Cumulative Permeation Research Articles

Designing a unique feedback mechanism for hydrogel-forming microneedle array patches: a concept study

Although microneedle array patch (MAP) technology is reaching ever closer to regulatory approval, it remains imperative that approaches to further improve patient acceptance are still explored. Addressing this perception, a water-filled reservoir was incorporated into a hydrogel-forming MAP system to provide a novel feedback mechanism. To confirm successful MAP skin insertion, the end user would both hear and feel the rupture of the water-filled reservoir. Interestingly, a 50-µL water-filled reservoir ruptured at 30.27 ± 0.39 N, which has previously been shown as the mean application force for MN insertion in human subjects following appropriate instruction. Importantly, no significant difference in % cumulative permeation of FITC-dextran 10 kDa and fluorescein sodium after 24 h was observed between a 50-µL reservoir and the current method of application that has been successfully used in both in vitro and in vivo studies (p > 0.05). Therefore, as drug delivery was not affected, this proof-of-concept study has shown that a water-filled reservoir feedback mechanism has the potential to serve as a viable tool for consistent MAP skin insertion.Graphical abstract

Fabrication and development of controlled release PLGA microneedles for macromolecular delivery using FITC-Dextran as model molecule

The use of biodegradable polymers has been prominent in the field of drug delivery due to its degradability and biocompatible properties. These polymers when used to prepare microneedles, impart high mechanical strength, sustained drug release profile, and long term biocompatibility. In this study, PLGA (poly (D, L-lactic co-glycolic acid)) and PVA (Polyvinyl Alcohol) were used in combination to optimize the microneedle fabrication for high molecular weight FITC Dextran (4 kDa MW) to be used as a model drug. FITC-Dextran loaded PLGA microneedles were fabricated using a mold casting technique. MNs were characterized for the textural properties, FITC-Dextran release profile, and in-vitro permeation profile. The fate of microneedles in the skin (ex vivo) was characterized using fluorescence and confocal imaging. The FITC -Dextran MNs (10 × 10 array) had a dimension of 415 ± 2.65 μm height, 207 ± 1.63 μm width of the base and a needle pitch of 463 ± 1.45 μm. The texture analysis data showed puncture force for FITC-Dextran loaded PLGA microneedles (28.46 ± 0.23 g) and PLGA microneedles (16.92 ± 0.04 g). The Cumulative permeation of FITC-Dextran after 48 h was 2.34 ± 0.40 μg/cm2 and it showed a 31 fold higher permeation profile than its respective control. Ex vivo imaging studies were used to characterize the fluorescence intensity of FITC-Dextran in the skin. This study demonstrates that incorporating higher molecular weight molecules into PLGA microneedles proved to be an effective strategy to sustain the release of macromolecules across stratum corneum/epidermis for transdermal delivery.

Development and Characterization of n-Propyl Gallate Encapsulated Solid Lipid Nanoparticles-Loaded Hydrogel for Intranasal Delivery.

The objective of the present study was to develop n-propyl gallate-loaded solid lipid nanoparticles (PG-SLNs) in a hydrogel (HG) formulation using Transcutol-P (TC-P) as a permeation enhancer. Modified solvent injection technique was applied to produce optimized PG-SLNs via the Quality by Design approach and central composite design. The in vitro mucoadhesion, scavenging activity, drug release, permeation studies of PG from PG-SLNs-loaded HG were evaluated under simulated nasal conditions. Compared with in vitro release behavior of PG from SLNs, the drug release from the PG-SLNs-loaded HG showed a lower burst effect and sustained release profile. The cumulative permeation of PG from PG-SLNs-loaded HG with TC-P was 600 μg/cm2 within 60 min, which is 3–60-fold higher than PG-SLNs and native PG, respectively. Raman mapping showed that the distribution of PG-SLNs was more concentrated in HG having lower concentrations of hyaluronic acid. The scavenging assay demonstrated increased antioxidant activity at higher concentrations of HG. Due to enhanced stability and mucoadhesive properties, the developed HG-based SLNs can improve nasal absorption by increasing residence time on nasal mucosa. This study provides in vitro proof of the potential of combining the advantages of SLNs and HG for the intranasal delivery of antioxidants.

Acid-base combination principles for preparation of anti-acne dissolving microneedles loaded with azelaic acid and matrine

To overcome the poor solubility, skin irritation, and low permeability of azelaic acid (AZA) existed on the marketed formulations, a co-drug principle via matrine (MAT) was adopted to prepare anti-acne dissolving microneedles (DMNs). The formula was optimized according to the solubility and antibacterial activity of novel ionic salt. The results indicated solubilization of AZA could be achieved at a molar ratio between AZA and MAT was 1:1. Meanwhile, synergistic antibacterial and anti-irritative properties were acquired. The matrix materials were composed of sodium carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP), and trehalose. And drug loadings of AZA and MAT in DMNs were 201.88 ± 4.81 µg and 259.71 ± 1.72 µg, respectively. After insertion into porcine skin for 10 h, the cumulative permeability of AZA and MAT were 68.16% ± 3.79% and 57.37 ± 5.17%, respectively, while just 4.13 ± 0.39% (p < 0.01) was detected for commercially available AZA gel. In vitro antibacterial experiment, bacteriostatic rates of DMNs were all above 95% for Staphylococcus aureus, Staphylococcus epidermidis, and Propionibacterium acnes. Besides, DMNs exhibited no cytotoxicity and skin irritation. In conclusion, combination between AZA and MAT addressed shortcomings of AZA, and made it easier, safer, and more effective in acne treatment.

Formulation by Design (FbD) approach to develop pharmaceutically amended Diclofenac Sodium hydrogel as compared to marketed gel

The aim of the present study was to develop pharmaceutically better performing Diclofenac Sodium hydrogel through FbD approaches as compared to marketed gel. The quality target product profile was set for the critical quality attributes of the gel. The key material variables like Carbopol 934P, propylene glycol and Triethanolamine (TEA) were optimized using design of experiments. A response surface central composite design was used considering viscosity, pH and cumulative percentage permeation of the drug up to 120 min as responses. TEA had a significant effect on the pH at concentrations of 0.3182-3.6818% (w/w). The applicability of the optimized formulations was influenced by both Carbopol 934P (0.6591-2.3409%; w/w) and propylene glycol (PG; 6.591-23.409%; w/w) content due to their ability to alter the formulation viscosity. The optimized formulation, determined mathematically, contained 1.5% (w/w) Carbopol 934P. 2.0% (w/w) TEA and 15% (w/w) PG. The optimized hydrogel and marketed gel were evaluated for viscosity, spreadability, skin irritation, homogeneity and grittiness, texture analysis, in vitro release and ex vivo permeation studies. When these evaluation parameters were compared with a marketed gel in respect of all the evaluating tests, the optimized hydrogel was found to be far better formulation than the marketed one.

Nanoemulgel for Improved Topical Delivery of Desonide: Formulation Design and Characterization.

This research aimed to develop a novel drug delivery system to improve treatment of skin disorders. The system is comprised of a Carbopol 980-based nanoemulgel (NE-gel) containing a desonide (DES; 0.05%, w/w) nanoemulsion (NE), which has a small particle size, high encapsulation efficiency, good thermodynamic stability, good permeation ability, and high skin retention. DES-loaded NE (DES-NE) was prepared by high-pressure homogenization. The developed formulation was characterized by differential scanning calorimetry (DSC), X-ray diffraction, drug release, skin permeation, and drug retention. DES in vitro release and skin permeation studies with different formulations of artificial membrane and rat abdominal skin were performed with the Franz diffusion cell system. Confocal laser scanning microscopy(CLSM) was used to detect the localization and permeation pathways of drugs in the skin. Compared with commercially available gel (CA-gel) and NE, the NE-gel release process conformed to the Higuchi release model (R2 = 0.9813). NE-gel prolonged the drug release time and allowed for reduced administration dose and frequency. The unit cumulative permeation of NE and NE-gel through the skin for 12 h was 63.13 ± 2.78 and 42.53 ± 2.06 μg/cm2, respectively, values significantly higher (p < 0.01) than that of the CA-gel (30.65 ± 1.25 μg/cm2) and CA-cream (15.21 ± 0.97 μg/cm2). The DES-NE and DES NE-gel skin drug retention was significantly higher than commercially available formulations (p < 0.01). Hence, the prepared NE-gel is a potential vehicle for improved topical DES delivery for better treatment of skin disorders.

Investigating the Potential of Transdermal Delivery of Avanafil Using Vitamin E-TPGS Based Mixed Micelles Loaded Films.

To avoid the first-pass metabolism of avanafil (AVA) and its altered absorption in the presence of food after oral administration, this study aimed to investigate the potential of TPGS-based mixed micelle (MM)-loaded film for transdermal delivery and the enhancement of bioavailability. A Box–Behnken design was employed to optimize the permeation behavior of AVA from the transdermal film across the skin. The variables were the hydrophile-lipophile balance (HLB) of the surfactant (X1), the concentration of mixed micelles (MMs) in the film (X2), and the concentration of the permeation enhancer (X3). The initial permeation of AVA after 1 h (Y1), and the cumulative permeation of AVA after 24 h (Y2) were the dependent variables. Ex vivo studies were carried out on freshly isolated rat skin to investigate the drug’s permeation potential and results were visualized using a fluorescence laser microscope. Moreover, the pharmacokinetic behavior after a single application on male Wistar rats, in comparison with films loaded with raw AVA, was evaluated. The results showed that the optimum factor levels were 9.4% for the HLB of the surfactant used, and 5.12% MMs and 2.99% penetration enhancer in the film. Imaging with a fluorescence laser microscope indicated the ability of the optimized film to deliver the payload to deeper skin layers. Furthermore, optimized AVA-loaded TPGS-micelles film showed a significant increase (p < 0.05) in the Cmax of AVA and the area under the AVA plasma curve (approximately three-fold). The optimized AVA-loaded TPGS-MM film thus represents a successful delivery system for enhancing the bioavailability of AVA.

Dermal Delivery of Niacinamide-In Vivo Studies.

In vivo human studies are considered to be the “gold standard” when investigating (trans)dermal delivery of actives. Previously, we reported the effects of a range of vehicles on the delivery of niacinamide (NIA) using conventional Franz cell studies. In the present work, dermal delivery of NIA was investigated in vivo in human subjects using confocal Raman spectroscopy (CRS) and tape stripping (TS). The vehicles investigated included propylene glycol (PG), Transcutol® P (TC), binary combinations of PG with oleic acid (OA) or linolenic acid (LA) and a ternary system comprising of TC, caprylic/capric triglyceride (CCT) and dimethyl isosorbide (DMI). For the CRS studies, higher area under curve (AUC) values for NIA were observed for the PG:LA binary system compared with PG, TC and TC:CCT:DMI (p < 0.05). A very good correlation was found between the in vitro cumulative permeation of NIA and the AUC values from Raman intensity depth profiles, with a Pearson correlation coefficient (R2) of 0.84. In addition, an excellent correlation (R2 = 0.97) was evident for the signal of the solvent PG and the active. CRS was also shown to discriminate between NIA in solution versus crystalline NIA. The findings confirm that CRS is emerging as a powerful approach for dermatopharmacokinetic studies of both actives and excipients in human.

Demonstration of Age‐Related Increases in Blood‐Brain Barrier Permeability and Microvascular Rarefaction in the Mouse Cerebral Cortex by Longitudinal Intravital Two‐Photon Microscopy and Optical Coherence Tomography (OCT)

Age-related blood-brain barrier disruption and cerebromicrovascular rarefaction contribute importantly to the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Recent advances in geroscience research enable development of novel interventions to reverse age-related alterations of the cerebral microcirculation for prevention of VCID and AD. To facilitate this research there is an urgent need for sensitive and easy-to-adapt imaging methods, which enable longitudinal assessment of changes in BBB permeability and brain capillarization in aged mice, that could be used in vivo to evaluate treatment efficiency. To enable longitudinal assessment of changes in BBB permeability in aged mice equipped with a chronic cranial window, we adapted and optimized two different intravital two-photon imaging approaches. By assessing relative fluorescence changes over the baseline within a volume of brain tissue, after qualitative image subtraction of the brain microvasculature, we confirmed that in 24 month old C57BL/6J mice cumulative permeability of the microvessels to fluorescent tracers of different molecular weights (0.3 kDa to 40 kDa) is significantly increased as compared to that of 5 month old mice. Real-time recording of vessel cross-sections showed that apparent solute permeability of single microvessels is significantly increased in aged mice vs. young mice. Cortical capillary density, assessed both by intravital two-photon microscopy and optical coherence tomography (OCT) was also decreased in aged mice vs. young mice. The presented methods have been optimized for longitudinal (over the period of 36 weeks) in vivo assessment of cerebromicrovascular health in preclinical geroscience research.

Dosage-efficacy relationship and pharmacodynamics validation of brucine dissolving microneedles against rheumatoid arthritis

This study aims to define an optimal dosage and to investigate the therapeutic effects of brucine dissolving microneedles (Bru-DMNs) on rheumatoid arthritis (RA). Composite PVP K30 and CS were selected as needle tip materials, single PVA as a backing material, and brucine (Bru) as the drug of this model. Bru-DMNs were successfully fabricated by a two-step centrifugation method. The DMNs produced satisfactory mechanical strength and biocompatibility, and the needle body was completely dissolved in approximately 10 min. After microneedle (MN) administration, the skin recovered to its original state within 6 h free of irritation. The transdermal test in vitro revealed that the skin transmittance of Bru could be significantly improved by MN administration. Drug load in the MN was released after 6 h, with cumulative permeability at 94.84%. To define the optimal dosage of Bru-DMNs for RA, the present study established an RA rat model and administered different concentrations of Bru solution or suspension. The optimal dosage of MN production (approximately 124.50 g/patch) was determined when Bru concentration was at 16 mg/mL. Further pharmacodynamics exploration revealed that drug loading MN effectively inhibited toe swelling of RA rats, reduced synovial hyperplasia due to articular cartilage erosion, and diminished swelling in the thymus and spleen. Network pharmacological analysis demonstrated that Bru might play a role in the RA treatment by regulating TNF-ɑ, IL-17and IL-1β. This regulation pathway was verified by ELISA and western blot assays.

In Vitro-In Vivo Correlation in Dermal Delivery: The Role of Excipients.

The composition of topical and transdermal formulations is known to determine the rate and the extent of drug delivery to and through the skin. However, to date, the role of excipients in these formulations on skin delivery of actives has received little attention from scientists in the field. Monitoring skin absorption of both drug and vehicle may provide insights into the mechanism by which excipients promote permeation and may facilitate the design of effective and safer products. Previously, we have investigated the use of quantitative Confocal Raman Spectroscopy (CRS) to investigate the delivery of an active to the skin, and we also reported the first fully quantitative study that compared this method with the well-established in vitro permeation test (IVPT) model. To further explore the potential of quantitative CRS in assessing topical delivery, the present work investigated the effects of commonly used excipients on the percutaneous absorption of a model drug, ibuprofen (IBU). Permeation of IBU and selected solvents following finite dose applications to human skin was determined in vitro and in vivo by Franz diffusion studies and quantitative CRS, respectively. The solvents used were propylene glycol (PG), dipropylene glycol (DPG), tripropylene glycol (TPG), and polyethylene glycol 300 (PEG 300). Overall, the cumulative amounts of IBU that permeated at 24 h in vitro were similar for PG, DPG, and TPG (p > 0.05). These three vehicles outperformed PEG 300 (p < 0.05) in terms of drug delivery. Concerning the vehicles, the rank order for in vitro skin permeation was DPG ≥ PG > TPG, while PEG 300 did not permeate the skin. A linear relationship between maximum vehicle and IBU flux in vitro was found, with a correlation coefficient (R2) of 0.95. When comparing in vitro with in vivo data, a positive in vitro–in vivo (IVIV) correlation between the cumulative permeation of IBU in vitro and the total amount of IBU that penetrated the stratum corneum (SC) in vivo was observed, with a Pearson correlation coefficient (R2) of 0.90. A strong IVIV correlation, R2 = 0.82, was found following the linear regression of the cumulative number of solvents permeated in vitro and the corresponding skin uptake in vivo measured with CRS. This is the first study to correlate in vivo permeation of solvents measured by CRS with data obtained by in vitro diffusion studies. The IVIV correlations suggest that CRS is a powerful tool for profiling drug and vehicle delivery from dermal formulations. Future studies will examine additional excipients with varying physicochemical properties. Ultimately, these findings are expected to lead to new approaches for the design, evaluation, and optimization of formulations that target actives to and through the skin.

Effect of continuous and multi-phasic current profiles on the iontophoretic transport of pramipexole, rasagiline and huperzine A: Depicting temporal variation and biodistribution in the skin

Transdermal iontophoresis is an interesting option for the non-invasive controlled delivery of therapeutic agents to treat neurodegenerative diseases. The current profile controls drug delivery kinetics and enables complex drug input profiles to be obtained. The aim of this study was to investigate the temporal variation in transport of pramipexole (PRA), rasagiline (RAS) and huperzine A (HUP) using continuous and multi-phasic current profiles by measuring cumulative permeation, transdermal flux and drug retention in the skin upon modulation of the applied current profile during a single experiment in vitro. Initial experiments with continuous current were conducted to establish a correlation between total delivery of PRA, RAS and HUP (i.e. sum of the cumulative permeation and skin deposition) and the amount of charge transferred. Subsequent experiments with multi-phasic current profiles, confirmed that the relationship between amounts of charge transferred and total delivery was able to predict the total delivery of each drug. Experimental values were within ± 15% of the predicted values. Current density and duration of current application were also shown to have a significant impact on the skin biodistribution of PRA. These results also provide insight into the rate of formation of iontophoretic drug reservoirs in the skin.

Optimization of valencene containing lipid vesicles for boosting the transungual delivery of itraconazole.

The objective of the present study was to prepare valencene (sesquiterpene) containing invasomes for itraconazole (ITZ) transungual delivery using central composite design. The phospholipid (X 1) and valencene (X 2) were selected as an independent variables, while vesicles size (Y 1), entrapment efficiency (Y 2) and in vitro drug release (Y 3) were chosen as dependent variables. The antifungal activity of optimized formulation was screened against Trichophyton rubrum, a common causative onychomycosis pathogen, by cup plate method. The optimized ITZ-loaded invasomes formulation presented vesicles size of 176.8 ± 6.03nm, entrapment efficiency of 83.21 ± 4.11% and in vitro drug release of 75.22 ± 5.03%. The ITZ-loaded invasomes gel formulation showed good homogeneity, pH 6.5 ± 0.23, viscosity 7.33 ± 0.67Pas and drug content 94.13 ± 1.13%. The spreadability and extrudability of developed ITZ-loaded invasomes gel were found to be 7.85 ± 0.24gcm/s and 162 ± 2.74g, respectively. The ITZ-loaded invasomes gel presented 71.11 ± 3.65% cumulative permeation of drug via goat hooves. The in vitro antifungal activity depicted that the ITZ-loaded invasomes gel and marketed preparation were presented zone of inhibition of 21.42mm and 10.64mm against T. rubrum respectively. Hence the prepared ITZ-loaded invasomes formulation could therefore be a promising topical dosage to mitigate the indications and hasten the cure for onychomycosis than conventional available therapies.

Transdermal Transport In Vitro of Domperidone by Compartmental Modeling Approach

Transdermal delivery can be alternatively chosen for domperidone to improve its low oral bioavailability. Development drugs into transdermal formulation need information about the transport mechanism of the drug. The purpose of this study was to develop models of domperidone transdermal transport in vitro based on compartmental modeling for understanding the domperidone transport mechanism. Domperidone solution (0,5 g/L in a citric buffer, pH 5) was filled into the donor compartment. The comparative study also conducted to examine the effect of different pH on domperidone transdermal transport in pH 1 (4g/L in 0,1 M HCl). The shed snake-skin and cellophane membrane were pretreated for 1 hour with chemical enhancers (oleic acid in propylene glycol) and assembled between the donor and the receptor compartment of the vertical diffusion cell. The receptor compartment was filled in with phosphate-buffered saline at a pH of 6.8. The permeation study was performed for 8 hours.&#x0D; Samples concentration was assayed by the UV-Spectrophotometry method. The cumulative permeation profiles of domperidone were analyzed using WinSAAM. Three and four-compartmental models were proposed with the one lag compartment. The evaluation of the appropriate number of compartments in the transport model was examined based on the visual goodness of fit (GOF) and the Corrected Akaike’s Information Criterion (AICc) values. Four-compartmental models with one lag compartment were the best model describing percutaneous domperidone transport either in pH donor of 5 or pH 1. The model indicates domperidone transport follows into two parallel routes, including a lag compartment.

Formulation development, Ex vivo evaluation and In vivo antihypertensive study of losartan potassium loaded nanoproniosomal gel: A novel vesicular approach for transdermal delivery

The transdermal nanoproniosomal gel of Losartan potassium was prepared to treat hypertension that is efficient to deliver the encapsulated drug over extended periods and to provide better bioavailability. In the present study, the nanoproniosomal gel of Losartan potassium was formulated by Lecithin, Cholesterol, Non-ionic surfactants using the Coacervation-phase separation method. The physical mixture of drug, lecithin, and cholesterol were subjected to compatibility study using FTIR spectroscopy. The prepared nanoproniosomal gels were subjected to various evaluation parameters like the determination of pH and viscosity, vesicle size analysis, rate of spontaneity, entrapment efficiency, zeta potential, ex vivo skin permeation studies, skin irritation test, stability studies and in vivo antihypertensive studies. The physical characterization of nanoproniosomal gels was found to be within the acceptable limits. The ex vivo skin permeation studies showed the cumulative permeation of 47.25% to 82.49% through the albino rat skin in 24 hrs for all the formulations which indicate the zero-order drug permeation with diffusion, non-fickian release as the possible mechanisms of drug release. Among all formulations, NLPG2 was selected as best formulation because it showed better characteristics than other formulations in several aspects like entrapment efficiency, vesicle size, ex vivo permeation studies, zeta potential, stability studies, and other evaluation parameters. The selected formulation NLPG2 showed the highest transdermal flux (28.67μg/cm2/h), with an enhancement ratio of 2.87 when compared to other formulations. In vivo antihypertensive study revealed that the formulation NLPG2 was successful to regress the rat BP to normal values in experimental hypertensive rats. Finally, it could be concluded that the formulation NLPG2 accentuates the flux of Losartan potassium and is an efficient transdermal therapeutic system for the delivery of a drug. The nanoproniosomal gels are suitable for once a day controlled release formulation.

Glove performance in a warming climate: The role of glove material and climate on permeation resistance to organophosphate insecticides

Hands and forearms are the principal sites of dermal exposure to organophosphate insecticides, which makes glove use one of the most important components of an exposure control strategy. However, the selection of suitable gloves depends on issues such as task, type, and concentration of organophosphate as well as cost. In addition, chemical protection performance of gloves may be temperature dependent, which is of increasing concern in a warming climate. Two recommended reusable glove materials (polyvinylchloride and nitrile butadiene rubber) and one single-use glove (nitrile/neoprene) were tested for permeation resistance to actual formulations of organophosphate insecticides with active ingredients dimethoate and malathion. Chemical resistance parameters were measured using American society for testing and materials permeation test cells and compared across glove, organophosphate type, and temperature. The three gloves demonstrated comparable and adequate chemical resistance (less than one µg cm−2 min−1 for up to 8 hr exposure; 25–60 °C) for dilute forms of dimethoate and malathion, used during spraying activities. However, the single-use nitrile/neoprene glove is not designed to fully cover the elbow which limits its suitability. In permeation tests that reflect “worst case” exposure scenario to concentrated (neat) organophosphate formulations, as in mixing/loading tasks, a significant variation in chemical resistance between gloves was observed. While polyvinylchloride offered the maximum resistance, physical degradation of nitrile butadiene rubber after 3 hr of continuous exposure makes it unsuitable for handling neat dimethoate. The single-use nitrile/neoprene glove material had considerably poorer permeation resistance (up to 155-fold greater permeation and 6-fold shorter breakthrough) against neat formulations. Overall, elevated temperature (>40 °C) was shown to result in significantly greater (P < 0.05) cumulative permeation of neat formulation insecticides. This work demonstrates the variation in glove performance and potential for greater exposure risk particularly when mixing concentrated pesticides at elevated temperature conditions such as an occluded human skin or hot greenhouses. Training and guidance on testing, selection, use, and storage of gloves should consider in-use exposure scenarios and temperature-induced reduction in chemical protective performance.

Development and Evaluation of Astaxanthin as Nanostructure Lipid Carriers in Topical Delivery.

The study is designed to formulate, optimize, and evaluate astaxanthin (ASTA)-loaded nanostructured lipid carrier (NLC) with an aim to improve its stability, water solubility, skin permeability and retention and reduce drug-related side effects. ASTA was extracted from Haematococcus pluvialis. ASTA-NLC was formulated by the technique of melt emulsification-ultrasonic and optimized taking solid:liquid lipid ratio, total lipid:drug ratio, drug concentration, emulsifier types, and amounts as independent variables with particle sizes (PS) and entrapment efficiency (EE) as dependent variables. The optimized formulation (N21) exhibited spherical surfaced stable nanoparticles of 67.4 ± 2.1nm size and 94.3 ± 0.5% EE. Formulation N21 was then evaluated for its physiological properties, physicochemical properties, drug content, in vitro release and skin penetration, and retention analysis. The ASTA-NLC was found to be nonirritating, homogenous, and with excellent stability and water solubility. In vitro release studies showed the cumulative release rate of NLC was 83.0 ± 3.4% at 48h. The skin penetration and retention studies indicated that cumulative permeability was 174.10 ± 4.38μg/cm2 and the retention was 8.00 ± 1.62μg/cm2 within 24h. It can be concluded that NLC serves as a promising carrier for site specific targeting with better stability and skin penetration.

Specific protein-protein interactions limit the cutaneous iontophoretic transport of interferon beta-1b and a poly-Arg interferon beta-1b analogue.

The first objective was to investigate the transdermal iontophoresis of interferon beta 1b (IFN); the second was to determine whether the addition of 10 Arg residues at the N-terminus, creating a highly charged poly-Arg analogue (Arg10-IFN), increased delivery. Cumulative permeation of IFN and Arg10-IFN after iontophoresis at 0.5mA/cm2 for 8h was 6.97±4.82 and 9.55±1.63ng/cm2, respectively - i.e. >1000-fold less than that of ribonuclease A, cytochrome c and human basic fibroblast growth factor. Co-iontophoresis of acetaminophen showed that, in contrast to lysozyme, neither IFN nor Arg10-IFN interacted with skin to decrease convective solvent flow. Furthermore, there was no statistically significant difference between (i) iontophoretic delivery of IFN across intact or laser porated skin and (ii) passive or iontophoretic delivery of IFN across laser porated skin. Chromatographic characterisation supported the hypothesis that IFN was bound strongly to albumin. The formation of a ~86kDa complex with albumin was probably responsible for the poor cutaneous delivery of IFN/Arg10-IFN despite the use of iontophoresis and/or laser microporation. Biopharmaceuticals might interact with specific proteins during iontophoretic transport and so decrease their (per)cutaneous delivery without affecting electroosmotic solvent flow, which is usually considered as a reliable marker to report on permeant binding during electrotransport across the skin.

Preparation and quality evaluation of a volatile oil microemulsion from Flos magnoliae and Centipeda minima.

In order to improve the water solubility of the volatile oils extracted from Flos magnoliae (FM) and Centipeda minima (CM), they were prepared as a microemulsion (ME), which were then used in the development of an FM and CM volatile oil ME for the treatment of allergic rhinitis (AR). ME was prepared by phase inversion emulsification, and the prescription factors such as emulsifier, co-emulsifier, oil phase, Km, which represents the ratio of the mass of emulsifier to that of the co-emulsifier, and preparation factors such as temperature affecting the formation of the ME were selected according to the formation area of ME in a pseudo-ternary phase diagram. The quality of the ME was evaluated based on its appearance, particle size, Zeta potential and stability. The content of eucalyptol in ME was determined by gas chromatography-mass spectrometry (GC-MS). The cumulative permeability of the ME within 24 h was measured with a transdermal diffusion tester. The results revealed that the best formula for preparation of the ME was as follows: Castor oil polyoxyethylene ether (EL-40) was the emulsifier; the co-emulsifier was anhydrous ethanol; the Km was 2:1; the mixed phase of volatile oil and isopropyl myristate with mass ratio of 1:1 was used as oil phase; and the preparation temperature was 25°C. The content of eucalyptol in the ME was 2.57 mg/g, and the cumulative permeability of the ME in 24 h was significantly increased compared with that of the reference oil solution. The appearance of the ME was uniform, and the solution was transparent. In conclusion, compared with traditional preparations, FM and CM volatile oil ME is a novel, improved and more effective preparation for the treatment of AR.

Borneol-mediated vardenafil hydrochloride patch for pediatric pulmonary arterial hypertension: Preparation, characterization and in vivo study.

Pediatric pulmonary arterial hypertension (PPAH) is a malignant progressive rare disease characterized by restricted pulmonary artery blood flow and progressively increasing blood pressure, which has shorter survival time of only about 10months as compared to adults. Previous studies have shown that low-dose vardenafil hydrochloride (Var) could significantly improve the symptoms of PPAH. However, Var is currently available only in tablet form in the market for erectile dysfunction, and no special preparation is available for PPAH. In this study, borneol-mediated vardenafil hydrochloride patch (BO-VarP) with sodium polyacrylate as the skeleton material was prepared by coating method, which was characterized by temperature resistance, formability, adhesive force, skin irritation and in vitro permeation. Blood concentration of optimized BO-VarP was measured by LC-MS/MS using intragastric administration (i.g.) as a control, and pharmacodynamic studies were conducted using a rat model of pulmonary arterial hypertension induced by monocrotaline. Optimized BO-VarP showed good appearance, with optimal temperature resistance and formability, appropriate adhesive force and low skin irritation, and its cumulative permeation flux was 14.9 times higher than patch without penetration enhancer. The blood concentration within therapeutic window of BO-VarP lasted longer than i.g., and BO-VarP could improve symptoms of PPAH by reducing pulmonary arterial pressure and right heart hypertrophy index. BO-VarP had good therapeutic effect in PPAH rats and suitable compliance in children, which provided a potential industrial transdermal delivery system for the treatment of PPAH.