Recombinant scFv-Fc Anti-kallikrein 7 Antibody-Loaded Thermosensitive Hydrogels Against Skin Desquamation Disorders.

Human tissue kallikrein-related peptidase 7 (KLK7) is a serine protease implicated in the physiology of skin desquamation, and its uncontrolled activity can lead to chronic diseases such as psoriasis, atopic dermatitis, and Netherton syndrome. For this reason, kallikrein 7 has been identified as a potential therapeutic target. This work aimed to evaluate Pluronic (PL) hydrogels as topical carriers of four specific scFv-Fc antibodies to inhibit KLK7. The hydrogels comprised PL F127 (30% w/v) alone and a binary F127/P123 (28-2% w/v) system. Each formulation was loaded with 1 µg/mL of each antibody and characterized by physicochemical and pharmaceutical techniques, considering antibody-micelle interactions and hydrogel behavior as smart delivery systems. Results showed that the antibodies were successfully loaded into the PL-based systems, and the sol-gel transition temperature was shifted to high values after the P123 addition. The antibodies released from the gels preserved their rheological properties (G' > G'', 35- to 41-fold) and inhibitory activity against KLK7, even after 24 h. This work presented potential agents targeting KLK7 that may provide strategies for treating skin abnormalities.

Poloxamer-based nanogels as delivery systems: how structural requirements can drive their biological performance?

Poloxamers or Pluronics®-based nanogels are one of the most used matrices for developing delivery systems. Due to their thermoresponsive and flexible mechanical properties, they allowed the incorporation of several molecules including drugs, biomacromolecules, lipid-derivatives, polymers, and metallic, polymeric, or lipid nanocarriers. The thermogelling mechanism is driven by micelles formation and their self-assembly as phase organizations (lamellar, hexagonal, cubic) in response to microenvironmental conditions such as temperature, osmolarity, and additives incorporated. Then, different biophysical techniques have been used for investigating those structural transitions from the mechanisms to the preferential component's orientation and organization. Since the design of PL-based pharmaceutical formulations is driven by the choice of the polymer type, considering its physico-chemical properties, it is also relevant to highlight that factors inherent to the polymeric matrix can be strongly influenced by the presence of additives and how they are able to determine the nanogels biopharmaceuticals properties such as bioadhesion, drug loading, surface interaction behavior, dissolution, and release rate control. In this review, we discuss the general applicability of three of the main biophysical techniques used to characterize those systems, scattering techniques (small-angle X-ray and neutron scattering), rheology and Fourier transform infrared absorption spectroscopy (FTIR), connecting their supramolecular structure and insights for formulating effective therapeutic delivery systems. Supplementary Information: The online version contains supplementary material available at 10.1007/s12551-023-01093-2.

Topical Drug Delivery: Innovative Controlled Release Systems.

One of the most innovative strategies for administrating bioactive molecules is the design of adequate drug delivery systems [...].

Protamine-mediated efficient transcellular and transmucosal delivery of proteins.

Proteins and peptides often require frequent needle-based administrations. Here, we report a non-parenteral delivery method for proteins through physical mixing with protamine, an FDA-approved peptide. Protamine was shown to promote tubulation and rearrangement of cellular actin, leading to enhanced intracellular delivery of proteins compared to poly(arginine)8 (R8). While the R8-mediated delivery resulted in significant lysosomal accumulation of the cargo, protamine directed the proteins to the nuclei with little lysosomal uptake. Intranasal delivery of insulin mixed with protamine effectively reduced blood glucose levels in diabetic mice 0.5 h after administration and the effect lasted for ∼6 h, comparable to subcutaneously injected insulin at the same dose. In mice, protamine was shown to overcome mucosal and epithelial barriers and modulate adherens junctions, promoting insulin penetration to the lamina propria layer for systemic absorption.

Pluronic® triblock copolymer-based nanoformulations for cancer therapy: A 10-year overview.

This paper provides a review of the literature on the use of Pluronic® triblock copolymers for drug encapsulation over the last 10 years. A special focus is given to the progress of drug delivery systems (e.g., micelles, liposomes, micro/nanoemulsions, hydrogels and nanogels, and polymersomes and niosomes); the beneficial aspects of Pluronic® triblock copolymers as biological response modifiers and as pharmaceutical additives, adjuvants, and stabilizers, are also discussed. The advantages and limitations encountered in developing site-specific targeting approaches based on Pluronic-based nanostructures in cancer treatment are highlighted, in addition to innovative examples for improving tumor cytotoxicity while reducing side effects.

Repellent active ingredients encapsulated in polymeric nanoparticles: potential alternative formulations to control arboviruses.

Dengue, yellow fever, Chinkungunya, Zika virus, and West Nile fever have infected millions and killed a considerable number of humans since their emergence. These arboviruses are transmitted by mosquito bites and topical chemical repellents are the most commonly used method to protect against vector arthropod species. This study aimed to develop a new generation of repellent formulations to promote improved arboviruses transmission control. A repellent system based on polycaprolactone (PCL)-polymeric nanoparticles was developed for the dual encapsulation of IR3535 and geraniol and further incorporation into a thermosensitive hydrogel. The physicochemical and morphological parameters of the prepared formulations were evaluated by dynamic light scattering (DLS), nano tracking analysis (NTA), atomic force microscopy (AFM). In vitro release mechanisms and permeation performance were evaluated before and after nanoparticles incorporation into the hydrogels. FTIR analysis was performed to evaluate the effect of formulation epidermal contact. Potential cytotoxicity was evaluated using the MTT reduction test and disc diffusion methods. The nanoparticle formulations were stable over 120 days with encapsulation efficiency (EE) of 60% and 99% for IR3535 and geraniol, respectively. AFM analysis revealed a spherical nanoparticle morphology. After 24 h, 7 ± 0.1% and 83 ± 2% of the GRL and IR3535, respectively, were released while the same formulation incorporated in poloxamer 407 hydrogel released 11 ± 0.9% and 29 ± 3% of the loaded GRL and IR3535, respectively. GRL permeation from PCL nanoparticles and PCL nanoparticles in the hydrogel showed similar profiles, while IR3535 permeation was modulated by formulation compositions. Differences in IR3535 permeated amounts were higher for PCL nanoparticles in the hydrogels (36.9 ± 1.1 mg/cm2) compared to the IR3535-PCL nanoparticles (29.2 ± 1.5 mg/cm2). However, both active permeation concentrations were low at 24 h, indicating that the formulations (PCL nanoparticles and PCL in hydrogel) controlled the bioactive percutaneous absorption. Minor changes in the stratum corneum (SC) caused by interaction with the formulations may not represent a consumer safety risk. The cytotoxicity results presented herein indicate the carrier systems based on poly-epsilon caprolactone (PCL) exhibited a reduced toxic effect when compared to emulsions, opening perspectives for these systems to be used as a tool to prolong protection times with lower active repellent concentrations.

Crosstalk between incretin hormones, Th17 and Treg cells in inflammatory diseases.

Intestinal epithelial cells constantly crosstalk with the gut microbiota and immune cells of the gut lamina propria. Enteroendocrine cells, secrete hormones, such as incretin hormones, which participate in host physiological events, such as stimulating insulin secretion, satiety, and glucose homeostasis. Interestingly, evidence suggests that the incretin pathway may influence immune cell activation. Consequently, drugs targeting the incretin hormone signaling pathway may ameliorate inflammatory diseases such as inflammatory bowel diseases, cancer, and autoimmune diseases. In this review, we discuss how these hormones may modulate two subsets of CD4 + T cells, the regulatory T cells (Treg)/Th17 axis important for gut homeostasis: thus, preventing the development and progression of inflammatory diseases. We also summarize the main experimental and clinical findings using drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) signaling pathways and their great impact on conditions in which the Treg/Th17 axis is disturbed such as inflammatory diseases and cancer. Understanding the role of incretin stimulation in immune cell activation and function, might contribute to new therapeutic designs for the treatment of inflammatory diseases, autoimmunity, and tumors.

Silk Fibroin/Poly(vinyl Alcohol) Microneedles as Carriers for the Delivery of Singlet Oxygen Photosensitizers.

Photodynamic therapy (PDT) is a medical treatment in which a combination of a photosensitizing drug and visible light produces highly cytotoxic reactive oxygen species (ROS) that leads to cell death. One of the main drawbacks of PDT for topical treatments is the limited skin penetration of some photosensitizers commonly used in this therapy. In this study, we propose the use of polymeric microneedles (MNs) prepared from silk fibroin and poly(vinyl alcohol) (PVA) to increase the penetration efficiency of porphyrin as possible applications in photodynamic therapy. The microneedle arrays were fabricated from mixtures in different proportions (1:0, 7:3, 1:1, 3:7, and 0:1) of silk fibroin and PVA solutions (7%); the polymer solutions were cast in polydimethylsiloxane (PDMS) molds and dried overnight. Patches containing grids of 10 × 10 microneedles with a square-based pyramidal shape were successfully produced through this approach. The polymer microneedle arrays showed good mechanical strength under compression force and sufficient insertion depth in both Parafilm M and excised porcine skin at different application forces (5, 20, 30, and 40 N) using a commercial applicator. We observe an increase in the cumulative permeation of 5-[4-(2-carboxyethanoyl) aminophenyl]-10,15,20-tris-(4-sulphonatophenyl) porphyrin trisodium through porcine skin treated with the polymer microneedles after 24 h. MNs may be a promising carrier for the transdermal delivery of photosensitizers for PDT, improving the permeation of photosensitizer molecules through the skin, thus improving the efficiency of this therapy for topical applications.

Mucoadhesive, Thermoreversible Hydrogel, Containing Tetracaine-Loaded Nanostructured Lipid Carriers for Topical, Intranasal Needle-Free Anesthesia.

Recent advances have been reported for needle-free local anesthesia in maxillary teeth by administering a nasal spray of tetracaine (TTC) and oxymetazoline, without causing pain, fear, and stress. This work aimed to assess whether a TTC-loaded hybrid system could reduce cytotoxicity, promote sustained permeation, and increase the anesthetic efficacy of TTC for safe, effective, painless, and prolonged analgesia of the maxillary teeth in dental procedures. The hybrid system based on TTC (4%) encapsulated in nanostructured lipid carriers (NLC) and incorporated into a thermoreversible hydrogel of poloxamer 407 (TTCNLC-HG4%) displayed desirable rheological, mechanical, and mucoadhesive properties for topical application in the nasal cavity. Compared to control formulations, the use of TTCNLC-HG4% slowed in vitro permeation of the anesthetic across the nasal mucosa, maintained cytotoxicity against neuroblastoma cells, and provided a three-fold increase in analgesia duration, as observed using the tail-flick test in mice. The results obtained here open up perspectives for future clinical evaluation of the thermoreversible hybrid hydrogel, which contains TTC-loaded NLC, with the aim of creating an effective, topical, intranasal, needle-free anesthesia for use in dentistry.

Development of a Mosquito Repellent Formulation Based on Nanostructured Lipid Carriers.

Arboviral diseases are a threat to global public health systems, with recent data suggesting that around 40% of the world's population is at risk of contracting arboviruses. The use of mosquito repellents is an appropriate strategy to avoid humans coming into contact with vectors transmitting these viruses. However, the cost associated with daily applications of repellents can make their use unfeasible for the low-income populations that most need protection. Therefore, the development of effective formulations offers a way to expand access to this means of individual protection. Consequently, research efforts have focused on formulations with smaller quantities of active agents and sustained release technology, aiming to reduce re-applications, toxicity, and cost. The present study investigates the development of nanostructured lipid carriers (NLCs) loaded with a mixture of the compounds icaridin (synthetic) and geraniol (natural), incorporated in cellulose hydrogel. The NLCs were prepared by the emulsion/solvent evaporation method and were submitted to physicochemical characterization as a function of time (at 0, 15, 30, and 60 days). The prepared system presented an average particle size of 252 ± 5 nm, with encapsulation efficiency of 99% for both of the active compounds. The stability profile revealed that the change of particle size was not significant (p > 0.05), indicating high stability of the system. Rheological characterization of the gels containing NLCs showed that all formulations presented pseudoplastic and thixotropic behavior, providing satisfactory spreadability and long shelf life. Morphological analysis using atomic force microscopy (AFM) revealed the presence of spherical nanoparticles (252 ± 5 nm) in the cellulose gel matrix. Permeation assays showed low fluxes of the active agents through a Strat-M® membrane, with low permeability coefficients, indicating that the repellents would be retained on the surface to which they are applied, rather than permeating the tissue. These findings open perspectives for the use of hybrid formulations consisting of gels containing nanoparticles that incorporate repellents effective against arthropod-borne virus. These systems could potentially provide improvements considering the issues of effectiveness, toxicity, and safety.

Ropivacaine-Loaded Poloxamer Binary Hydrogels for Prolonged Regional Anesthesia: Structural Aspects, Biocompatibility, and Pharmacological Evaluation.

This study reports the development of thermosensitive hydrogels for delivering ropivacaine (RVC), a wide clinically used local anesthetic. For this purpose, poloxamer- (PL-) based hydrogels were synthesized for evaluating the influence of polymer concentration, hydrophilic-lipophilic balances, and binary system formation on biopharmaceutical properties and pharmacological performance. Transition temperatures were shifted, and rheological analysis revealed a viscoelastic behavior with enhanced elastic/viscous modulus relationship (G'/G " = 1.8 to 22 times), according to hydrogel composition and RVC incorporation. The RVC release from PL407 and PL407/338 systems followed the Higuchi model (R 2 = 0.923-0.989), indicating the drug diffusion from hydrogels to the medium. RVC-PL hydrogels were potentially biocompatible evoking low cytotoxic effects (in fibroblasts and Schwann cells) and mild/moderate inflammation signs on sciatic nerve nearby histological evaluation. In vivo pharmacological assays demonstrated that PL407 and PL407/338 evoked differential analgesic effects, by prolonging the sensory blockade duration up to ~340 and 250 min., respectively. All those results highlighted PL407 and PL407/338 as promising new strategies for sustaining analgesic effects during the postoperative period.

Sulforaphane-loaded hyaluronic acid-poloxamer hybrid hydrogel enhances cartilage protection in osteoarthritis models.

Sulforaphane (SFN) is an isothiocyanate with anti-arthritic and immuno-regulatory activities, supported by the downregulation of NF-κB pathway, reduction on metalloproteinases expression and prevention of cytokine-induced cartilage degeneration implicated in OA progression. SFN promising pharmacological effects associated to its possible use, by intra-articular route and directly in contact to the site of action, highlight SFN as promising candidate for the development of drug-delivery systems. The association of poloxamers (PL) and hyaluronic acid (HA) supports the development of osteotrophic and chondroprotective pharmaceutical formulations. This study aims to develop PL-HA hybrid hydrogels as delivery systems for SFN intra-articular release and evaluate their biocompatibility and efficacy for osteoarthritis treatment. All formulations showed viscoelastic behavior and cubic phase organization. SFN incorporation and drug loading showed a concentration-dependent behavior following HA addition. Drug release profiles were influenced by both diffusion and relaxation of polymeric chains mechanisms. The PL407-PL338-HA-SFN hydrogel did not evoke pronounced cytotoxic effects on either osteoblast or chondrosarcoma cell lines. In vitro/ex vivo pharmacological evaluation interfered with an elevated activation of NF-κB and COX-2, increased the type II collagen expression, and inhibited proteoglycan depletion. These results highlight the biocompatibility and the pharmacological efficacy of PL-HA hybrid hydrogels as delivery systems for SFN intra-articular release for OA treatment.

Sericin based nanoformulations: a comprehensive review on molecular mechanisms of interaction with organisms to biological applications.

BACKGROUND: The advances in products based on nanotechnology have directed extensive research on low-cost, biologically compatible, and easily degradable materials. MAIN BODY: Sericin (SER) is a protein mainly composed of glycine, serine, aspartic acid, and threonine amino acids removed from the silkworm cocoon (particularly Bombyx mori and other species). SER is a biocompatible material with economic viability, which can be easily functionalized due to its potential crosslink reactions. Also, SER has inherent biological properties, which makes possible its use as a component of pharmaceutical formulations with several biomedical applications, such as anti-tumor, antimicrobials, antioxidants and as scaffolds for tissue repair as well as participating in molecular mechanisms attributed to the regulation of transcription factors, reduction of inflammatory signaling molecules, stimulation of apoptosis, migration, and proliferation of mesenchymal cells. CONCLUSION: In this review, the recent innovations on SER-based nano-medicines (nanoparticles, micelles, films, hydrogels, and their hybrid systems) and their contributions for non-conventional therapies are discussed considering different molecular mechanisms for promoting their therapeutic applications.

New Strategies for Improving Budesonide Skin Retention.

The aim of this work was to evaluate the ex vivo effect of the combination of two strategies, complexation with cyclodextrin, and poloxamer hydrogels, for improving water solubility in the dermal absorption of budesonide. Two hydrogels containing 20% poloxamer 407, alone or in combination with poloxamer 403, were prepared. Each formulation was loaded with 0.05% budesonide, using either pure budesonide or its inclusion complex with hydroxypropyl-ß-cyclodextrin, and applied in finite dose conditions on porcine skin. The obtained results showed that for all formulations, budesonide accumulated preferentially in the epidermis compared to the dermis. The quantity of budesonide recovered in the receptor compartment was, in all cases, lower than the LOQ of the analytical method, suggesting the absence of possible systemic absorption. The use of a binary poloxamer mixture reduced skin retention, in line with the lower release from the vehicle. When the hydrogels were formulated with the inclusion complex, an increase in budesonide skin retention was observed with both hydrogels. Poloxamer hydrogel proved to be a suitable vehicle for cutaneous administration of budesonide.

Trends in nanoformulations for atopic dermatitis treatment.

INTRODUCTION: Immunological skin dysfunctions trigger the synthesis and release of inflammatory cytokines, which induce recurrent skin inflammation associated with chronic itching, inefficient barrier behavior, and reduced skin hydration. These features characterize a multifactorial chronic inflammatory disease atopic dermatitis (AD). AD therapy includes anti-inflammatory drugs and immunosuppressors as well as non-pharmacological alternatives such as emollients, moisturizers, and lipids (ceramides, phospholipids) for modulating the skin hydration and the barrier repair. However, these treatments are inconvenient with low drug skin penetration and insufficient maintenance on the application site. AREAS COVERED: Nanotechnology-based therapies can be a great strategy to overcome these limitations. Considering the particular skin morphological organization, SC lipid matrix composition, and immunological functions/features related to nanocarriers, this review focuses on recent developments of nanoparticulate systems (polymeric, lipid-based, inorganic) as parent or hybrid systems including their chemical composition, physico-chemical and biopharmaceutical properties, and differential characteristics that evaluate them as new effective drug-delivery systems for AD treatment. EXPERT OPINION: Despite the several innovative formulations, research in nanotechnology-based carriers should address specific aspects such as the use of moisturizers associated to pharmacological therapies, toxicity studies, scale-up production processes and the nanocarrier influence on immunological response. These approaches will help researchers choose the most appropriate nanocarrier system and widen nanomedicine applications and commercialization.

Changes in fertilization medium viscosity using hyaluronic acid impact bull sperm motility and acrosome status.

The female reproductive tract, in particular the composition of the uterine and oviduct fluids, is responsible, at least in part, for triggering sperm cell modifications, essential for the acquisition of fertilization ability. Hyaluronic acid (HA) is a glycosaminoglycan present in these fluids, and its role in the fertilization process and sperm functionality is still barely understood. This work was designed to (a) determine the rheological characteristics of the fertilization medium by the addition of HA and (b) determine the HA influence on sperm motility and functional status. To that end, the in vitro fertilization medium was supplemented with 4 doses of HA (6, 60, 600 and 6,000 µg/ml) and analysed for viscosity and adhesion strength characteristics. Then, thawed semen from 6 bulls were incubated in these media and assessed at 4 different moments for morphological and functional parameters (plasma and acrosomal membrane integrities, mitochondrial membrane potential, capacitation, acrosomal reaction, and motility). The rheological evaluation showed that the addition of HA was able to increase both the viscosity and the adhesion strength of the fertilization medium, especially in the 6,000 µg/ml group in which the effect was more pronounced. No influence of HA could be observed on mitochondrial potential, and acrosomal and plasma membrane integrities. However, HA supplementation, at lower doses, led to an increase in the number of reacted sperm, as well as changes in motility parameters, with increase in the number of motile, rapid and progressive spermatozoa. In conclusion, the addition of HA alters the rheological properties of the fertilization medium and leads to the improvement of the properties related to sperm motility and capacitation, without compromising other functional aspects of the cell.

Evaluation of Budesonide-Hydroxypropyl-ß-Cyclodextrin Inclusion Complex in Thermoreversible Gels for Ulcerative Colitis.

BACKGROUND: New formulations for topical treatment of ulcerative colitis with budesonide inclusion complex (BUDHP-ß-CD) and poloxamers (PL) were developed for future clinical use. AIMS: This study evaluated the efficacy of such novel formulations in a rat model of colitis. METHODS: The PL-BUDHP-ß-CD systems were prepared by direct dispersion of the complex (BUD concentration 0.5 mg mL-1) in solutions with PL407 or PL403. Male Wistar rats underwent TNBS-induced colitis and were treated for 5 days by a rectal route, as follows: BUD 1: BUDHP-ß-CD + PL407 (18%); BUD 2: BUDHP-ß-CD + PL407 (20%); BUD 3: BUDHP-ß-CD + PL407 (18%) + PL403 (2%); BUD 4: plain BUD; BUD 5: BUDHP-ß-CD; C1: HP-ß-CD + PL407 (18%); C2: HP-ß-CD + PL407 (20%); C3: HP-ß-CD + PL407 (18%) + PL403 (2%); C4: saline. A negative control group without colitis was also used. Colitis was assessed via myeloperoxidase (MPO) activity, and macroscopic and microscopic damage score in colon tissues. Protein levels of TNF-α, IL-1ß, IL-10 and endogenous glucocorticoids were obtained using ELISA. RESULTS: BUDHP-ß-CD poloxamer formulations had similar MPO activity when compared with the negative control group. All formulations presented lower MPO activity than BUDHP-ß-CD and plain BUD (p < 0.001). BUD 2 produced lower microscopic score values than plain BUD and BUDHP-ß-CD (p < 0.01). All formulations with BUDHP-ß-CD poloxamers reduced TNF-α levels (p < 0.05). CONCLUSION: Novel budesonide inclusion complex formulations improved microscopic damage and reduced colonic MPO activity and TNF-α levels.

Physico-Chemical Characterization and Biopharmaceutical Evaluation of Lipid-Poloxamer-Based Organogels for Curcumin Skin Delivery.

Organogels (ORGs) are semi-solid materials, in which an organic phase is immobilized by a three-dimensional network composed of self-organized system, forming the aqueous phase. In this context, lipid-Pluronics (PLs) ORGs form a two-phase system which can be effectively used as skin delivery systems, favoring their permeation across the skin. In this study, we presented the development of ORG skin drug-delivery systems for curcumin (CUR), a liposoluble phenolic pigment extracted from the turmeric rhizome. In special, we designed the formulation compositions in order to carry high amounts of CUR soluble in oleic acid (OA), as organic phase, entrapped into an aqueous phase composed of micellar PL-based hydrogels by associating two polymers with different hydrophilic-lipophilic balances, Pluronic F-127 (PL F-127), and Pluronic L-81 (PL L-81), to enhance the permeation across the skin. Results revealed that the incorporation of PL L-81 favored the CUR incorporation into micelle-micelle interface. CUR insertion into OA-PL F-127/L-81 reduced both G'/G" relationship (∼16 x) and viscosity values (η* ∼ 54 mPa.s, at 32.5°C), disturbing the ORG network structural organization. In vitro permeation assays through Strat-M® skin-model membranes showed that higher CUR-permeated amounts were obtained for OA-PL F-127/L-81 (4.83 µg.cm-2) compared to OA-PL F-127 (3.51 µg.cm-2) and OA (2.25 µg.cm-2) or hydrogels (∼1.2 µg.cm-2, p < 0.001). Additionally, ORG formulations presented low cytotoxic effects and evoked pronounced antileishmanial activity (IC50 < 1.25 µg.ml-1), suggesting their potential use as skin delivery systems against Leishmania amazonensis. Results from this study pointed out OA-PL-based ORGs as promising new formulations for possible CUR topical administration.

Lipid-based carriers for the delivery of local anesthetics.

INTRODUCTION: There is a clinical need for pharmaceutical dosage forms devised to prolong the acting time of local anesthetic (LA) agents or to reduce their toxicity. Encapsulation of LA in drug delivery systems (DDSs) can provide long-term anesthesia for inpatients (e.g. in immediate postsurgical pain control, avoiding the side effects from systemic analgesia) and diminished systemic toxicity for outpatients (in ambulatory/dentistry procedures). The lipid-based formulations described here, such as liposomes, microemulsions, and lipid nanoparticles, have provided several nanotechnological advances and therapeutic alternatives despite some inherent limitations associated with the fabrication processes, costs, and preclinical evaluation models. AREAS COVERED: A description of the currently promising lipid-based carriers, including liposomes, microemulsions, and nanostructured lipid carriers, followed by a systematic review of the existing lipid-based formulations proposed for LA. Trends in the research of these LA-in-DDS are then exposed, from the point of view of administration route and alternatives for non-traditionally administered LA molecules. EXPERT OPINION: Considering the current state and potential future developments in the field, we discuss the reasons for why dozens of formulations published every year fail to reach clinical trials; only one lipid-based formulation for the delivery of local anesthetic (Exparel®) has been approved so far.

Synthesis and characterization of nanostructured lipid-poloxamer organogels for enhanced skin local anesthesia.

The aim of this study was to synthesize a novel drug delivery system using organogels (ORGs) and characterize its physicochemical properties, in vitro and ex vivo permeation abilities, cytotoxicity and in vivo local anesthetic effects. The ORG formulations contained a mixture of oleic acid-lanolin (OA-LAN), poloxamer (PL407), and the commonly used local anesthetic lidocaine (LDC). The main focus was to evaluate the impact of LAN and PL407 concentrations on the ORG structural features and their biopharmaceutical performance. Results revealed that LDC, OA, and LAN incorporation separately shifted the systems transitions phase temperatures and modified the elastic/viscous moduli relationships (G'/G″ = ~15×). Additionally, the formulation with the highest concentrations of LAN and PL407 reduced the LDC flux from ~17 to 12 µg·cm-2·h-1 and the permeability coefficients from 1.2 to 0.62 cm·h-1 through ex vivo skin. In vivo pharmacological evaluation showed that the ORG-based drug delivery system presented low cytotoxicity, increased and prolonged the local anesthetic effects compared to commercial alternatives. The data from this study indicate that ORG represent a promising new approach to effectively enhance the topical administration of local anesthetics.