Permeation Enhancing Properties Research Articles

Effect of ursodiol on alginate/PLL nanoparticles with non-ionic surfactant for gene delivery

Hearing loss is a widespread condition, affecting people from a range of demographics. Gene therapy is an emerging method for the amelioration of this condition. Challenges associated with the delivery of genes to various sites within the ear remain a significant challenge. In the present work, a novel polymer nanoparticle delivery system was developed, incorporating a bile acid excipient. Bile acids have previously been shown to improve drug delivery through their permeation enhancing properties; however, few studies report their use in gene delivery systems. Nanoparticles were developed with sodium alginate and poly-L-lysine through an ionotropic gelation method. Various surfactants including Tween-80 and poly-ethylene glycol 6000 were incorporated to both improve the solubility of the bile acid, ursodiol, and to modify nanoparticle properties. The evaluation of the nanoparticle’s safety profiles was the primary outcome of this study. The secondary aims were to perform genetic studies, such as transfection efficiency. The nanoparticles generated in this study demonstrated formulation-dependent variability in particle size ranging from 30 to 300 nm. Several of the developed formulations demonstrated suitable safety profiles; further, the introduction of bile acid helped to reduce toxicity. Transfection efficiency for all formulations remained low, potentially due to poor plasmid release inside the cell. Poor transfection efficiency is one of the key pitfalls associated with polymer nanoparticles Overall the present study developed nanoparticles with suitable safety profiles but limited efficacy. The use of modified polymers, additional excipients, and cell-targeting peptides are potential methods that may be explored in future studies to help further improve gene delivery.

Multi-hierarchical nanoparticles with tunable core by emulsion polymerization processes

Nanoparticles (NPs) with functional cores are gaining research interest due to their advanced architecture. However, exposed reactive groups on NP surfaces can lead to material side reactions and biomedical tissue damage. NPs with multi-hierarchical morphologies can be synthesized by various methods; however, controlling the size and position of the functional groups using conventional and scalable methods is still a challenge. This study explores emulsion-based polymerization methods for producing multi-hierarchical NPs with varying sizes and compositions. We compared micro-, macro-, and semi-batch emulsion polymerization using 2-hydroxyethyl methacrylate (HEMA) and pentafluorophenyl methacrylate (PFMA) as co-monomers. The components present in PFMA can be substituted and are used for post-synthetic functionalization. The results suggest that the architecture of the synthesized NPs is multi-hierarchical, with the substitutable pentafluorophenyl units surrounded by HEMA monomers. Additionally, we evaluated the NPs' ability to enhance dermal drug penetration using nile red as a hydrophobic drug model. Significant variations in skin permeation enhancement properties were observed among the NPs, underscoring the impact of the synthesis method on nanocarriers' drug delivery performance.

Thiolated Cellulose: A Dual-Acting Mucoadhesive and Permeation-Enhancing Polymer.

This study aims to design an anionic, thiolated cellulose derivative and to evaluate its mucoadhesive and permeation-enhancing properties utilizing enoxaparin as a model drug. 2-Mercaptosuccinic acid-modified cellulose (cellulose-mercaptosuccinate) was synthesized by the reaction of cellulose with S-acetylmercaptosuccinic anhydride. The chemical structure of the target compound was confirmed by FTIR and 1H NMR spectroscopy. The thiol content was determined by Ellman's test. The conjugate exhibited 215.5 ± 25 μmol/g of thiol groups and 84 ± 16 μmol/g of disulfide bonds. Because of thiolation, mucoadhesion on porcine intestinal mucosa was 9.6-fold enhanced. The apparent permeability (Papp) of the model dye Lucifer yellow was up to 2.2-fold improved by 0.5% cellulose-mercaptosuccinate on a Caco-2 cell monolayer. Enoxaparin permeation through rat intestinal mucosa increased 2.4-fold in the presence of 0.5% cellulose-mercaptosuccinate compared with the drug in buffer only. In vivo studies in rats showed an oral bioavailability of 8.98% using cellulose-mercaptosuccinate, which was 12.5-fold higher than that of the aqueous solution of the drug. Results of this study show that the modification of cellulose with 2-mercaptosuccinic acid provides mucoadhesive and permeation-enhancing properties, making this thiolated polymer an attractive excipient for oral drug delivery.

A shea butter-based ketamine ointment: The antidepressant effects of transdermal ketamine in rats

The delayed onset of monoaminergic antidepressants and disadvantages of traditional administration routes created the need for alternative non-invasive delivery methods with rapid onset therapeutic effect. Ketamine attracted attention as a fast-acting glutamatergic antidepressant with ideal physiochemical properties for alternative routes of administration. However, there is no sufficient data for its transdermal use in depression. In this proof-of-concept study, we investigated the antidepressant effects of transdermal ketamine delivered via a novel ointment with skin protective, emulsifying and permeation enhancing properties. A shea butter-based 5% (w/w) ketamine ointment or a drug-free vehicle ointment were applied to the shaved dorsal skin of male Wistar rats for 2 days, twice a day. Behavioral despair, locomotor activity and anxiety-like behavior were respectively assessed in the forced swim test (FST), open field test (OFT), and elevated plus maze (EPM). The pharmacokinetic profile of the ointment was analyzed with high-performance liquid chromatography. Transdermal ketamine ameliorated behavioral despair without altering general locomotor activity and anxiety-like behavior, showing that skin-friendly drug carriers like shea butter may constitute promising alternatives to current routes of delivery for ketamine. Tested transdermal method aims to provide more sustainable drug delivery for long-term treatment schedules. Future studies can investigate its long-term use, side effects and abuse liability.

Lipid-based nanoparticles: Enhanced cellular uptake via surface thiolation

The aim of this study was to evaluate the uptake mechanism of thiolated nanostructured lipid carriers (NLCs). NLCs were decorated with a short-chain polyoxyethylene(10)stearyl ether with a terminal thiol group (NLCs-PEG10-SH) or without (NLCs-PEG10-OH) as well as with a long-chain polyoxyethylene(100)stearyl ether with thiolation (NLCs-PEG100-SH) or without (NLCs-PEG100-OH). NLCs were evaluated for size, polydispersity index (PDI), surface morphology, zeta potential and storage stability over six months. Cytotoxicity, adhesion to the cell surface and internalization of these NLCs in increasing concentrations were evaluated on Caco-2 cells. The influence of NLCs on the paracellular permeability of lucifer yellow was determined. Furthermore, cellular uptake was examined with and without various endocytosis inhibitors as well as reducing and oxidizing agents. NLCs were obtained in a size ranging from 164 to 190 nm, a PDI of 0.2, a negative zeta potential < –33 mV and stability over six months. Cytotoxicity was shown to be concentration dependent and to be lower for NLCs with shorter PEG chains. Permeation of lucifer yellow was 2-fold increased by NLCs-PEG10-SH. All NLCs displayed concentration dependent adhesion to the cell surface and internalization, which was in particular 9.5-fold higher for NLCs-PEG10-SH compared to NLCs-PEG10-OH. Short PEG chain NLCs and especially thiolated short PEG chain NLCs showed higher cellular uptake than NLCs with longer PEG chain. Cellular uptake of all NLCs was mainly clathrin-mediated endocytosis. Thiolated NLCs showed also caveolae-dependent and clathrin- and caveolae-independent uptake. Macropinocytosis was involved in NLCs with long PEG chains. NLCs-PEG10-SH indicated thiol-dependent uptake, which was influenced by reducing and oxidizing agents. Due to thiol groups on the surface of NLCs their cellular uptake and paracellular permeation enhancing properties can be substantially improved.

Yeast Particles for Encapsulation of Terpenes and Essential Oils.

Terpenes and essential oils are materials of great commercial use due to their broad spectra of antibacterial, antifungal, membrane permeation enhancement and antioxidant biological properties, as well as for their use as flavors and fragrances. Yeast particles (YPs) are 3-5 µm hollow and porous microspheres, a byproduct of some food-grade yeast (Saccharomyces cerevisiae) extract manufacturing processes, that have been used for the encapsulation of terpenes and essential oils with high payload loading capacity (up to 500% weight) and efficiency, providing stability and sustained-release properties. This review focuses on encapsulation approaches for the preparation of YP-terpene and essential oil materials that have a wide range of potential agricultural, food and pharmaceutical applications.

Influence of the Size and Charge of Carbon Quantum Dots on Their Corneal Penetration and Permeation Enhancing Properties.

Reaching the corneal endothelium through the topical administration of therapeutic drugs remains a challenge in ophthalmology. Besides, endothelial cells are not able to regenerate, and diseases at this site can lead to corneal blindness. Targeting the corneal endothelium implies efficient penetration through the three corneal layers, which still remains difficult for small molecules. Carbon quantum dots (CQDs) have demonstrated great potential for ocular nanomedicine. This study focuses on the corneal penetration abilities of differently charged CQDs and their use as permeation enhancers for drugs. Excised whole bovine eyes were used as an ex vivo model to investigate corneal penetration of CQDs derived from glucosamine using β-alanine, ethylenediamine, or spermidine as a passivation agent. It was found that negatively charged CQDs have limited corneal penetration ability, while positively charged CQDs derived from glucosamine hydrochloride and spermidine (CQD-S) penetrate the entire corneal epithelium all the way down to the endothelium. CQD-S were shown to enhance the penetration of FITC-dextran 150 kDa, suggesting that they could be used as efficient penetration enhancers for therapeutic delivery to the corneal endothelium.

The effects of Lavandula angustifolia essential oil on analgesic effects and percutaneous absorption of naproxen sodium gel; an in vivo and in vitro study.

The percutaneous bioavailability of naproxen is low and several technologies have been utilized to overcome the problem. Although, some studies have reported the permeation-enhancing properties of natural essential oils, no research has reflected the effectiveness of Lavandula angustifolia essential oil (LAEO) on increasing the percutaneous absorption of naproxen sodium from a topical gel. Therefore, the present study was designed to investigate whether LAEO increased the percutaneous absorption and the analgesic effects of naproxen sodium topical gel. In the present study, naproxen topical gel was formulated using carbopol 940 (a gelling agent) and several vehicles such as PEG 400, ethanol, and water and the properties of gels were measured. Percutaneous absorption-enhancing properties of LAEO were measured too. Based on our data, the essential oil-containing formulation of naproxen represented greater penetration into (222.19 ± 24.87 vs. 107.65 ± 6.38 μg/cm2 ), and also across (22.07 ± 4.42 vs. 13.14 ± 2.87 μg/cm2 ) skin layers compared to the naproxen gel. Additionally, a significant analgesic property was observed in the naproxen topical gel containing 0.5% essential oil during both first and late phases of formalin test, as well as the late phase of tail-flick test. It could be concluded that LAEO significantly enhanced naproxen percutaneous absorption and also its analgesic effects.

Chemical Permeation Enhancers for Topically-Applied Vitamin C and Its Derivatives: A Systematic Review

This paper reports the permeation-enhancing properties and safety of different chemical permeation enhancers (CPEs) on the topical delivery of vitamin C (VC) and its derivatives. A literature search using search keywords or phrases was done in PubMed®, ScienceDirect, and MEDLINE databases. The calculated Log P (cLog P) values were referenced from PubChem and the dermal LD50 values were referenced from safety data sheets. Thirteen studies described the permeation-enhancing activity of 18 identified CPEs in the topical delivery of VC. Correlation analysis between ER and cLog P values for porcine (r = 0.114) and rabbit (r = 0.471) showed weak and moderate positive correlation, while mouse (r = −0.135), and reconstructed human epidermis (r = −0.438) had a negative correlation. The majority (n = 17) of the CPEs belonged to Category 5 of the Globally Harmonized System of Classification or low toxicity hazard. CPEs alone or in combination enhanced permeation (ER = 0.198–106.57) of VC in topical formulations. The combination of isopropyl myristate, sorbitan monolaurate, and polyoxyethylene 80 as CPEs for VC resulted in the highest permeation enhancement ratio.

Tailoring functional spray-dried powder platform for efficient donepezil nose-to-brain delivery

Shortcomings of oral donepezil administration in the treatment of Alzheimer’s disease have paved the way for ongoing investigations towards more efficient and safe donepezil nose-to-brain delivery. Herein we present the development of advantageous powder platform for donepezil nose-to-brain delivery, coupling careful design of chitosan and mannitol-based carrier matrix with spray-drying technology advantages and early consideration of adequate nasal administration mode, employing QbD approach. Unprecedentedly, ultrasonic nozzle was used to atomise the drying feed in response to size-related requirements for nasal aerosol particles. The optimised spray-drying process resulted in free-flowable dry powder with a great majority of particles larger than 10 µm, ensuring localised nasal deposition upon aerosolization, as evidenced by using 3D-printed nasal cavity model. QbD approach coupling formulation, process and administration parameters enabled optimisation of drug deposition profile reaching tremendously high 65.5 % of the applied dose deposited in the olfactory region. The leading formulation exhibited favourable swelling, mucoadhesion, drug release and permeation-enhancing properties, suiting the needs for efficient brain-targeted delivery. Results of in vitro biocompatibility and physico-chemical stability studies confirmed the leading formulation potential for safe and efficient donepezil nose-to-brain delivery. The obtained results encourage extending the study to an appropriate in vivo model needed for the final proof-of-concept.

Thiolated Nanoparticles for Biomedical Applications: Mimicking the Workhorses of Our Body.

Advances in nanotechnology have generated a broad range of nanoparticles (NPs) for numerous biomedical applications. Among the various properties of NPs are functionalities being related to thiol substructures. Numerous biological processes that are mediated by cysteine or cystine subunits of proteins representing the workhorses of the bodies can be transferred to NPs. This review focuses on the interface between thiol chemistry and NPs. Pros and cons of different techniques for thiolation of NPs are discussed. Furthermore, the various functionalities gained by thiolation are highlighted. These include overall bio‐ and mucoadhesive, cellular uptake enhancing, and permeation enhancing properties. Drugs being either covalently attached to thiolated NPs via disulfide bonds or being entrapped in thiolated polymeric NPs that are stabilized via inter‐ and intrachain crosslinking can be released at the diseased tissue or in target cells under reducing conditions. Moreover, drugs, targeting ligands, biological analytes, and enzymes bearing thiol substructures can be immobilized on noble metal NPs and quantum dots for therapeutic, theranostic, diagnostic, biosensing, and analytical reasons. Within this review a concise summary and analysis of the current knowledge, future directions, and potential clinical use of thiolated NPs are provided.

Peptide drug delivery: oral approaches

The strategy for the development of oral biomolecules has always been a challenge for researchers due to their high molecular weight, chemical or enzymatic degradation and impermeability through the intestinal mucosa. Thiolate polymers – thiomers appear to be the most promising excipients for non-parenteral administration of very poorly absorbing drug hydrophilic macromolecules such as peptides, proteins and nucleic acids, which would improve the bioavailability of these therapeutic agents. Due to the immobilization of thiol groups on well-established multifunctional polymers such as polyacrylates and chitosans, their mucoadhesive, releasecontrolling, permeation enhancement and enzyme-inhibiting properties are significantly improved.

Thiolated cyclodextrins: Mucoadhesive and permeation enhancing excipients for ocular drug delivery

Thiolated β-cyclodextrin (β-CD) has the potential to enhance mucoadhesive and permeation enhancing properties on ocular mucosa. Thiolated β-CD was synthesized via replacement of all primary hydroxyl groups on β-CD backbone by halogen followed by substitution with thiol groups. The structure was confirmed by FT-IR and 1H NMR spectroscopy. Thiolated CD was characterized for hemolytic effect, ocular irritation, solubility enhancement, viscoelastic behavior and mucoadhesive properties. Moreover, the permeation enhancing effect of thiolated oligomer on different ocular tissues including conjunctiva, sclera and cornea was evaluated with sodium fluorescein (Na-Flu) as a marker. Thiolated β-CD displayed 5360 ± 412 µmol/g thiol groups. The newly synthesized oligomer did not show any hemolytic effect on red blood cells at a concentration of 0.5% (m/v) for an incubation period of 3 h and minimal corneal irritation effects without any inflammation within 72 h. Thiolated β-CD exhibited a 5.3-fold improved aqueous solubility as compared to the unmodified β-CD. Thiolated oligomer (0.5% m/v) enhanced the viscosity of mucus up to 6.2-fold within 4 h and provided a 26-fold prolonged ocular residence time due to mucoadhesion. Moreover, 0.5% (m/v) thiolated β-CD enhanced the permeation of Na-Flu 9.6-, 7.1- and 5.3-fold on conjunctiva, sclera and cornea, respectively. Based on these findings, thiolated β-CD might be a promising auxiliary agent for ocular drug delivery.

Formulation development and pharmacokinetic investigation of self-assembled hybrid niosomes for oral delivery of 17-Hydroxyprogesterone caproate

17-Hydroxyprogesterone caproate (HPC) is an approved efficacious drug for reducing the incidence of a preterm birth defect by intramuscular (I.M.) injection. Oral administration of HPC encounters challenges given by slow absorption and low bioavailability. Thus, the objective of this study was to explore the feasibility of delivering HPC through the oral route using niosomes. Niosomes were prepared with different non-ionic surfactants having permeation enhancing properties (NSPEs) in combination with Span 60 and cholesterol to form hybrid niosomes and later screened for the lead formulation by variability studies. All the formulations were characterized in terms of entrapment efficiency, particle size. Results indicated that 1:2:2 M ratio of Brij 76: cholesterol: Span 60 (N2-c) demonstrated optimal characteristics with entrapment efficiency (92.2 ± 1.05%), particle size (62.9 ± 0.65 nm), PDI (0.2 ± 0.003) and zeta potential (−22.2 ± 0.85 mV) and was chosen as the lead formulation. Ex vivo intestinal permeation study showed significantly high permeation of HPC. In vivo pharmacokinetics in rats showed an increase in oral bioavailability (AUC0-t) by niosomes (1.8-fold, 802.4 ± 273.84 h*ng/mL) compared to the oral suspension and better efficacy than intramuscular injection. Overall, results showed hybrid niosomes enhanced the bioavailability of HPC by increasing the intestinal permeation, which may be a better approach to minimize side effects of administration associated with intramuscular injection.

Per-6-Thiolated Cyclodextrins: A Novel Type of Permeation Enhancing Excipients for BCS Class IV Drugs.

The purpose of the study was to develop a per-6-thiolated α-cyclodextrin (α-CD) by substituting all primary hydroxyl groups of α-CD with thiol groups and to assess its solubility-improving and permeation-enhancing properties for a BCS Class IV drug in vitro as well as in vivo. The primary hydroxyl groups of α-CD were replaced by iodine, followed by substitution with −SH groups. The structure of per-6-thiolated α-CD was approved by FT-IR and 1H NMR spectroscopy. The per-6-thiolated was characterized for thiol content, −SH stability, cytotoxicity, and solubility-improving properties by using the model BCS Class IV drug furosemide (FUR). The mucoadhesive properties of the thiolated oligomer were investigated via viscoelastic measurements with porcine mucus, whereas permeation-enhancing features were evaluated on the Caco-2 cell monolayer and rat gut mucosa. Furthermore, oral bioavailability studies were performed in rats. The per-6-thiolated α-CD oligomer displayed 4244 ± 402 μmol/g thiol groups. These −SH groups were stable at pH ≤ 4, exhibiting a pKa value of 8.1, but subject to oxidation at higher pH. Per-6-thiolated α-CD was not cytotoxic to Caco-2 cells in 0.5% (m/v) concentration within 24 h. It improved the solubility of FUR in the same manner as unmodified α-CD. The addition of per-6-thiolated α-CD (0.5% m/v) increased the mucus viscosity up to 5.8-fold at 37 °C within 4 h. Because of the incorporation in per-6-thiolated α-CD, the apparent permeability coefficient (Papp) of FUR was 6.87-fold improved on the Caco-2 cell monolayer and 6.55-fold on the intestinal mucosa. Moreover, in vivo studies showed a 4.9-fold improved oral bioavailability of FUR due to the incorporation in per-6-thiolated α-CD. These results indicate that per-6-thiolated α-CD would be a promising auxiliary agent for the mucosal delivery of, in particular, BCS Class IV drugs.

Apixaban Ultrafine O/W Nano Emulsion Transdermal Drug Delivery System: Formulation, In Vitro and Ex Vivo Characterization -

Apixaban (APX) is a potent oral anticoagulant drug that directly inhibit coagulation factor Xa for prevention of venous thromboembolism (VTE) following total hip or knee replacement surgery. Orally APX has poor water solubility (0.028 mg/mL) and relative low bioavailability (50%). Transdermal APX delivery was utilized as a convenient alternative route to control oral limitations. This study designed to formulate ultrafine APX o/w nanoemulsion with self-permeation enhancing properties through skin barrier utilizing the ultrafine (> 50 nm) nanosized droplets as well as nanoemulsion components themselves to act as a permeation enhancer. Solubility study result in selecting triacetin oil, triton-x-100 and carbitol as oil phase, surfactant and cosurfactant respectively, while pseudoternary phase diagram construct nanoemulsion area for choosing formulations. Twenty-one o/w nanoemulsions prepared and characterized for droplet size, pH values, percent transmittance, electroconductivity, APX content, in vitro APX release, and ex vivo permeation through Albino Wistar rat abdominal skin to simulate human skin. Among formulations, ten preparations demonstrate ultrafine APX o/w nanoemulsions with high percent transmittance and electroconductivity, pH values appropriate for skin application, ultrafine droplet sizes (> 50 nm) and accepted APX content. In vitro release studies reveal significant (p ≤ 0.05) increase in APX dispersibility and diffusion through dialysis membrane. Ex vivo APX permeation through rat abdominal skin was significantly (p ≤ 0.05) increased in comparison with pure drug as assured by significant (p ≤ 0.05) enhancement in permeation parameters Jss, KP and ER with shorter Tlag, which could be attributed to permeation enhancing properties of nanoemulsion formulation itself.

Buccal mucosal accumulation of dapoxetine using supersaturation, co-solvent and permeation enhancing polymer strategy

Purposewe have presented the potential of using mixed solvents, supersaturation and penetration enhancing polymers for achieving a good route for poorly soluble and absorbable drugs like dapoxetine HCl. MethodsThe gel formulation step was based on studying the solubility of DAP. HCl in different organic solvents which can be used as cosolvents. The highest solubility solvent was chosen to be evaluated for its permeation efficiency in pure state and mixed with water in three levels (20, 40 and 60%). The suitable binary mixture was formulated into gel formulations with two levels of drug loading (12 mg/ml and 24 mg/ml) with two levels of polymer concentrations as stabilizing anti-nucleating agents. The stable gel formulations were evaluated for rheological mucoadhesive, drug release and permeation properties. The gels, in general, gave lower flux values than the binary mixture alone. In addition, the permeation profiles were of infinite dose type with a straight steady-state flux line. The chosen formulation was chosen to be compared with the commercial tablets in a bioequivalence in vivo study in human volunteers. ResultsTranscutol P, PEG 200 and PEG 400 were chosen as it achieved the highest DAP. HCl solubility and due to their water miscibility. Transcutol P gave the highest flux among the selected cosolvents due to its permeation enhancing properties. Mixing Transcutol P with water gave exceptional results as the binary mixture of 60% Transcutol in water gave a higher flux than pure Transcutol P. The gel formula gave an AUC0-∞ (1644.5 ± 50.2 ng h/ml) higher than the one form that tablet product (901.26 ± 30.02 ng h/ml). And the relative bioavailability of the buccal gel was 547% As compared to the oral tablet product. Surprisingly, the gel formulation gave a sustained concentration of DAP. HCl over a period of 5 h. ConclusionCombining these findings with the permeation data, it can be suggested that supersaturation and transcutol P helped in the formation of DAP. HCl depot sites inside the buccal mucosa. This could help in the future to formulate dosage forms that can form drug depot sites inside buccal mucosa for sustained drug action.

Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers

Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.

Mechanisms of white mustard seed (Sinapis alba L.) volatile oils as transdermal penetration enhancers

We investigated the transdermal drug permeation enhancement properties and associated mechanisms of white mustard (Sinapis alba L.) seed volatile oil (SVO). Using gas chromatography–mass spectrometry, we showed that SVO was composed primarily of allylisothiocyanate and isothiocyanatocyclopropane. Compared with azone, SVO had better penetration-enhancing effects on three model drugs (5-Fluorouracil, Osthole, and Paeonol), with each having different oil-water partition coefficients. Histopathology showed that SVO did not induce skin irritation when the concentration was lower than 2% (v/v), and it induced less irritation than azone. According to attenuated total reflection-Fourier transform infrared spectroscopy and transmission electron microscopy, SVO induced skin lipid structural disorder and increased the distance between the stratum corneum, which is beneficial to the penetration of drugs. Cellular experiments showed that SVO inhibited Ca2+-ATPase activity, increased intracellular Ca2+ concentration, and changed the membrane potential in HaCaT cells, which promoted drug transfer into the skin. Our findings reveal that SVO is a safe and efficient natural product that has great potential as skin penetration enhancer.

Glyceryl ester surfactants: Promising excipients to enhance the cell permeating properties of SEDDS

AimThe aim of the study is the evaluation of the impact of glyceryl ester surfactants on cell permeating properties of SEDDS (self-emulsifying drug delivery systems). MethodsSEDDS containing the glyceryl ester surfactants polyglyceryl-3-stearate (TGlysurf9), polyglyceryl-5-oleate (TGlysurf11.5) and glyceryl stearate citrate (TGlysurf12) were prepared and characterized regarding droplet size and zeta potential. Toxicity studies were performed on Caco-2 cells using resazuring assay. The formulations were loaded with fluorescein diacetate (FDA) and curcumin, and cell uptake studies on Caco-2 cells were performed. Cell uptake was visualized via real time live confocal microscopy. Cell permeability of the SEDDS was tested and trans-epithelial electrical resistance (TEER) measurements were performed. Furthermore, the anti-proliferative and anti-migration activity of curcumin loaded in the SEEDS was investigated. ResultsThe developed SEDDS (0.05% m/v) showed no cytotoxicity on Caco-2 cells after 3 h of incubation. Glyceryl esters-SEDDS showed a significant higher FDA and curcumin cell uptake than SEDDS without glyceryl ester surfactants (p < 0.05). TGlysurf9-SEDDS showed thereby the most pronounced permeation enhancing properties. TEER remained constant during the permeation study. Curcumin loaded in TGlysurf9-SEDDS exhibited 1.9-fold higher anti-proliferative effect than curcumin loaded in SEDDS without glyceryl ester surfactants. Furthermore, curcumin loaded in glyceryl ester-SEDDS inhibited Caco-2 cells migration to a higher extent than unloaded curcumin and curcumin loaded in SEDDS without the glyceryl ester surfactants. ConclusionsGlyceryl ester surfactants and in particular polyglyceryl-3-stearate might be a promising excipient for the formulation of SEDDS exhibiting enhanced cellular uptake and permeation enhancing properties.