears to show promise in other mucosal delivery systems, but has not yet been considered for buccal mucosal drug delivery. This review provides an update on recent approaches that have shown promise in enhancing the buccal mucosal transport of macromolecules, with a major focus on proteins and peptides.

Adipose-derived stem cells incorporated into platelet-rich plasma improved bone regeneration and maturation in vivo.

BACKGROUND/AIM: Some cases of tooth loss related to dental trauma require bone-grafting procedures to improve the aesthetics before prosthetic rehabilitation or to enable the installation of dental implants. Bone regeneration is often a challenge and could be largely improved by mesenchymal stem cells therapy. However, the appropriate scaffold for these cells still a problem. This study evaluated the in vivo effect of human adipose-derived stem cells incorporated into autogenous platelet-rich plasma in bone regeneration and maturation. MATERIAL AND METHODS: Adipose-derived stem cells were isolated from lipoaspirate tissues and used at passage 4. Immunophenotyping and multilineage differentiation of cells were performed and mesenchymal stem cells characteristics confirmed. Bicortical bone defects (10 mm diameter) were created in the tibia of six beagle dogs to evaluate the effect of adipose-derived stem cells incorporated into platelet-rich plasma scaffolds, platelet-rich plasma alone, autogenous bone grafts, and clot. Samples were removed 6 weeks postsurgeries and analyzed by quantification of primary and secondary bone formation and granulation tissue. RESULTS: Adipose-derived stem cells incorporated into platelet-rich plasma scaffolds promoted the highest bone formation (primary + secondary bone) (P < 0.001), the highest bone maturation (secondary bone) (P < 0.001), and the lowest amount of granulation tissue (P < 0.001). CONCLUSIONS: Adipose-derived stem cells incorporated into platelet-rich plasma scaffolds promote more bone formation and maturation, and less granulation tissue in bone defects created in canine tibia. Therefore, platelet-rich plasma can be considered as a candidate scaffold for adipose-derived stem cells to promote bone regeneration.

In vitro and in vivo genotoxic evaluation of Bothrops moojeni snake venom.

CONTEXT: Bothrops moojeni Hoge (Viperidae) venom is a complex mixture of compounds with therapeutic potential that has been included in the research and development of new drugs. Along with the biological activity, the pharmaceutical applicability of this venom depends on its toxicological profile. OBJECTIVE: This study evaluates the cytotoxicity and genotoxicity of the Bothrops moojeni venom (BMV). MATERIAL AND METHODS: The in vitro cytotoxicity and genotoxicity of a pooled sample of BMV was assessed by the MTT and Comet assay, respectively. Genotoxicity was also evaluated in vivo through the micronucleus assay. RESULTS: BMV displayed a 50% cytotoxic concentration (CC50) on Vero cells of 4.09 µg/mL. Vero cells treated with 4 µg/mL for 90 min and 6 h presented significant (p < 0.05, ANOVA/Newman-Keuls test) higher DNA damage than the negative control in the Comet assay. The lower DNA damage found after 6 h compared with the 90 min treatment suggests a DNA repair effect. Mice intraperitoneally treated with BMV at 10, 30, or 80 µg/animal presented significant genotoxicity (p < 0.05, ANOVA/Newman-Keuls test) in relation to the negative control after 24 h of treatment. Contrary to the in vitro results, no DNA repair seemed to occur in vivo up to 96 h post-venom inoculation at a dose of 30 µg/animal. DISCUSSION AND CONCLUSION: The results show that BMV presents cyto- and genotoxicity depending on the concentration/dose used. These findings emphasize the importance of toxicological studies, including assessment of genotoxicity, in the biological activity research of BMV and/or in the development of BMV-derived products.

The rheology of injectable hyaluronic acid hydrogels used as facial fillers: A review.

Injectable hyaluronic acid (HA) hydrogels have been popularized in facial aesthetics as they provide a long-lasting effect, low risk of complications, allergenicity tests are not required before application and can be easily removed by the action of hyaluronidases. On the other hand, the development of these systems requires in-depth studies of chemical mechanisms involved in hydrogel formation. Ideal dermal fillers should temporarily fluidize during extrusion through the needle and quickly recover their original shape after application. Hydrogels with more elastic properties, for example, are difficult to inject while viscous materials are too liquid. A balance between both properties should be achieved. Each region of the face requires products with distinct rheological properties. High G' dermal fillers are preferable for deeper wrinkles whereas the counterpart with lower values of G' is more indicated in superficial wrinkles or lip augmentation. Factors such as molecular weight and concentration of HA, pH, type and concentration of the crosslinking agent, particle size, crosslinking reaction time and crosslinking agent/polysaccharide ratio should be modulated to achieve specific rheological properties. In this review, the effect of each variable is discussed in detail to guide the rational development of new dermal fillers.

Development of biopolymer films loaded with fluconazole and thymol for resistant vaginal candidiasis.

Vulvovaginal candidiasis (VVC) is an opportunistic infection caused by a fungus of the Candida genus, affecting approximately 75 % of women during their lifetime. Fungal resistance cases and adverse effects have been the main challenges of oral therapies. In this study, the topical application of thin films containing fluconazole (FLU) and thymol (THY) was proposed to overcome these problems. Vaginal films based only on chitosan (CH) or combining this biopolymer with pectin (PEC) or hydroxypropylmethylcellulose acetate succinate (HPMCAS) were developed by the solvent casting method. In addition to a higher swelling index, CH/HPMCAS films showed to be more plastic and flexible than systems prepared with CH/PEC or only chitosan. Biopolymers and FLU were found in an amorphous state, contributing to explaining the rapid gel formation after contact with vaginal fluid. High permeability rates of FLU were also found after its immobilization into thin films. The presence of THY in polymer films increased the distribution of FLU in vaginal tissues and resulted in improved anti-Candida activity. A significant activity against the resistant C. glabrata was achieved, reducing the required FLU dose by 50 %. These results suggest that the developed polymer films represent a promising alternative for the treatment of resistant vulvovaginal candidiasis, encouraging further studies in this context.

Nanoemulsions and nanocapsules loaded with Melaleuca alternifolia essential oil for sepsis treatment.

Sepsis represents a complex clinical syndrome that results from a harmful host response to infection. The infections most associated with sepsis are pneumonia, intra-abdominal infection, and urinary tract infection. Tea tree oil (TTO) has shown high antibacterial activity; however, it exhibits low aqueous solubility and high volatility, which have motivated its nanoencapsulation. In this study, the performance of nanoemulsions (NE) and nanocapsules (NC) loaded with TTO was compared. These systems were prepared by spontaneous emulsification and nanoprecipitation methods, respectively. Poly-ε-caprolactone or Eudragit® RS100 were tested as polymers for NCs whereas Tween® 80 or Pluronic® F68 as surfactants in NE preparation. Pluronic® F68 and Eudragit® RS100 resulted in more homogeneous and stable nanoparticles. In accelerated stability studies at 4 and 25 °C, both colloidal suspensions (NC and NE) were kinetically stable. NCs showed to be more stable to photodegradation and less cytotoxic than NEs. After sepsis induction by the cecal ligation and puncture (CLP) model, both NE and NC reduced neutrophil infiltration into peritoneal lavage (PL) and kidneys. Moreover, the systems increased group thiols in the kidney and lung tissue and reduced bacterial growth in PL. Taken together, both systems showed to be effective against injury induced by sepsis; however, NCs should be prioritized due to advantages in terms of cytotoxicity and physicochemical stability.

Development of ophthalmic nanoemulsions of ß-caryophyllene for the treatment of Acanthamoeba keratitis.

Although rare, amoebic keratitis (AK) is a disease caused by Acanthamoeba spp. that can lead to blindness. The drugs currently available for its treatment are very toxic, which has motivated the investigation for more effective and safe therapeutic options. In this study, the in vitro activity of ß-caryophyllene (BCP) was exploited taking into account its action against other protozoans as well as its well-known healing and anti-inflammatory properties (aspects relevant for the AK pathogenesis). On the other hand, high volatilization and oxidation phenomena are found for this compound, which led to its incorporation into nanoemulsions (NEs). Two emulsifying agents were tested, resulting in monodisperse systems with reduced droplet size (<265 nm) and high surface charge (positive and negative for NEs prepared with cetrimonium bromide -CTAB and Phosal® 50+, respectively). NEs prepared with CTAB were shown to be more stable after long-term storage at 4 and 25 °C than those prepared with Phosal®. Pure BCP, at the highest concentration (500 µM), resulted in a level of inhibition of Acanthamoeba trophozoites equivalent to that of reference drug (chlorhexidine). This activity was even greater after oil nanoencapsulation. The reduced droplet size could improve the interaction of the oil with the microorganism, justifying this finding. Changes in surface charge did not impact the activity. Positively charged NEs improved the interaction and retention of BCP in the cornea and thus should be prioritized for further studies.

An update of nano-based drug delivery systems for cannabinoids: Biopharmaceutical aspects & therapeutic applications.

Nanotechnology has been widely used to improve stability, efficacy, release control and biopharmaceutical aspects of natural and synthetic cannabinoids. In this review, the main types of cannabinoid-based nanoparticles (NPs) reported so far are addressed, taking into account the advantages and disadvantages of each system. Formulation, preclinical and clinical studies performed with colloidal carriers were individually analyzed. Lipid-based nanocarriers have been recognized for their high biocompatibility and ability to improve both solubility and bioavailability. Δ9-tetrahydrocannabinol-loaded lipid systems designed to treat glaucoma, for example, showed superior in vivo efficacy in comparison to market formulations. The analyzed studies have shown that product performance can be modulated by varying particle size and composition. In the case of self-nano-emulsifying drug delivery systems, the reduced particle size shortens the time to reach high plasma concentrations while the incorporation of metabolism inhibitors extends the plasma circulation time. The use of long alkyl chain lipids in NP formulations, in turn, is strategized to achieve intestinal lymphatic absorption. Polymer NPs have been prioritized when a sustained or site-specific cannabinoid release is desirable (e.g., CNS-affecting diseases/cancer). The functionalization of the surface of polymer NPs makes their action even more selective whereas surface charge modulation is highlighted to provide mucoadhesion. The present study identified promising systems for targeted applications, making the process of optimizing new formulations more effective and faster. Although NPs have shown a promising role in the treatment of several difficult-to-treat diseases, more translational studies should be performed to confirm the benefits reported here.