Sonophoresis enhances the skin penetration of 5-aminolevulinic acid: A promising pretreatment for photodynamic therapy.

5-aminolevulinic acid (5-ALA) has a poor penetrance of the skin with topical application, which reduces the efficacy of photodynamic therapy (PDT). Sonophoresis involves the use of sound waves or ultrasonic energy to enhance the topical or transdermal delivery of drugs. The purpose of this study was to investigate the effects of sonophoresis on the penetration of 5-ALA into the skin. We calculated in vitro transdermal accumulation of ALA, and the fluorescence images were collected for analysis. The cumulative amount of 5-ALA that penetrated the skin with sonophoresis increased over time and was significantly larger than that without sonophoresis (p < 0.01). With 5% 5-ALA and sonophoresis, the distinct localization of 5-ALA-PpIX in sebaceous glands started to appear 30 min after 5-ALA application, which is much earlier than with 5% 5-ALA only. For all incubation times, fluorescence intensities distributing in sebaceous glands were significantly higher in sonophoresis treated than non-sonophoresis treated skin (p < 0.05). Sonophoresis could be a technique of choice for enhancing the production of 5-ALA-induced PpIX and improving the efficacy of 5-ALA-based PDT, which may decrease the treatment time, lower the cost of therapy and enhance the clinical improvement, allowing many more patients to be treated.

Sonophoresis with ultrasound-responsive liquid-core nuclei for transdermal drug delivery.

BACKGROUND: Sonophoresis can increase the delivery efficiency of various drugs into the skin. A recent advance in sonophoresis is the use of ultrasound-responsive liquid-core nuclei (URLN) to increase the probability of cavitation. In this study, we developed a URLN and ultrasound device, and demonstrated its effectiveness through in vitro and clinical tests. MATERIALS AND METHODS: Three types of experiments were designed to evaluate the efficiency of sonophoresis with URLN. First, a Franz diffusion cell with cosmetic ingredients was used to analyze quantitatively the amount of drug delivered to the porcine skin. Second, after the application of sonophoresis with URLN, the porcine skin surface was examined using scanning electron microscopy (SEM) to see the changes in morphology. Finally, a clinical test was performed to verify the utility of sonophoresis with URLN. RESULTS: The results indicate that sonophoresis with URLN can increase the amount of compound delivered by approximately 11.9-fold over 6 h for niacinamide and by 7.33-fold over 6 h for adenosine. In addition, we observed approximately 20-30 µm sized pores on porcine skin in SEM images. In clinical testing, the application of sonophoresis with cosmetics containing URLN for 3 min improved the efficiency of transdermal drug delivery by 1.9-fold, the depth of absorption by 2.0-fold, and the speed of absorption by 2.0-fold at 30 min after application. CONCLUSION: We expect that sonophoresis with specialized URLN in transdermal drug delivery could be used widely for various skin-related applications.

Microneedle system: a modulated approach for penetration enhancement.

The microneedles show advantages over transdermal drug delivery systems on account of better skin permeation bypassing the stratum corneum. To increase the flux of permeation, penetration enhancement techniques like physical and chemical methods are combined with a trans-epidermal delivery system across the skin causing minimal pain. These techniques include iontophoresis, sonophoresis, and electroporation for physical enhancement of drug delivery via topical route by either disrupting the structure of the stratum corneum or by creating pores/micro-channels within the skin. The use of chemical penetrants such as ethanol, lipids, surfactants, and terpenes improves the release kinetics by mechanisms like fluidization of lipids, denaturation of proteins, etc. A combination of microneedles and these techniques show a significant increase in the permeability of drugs across the skin by 5-10 times compared to microneedles alone. This review article focuses on various advanced strategies like the use of drug-polymer complexes, application of ultrasound frequency or tolerable electric current, formation of nano-formulations, etc. with microneedle delivery for transportation of high payload of actives, macromolecules, antibodies, gene, proteins, and peptides. In the near future, microneedle systems will offer potential targeted drug delivery, self-sealable administration across the skin, and minimally invasive vaccine transportation in cancer, diabetes, Alzheimer's, and cardiovascular diseases.HighlightsPhysical penetration enhancement techniques: iontophoresis, electroporation, and sonophoresis.Chemical penetration enhancers: polymers, lipids, surfactants.Strategies to use microneedle system with penetration enhancement techniques.The significant difference in the penetration ability of high payload actives.

Low-Frequency Sonophoresis as an Active Approach to Potentiate the Transdermal Delivery of Agomelatine-Loaded Novasomes: Design, Optimization, and Pharmacokinetic Profiling in Rabbits.

The first melatonergic antidepressant drug, agomelatine (AGM), is commonly used for controlling major depressive disorders. AGM suffers low (< 5%) oral bioavailability owing to the hepatic metabolism. The current work investigated the potential of low-frequency sonophoresis on enhancing transdermal delivery of AGM-loaded novasomes and, hence, bioavailability of AGM. Drug-loaded novasomes were developed using free fatty acid (stearic acid or oleic acid), surfactant (span 60 or span 80), and cholesterol via thin-film hydration technique. The systems (N1-N16) were assessed for zeta potential (ZP), particle size (PS), encapsulation efficiency (EE%), and drug percent released after 0.5 h (Q0.5 h) and 8 h (Q8h), drug-crystallinity, morphology, and ex vivo drug permeation. Skin pre-treatment with low-frequency ultrasound (LFU) waves, via N13-novasomal gel systems, was optimized to enhance ex vivo drug permeation. Influences of LFU mode (continuous or pulsed), duty cycle (50% or 100%), and application period (10 or 15 min) were optimized. The pharmacokinetics of the optimized system (N13-LFU-C4) was assessed in rabbits. N13 was the best achieved novasomal system with respect to PS (471.6 nm), ZP (- 63.6 mv), EE% (60.5%), Q0.5 h (27.8%), Q8h (83.9%), flux (15.5 µg/cm2/h), and enhancement ratio (6.9). N13-LFU-C4 was the optimized novasomal gel system (desirability; 0.997) which involves skin pre-treatment with LFU in a continuous mode, at 100% duty cycle, for 15 min. Compared to AGM dispersion, the significantly (P < 0.05) higher flux (26.7 µg/cm2/h), enhancement ratio (11.9), Cmax (118.23 ng/mL), and relative bioavailability (≈ 8.6 folds) could elucidate the potential of N13-LFU-C4 system in improving transdermal drug permeability and bioavailability.

Monitoring the topical delivery of ultrasmall gold nanoparticles using optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) is a promising imaging modality for skin cancer diagnosis. However, this capability has been hindered by the low contrast between normal and neoplastic tissue. To overcome this limitation, gold nanoparticles have been used to enhance the contrast in OCT images and are topically administered to reduce the risk of systematic side effects associated with intravenous injection. To ensure efficient penetration and distribution of the nanoparticles, an enhanced delivery strategy is required. In this porcine study, we assessed two delivery methods: (a) using dimethyl sulfoxide (DMSO) and (b) via sonophoresis. MATERIALS AND METHODS: The gold nanoparticles were topically applied on pig skin before evaluating DMSO and sonophoresis as penetration enhancers in topical administration. The OCT images were taken from the same locations to monitor signal change. CONCLUSION: The combination of DMSO and sonophoresis is an effective method to enhance the penetration and diffusion rate of nanoparticles during topical administration. SIGNIFICANCE: Topical administration of nanoparticles is advantageous in dermatological applications. Nevertheless, efficient topical delivery remains a challenge. DMSO and sonophoresis can be used as two effective approaches to enhance topical delivery of nanoparticles.

Potential of Sonophoresis as a Skin Penetration Technique in the Treatment of Rheumatoid Arthritis with Transdermal Patch.

Rheumatoid arthritis, a chronic disorder, limits the use of chemical penetration enhancers for a prolonged period of time. Moreover, systemic routes of administration of the first-line drug, methotrexate, have shown undesirable systemic as well as local side effects. The objective of this research was to overcome the limitations associated with treatment of rheumatoid arthritis by utilizing three physical transdermal penetration enhancement techniques namely cold-laser, electroporation, and sonophoresis to deliver methotrexate. Methotrexate patch was prepared using solvent casting method and the ex-vivo release of methotrexate in combination with three physical penetration enhancers (sonophoresis, electroporation, and cold laser) were studied. The best technique was employed in pre-clinical testing in arthritic and control groups of male Wistar rats excluding remaining two techniques. The comparative ex-vivo studies showed that the penetration enhancement of methotrexate is maximum by sonophoresis followed by electroporation and cold laser (sonophoresis > electroporation > cold laser). In pharmacodynamic studies, the reduction in diameter of injected and non-injected paw on day 5 and day 21 for group 4 (ultrasound pre-treated group) was higher as compared to group 3 (group receiving only methotrexate patch). The motility score and the reduction in pain were significantly improved for group 4 than group 3 on both day 5 and day 21 (P Ë‚ 0.05) which confirmed the faster recovery of animals of group 4 due to penetration enhancement of methotrexate patch by ultrasound treatment. From the results, it can be concluded that sonophoresis along with methotrexate patch has shown a significant effect in the treatment of rheumatoid arthritis.

Enhanced Transdermal Drug Delivery by Sonophoresis and Simultaneous Application of Sonophoresis and Iontophoresis.

Transdermal drug delivery has advantages of topical drug administration compared to the other conventional administration methods. However, the skin penetration of drugs is limited by the barrier properties of stratum corneum. The combinational strategy has been investigated to improve the skin permeability of the drug. For this study, we devised an improved device that can perform not only the single application of sonophoresis or iontophoresis but also the simultaneous application. The enhancement effect of sonophoresis was evaluated for various cosmeceutical drugs using a Franz diffusion cell. The enhancement ratio of niacinamide and retinol with sonophoresis was increased to 402% and 292%, respectively. The relationship was found between the enhancement effect of sonophoresis and the physicochemical properties of drugs. In particular, the simultaneous treatment of sonophoresis and iontophoresis enhanced skin penetration of glutamic acid to 240% using the fabricated device. The simultaneous application showed significantly higher enhancement ratio than application of sonophoresis or iontophoresis alone. Moreover, the improved device achieved skin penetration enhancement of various cosmeceutical drugs with lower intensity and a short application time. This combined strategy of transdermal physical enhancement methods is advantageous in terms of decline in energy density, thereby reducing the skin irritation. The miniaturized device with sonophoresis and iontophoresis is a promising approach due to enhanced transdermal drug delivery and feasibility of self-administration in cosmetic and therapeutic fields.

Enhancement of Galantamine HBr Skin Permeation Using Sonophoresis and Limonene-Containing PEGylated Liposomes.

This study aimed to investigate the effect of low-frequency sonophoresis (SN) and limonene-containing PEGylated liposomes (PL) on the transdermal delivery of galantamine HBr (GLT). To evaluate the skin penetration mechanism, confocal laser scanning microscopy (CLSM), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) were employed. The application of SN led to more GLT penetration into and through the skin than GLT solution alone. The liposomes also improved GLT permeation, and 2% limonene-containing PL (PL-LI2%) exhibited the highest GLT permeation, followed by PL-LI1%, PL-LI0.1%, and PL. The CLSM images of PL-LI2% resulted in the highest fluorescence intensity of fluorescent hydrophilic molecules in the deep skin layer, and the rhodamine PE-labeled liposome membrane was distributed in the intercellular region of the stratum corneum (SC). PL-LI2% induced significant changes in intercellular lipids in the SC, whereas SN had no effect on intercellular lipids of the SC. DSC thermograms showed that the greatest decrease in the lipid transition temperature occurred in PL-LI2%-treated SC. SN might improve drug permeation through an intracellular pathway, while limonene-containing liposomes play an important role in delivering GLT through an intercellular pathway by increasing the fluidity of intercellular lipids in the SC. Moreover, a small vesicle size and high membrane fluidity might enhance the transportation of intact vesicles through the skin.

Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy.

Biological systems are exquisitely sensitive to the location and timing of physiologic cues and drugs. This spatiotemporal sensitivity presents opportunities for developing new therapeutic approaches. Polymer-based delivery systems are used extensively for attaining localized, sustained release of bioactive molecules. However, these devices typically are designed to achieve a constant rate of release. We hypothesized that it would be possible to create digital drug release, which could be accelerated and then switched back off, on demand, by applying ultrasound to disrupt ionically cross-linked hydrogels. We demonstrated that ultrasound does not permanently damage these materials but enables nearly digital release of small molecules, proteins, and condensed oligonucleotides. Parallel in vitro studies demonstrated that the concept of applying temporally short, high-dose "bursts" of drug exposure could be applied to enhance the toxicity of mitoxantrone toward breast cancer cells. We thus used the hydrogel system in vivo to treat xenograft tumors with mitoxantrone, and found that daily ultrasound-stimulated drug release substantially reduced tumor growth compared with sustained drug release alone. This approach of digital drug release likely will be applicable to a broad variety of polymers and bioactive molecules, and is a potentially useful tool for studying how the timing of factor delivery controls cell fate in vivo.

Comparative analysis of the effects of CO2 fractional laser and sonophoresis on human skin penetration with 5-aminolevulinic acid.

Successful delivery of a photosensitizer into the skin is an important factor for effective photodynamic therapy (PDT). The effective method to increase drug penetration within short incubation time overcoming skin barrier have been investigated. This study was performed to analyze and compare the effectiveness of ablative fractional laser (FXL) pretreatment and/or sonophoresis for enhancing the penetration of 5-aminolevulinic acid (ALA) into human skin in vivo. Twenty-four identical 1 × 1 cm2 treatment areas were mapped on the backs of ten healthy male subjects. Each area received FXL pretreatment and/or sonophoresis with different energy settings and ALA incubation times. After treatments, porphyrin fluorescence reflecting the ALA penetration were measured. Application of ablative CO2 FXL pretreatment resulted to higher fluorescence intensities than the non-treatment group. Incubation times were positively correlated with the increments of ALA penetration. However, increasing pulse energy or combining with sonophoresis did not show additional positive effects on ALA penetration. Ablative CO2 FXL pretreatment effectively facilitated ALA penetration in human skin in vivo. Ablative CO2 FXL alone without sonophoresis setting pulse energy of 10 and 20 mJ with more than 60 min of ALA incubation time could be an ideal setting for ALA penetration.

Recent progress in transdermal sonophoresis.

Transdermal drug administration has a number of advantages that cannot be leveraged for therapeutic benefits because of the robust barrier provided by the stratum corneum. One of the promising techniques for circumventing the stratum corneum is sonophoresis - the use of ultrasound for facilitating transdermal drug delivery. In this review, the mechanisms underlying sonophoresis and the utilization of the technique for transdermal delivery are discussed. The challenges of this mode of drug administration have also been highlighted and insight from a number of toxicological studies is described.

Influence of sonophoresis on transdermal drug delivery of hydrophilic compound-loaded lipid nanocarriers.

The effect of sonophoresis on the transdermal drug delivery of sodium fluorescein (NaFI)-loaded lipid nanocarriers such as liposomes (LI), niosomes (NI) and solid lipid nanoparticles (SLN) was investigated by confocal laser scanning microscopy (CLSM), fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The results showed that SN decreased the skin penetration of NaFI-loaded SLN (6.32-fold) and NI (1.79-fold), while it increased the penetration of NaFI-loaded LI (5.36-fold). CLSM images showed the red fluorescence of the LI and NI bilayer on the superficial layer of the stratum corneum. However, the red fluorescent probe of the SLN was not visualized in the skin. FTIR results of the LI and NI with SN showed no effect on lipid stratum corneum ordering, suggesting that the fragment of bilayer vesicles might repair the damaged skin. For SLN, the strengthening of stratum corneum by covering the disrupted skin with solid lipids was shown. SEM images show disrupted carriers of all the formulations adsorbed onto the damaged skin. In conclusion, the SN changed the properties of both the skin surface and lipid nanocarrier, demonstrating that disrupted skin might be repaired by a disrupted nanocarrier.

Treatment of striae distensae with needling therapy versus microdermabrasion with sonophoresis.

UNLABELLED: Striae distensae (SD) is a challenging cosmetic problem for which various treatment modalities have been applied. Our aim was to evaluate the efficacy and tolerability of needling therapy versus microdermabrasion with sonophoresis in the treatment of SD. MATERIALS AND METHODS: Forty female patients with SD (mean duration 2.98 ± 2.66) were enrolled in this study. Patients were assigned to two groups, Group 1 treated with needling therapy and Group 2 treated by microdermabrasion with sonophoresis. In Group 1, three sessions of needling therapy were performed for each patient with 4-week interval between the sessions, while in Group 2, ten sessions of combined microdermabrasion and sonophoresis were performed for each patient. Skin biopsies were taken from the most atrophic site stained with hematoxylin and eosin stain and Masson trichrome stains to study the histopathological changes and efficacy of treatment, respectively. RESULTS: There was a significant clinical improvement in SD in Group 1 compared with Group 2. Amount of collagen, number of fibroblasts, and epidermal thickness increased in the dermis at the end of treatment sessions (90% in Group 1 compared to 50% in Group 2). CONCLUSION: Needling therapy is an easy, safe, and economic method and considered as a suitable modality in management of striae.

Efficacy of 694-nm fractional Q-switched ruby laser (QSRL) combined with sonophoresis on levorotatory vitamin C for treatment of melasma in Chinese patients.

Melasma is a common acquired and distressing pigmentary disorder presenting to dermatology clinics. It is notably difficult to cure and has a tendency to relapse. The efficacy of classical Q-switched laser in treatment of melasma remains controversial. This study aims to investigate the efficacy and safety of 694-nm fractional QSRL combined with sonophoresis on levorotatory vitamin C for the treatment of melasma patients. Twenty-six patients with melasma were enrolled. Each patient received four to six fractional QSRL treatments at pulse energies of 2.5 to 4 J/cm(2) combined with sonophoresis on levorotatory vitamin C at 2-week intervals. The severity and the area of melasma were assessed by two investigators using the melasma area and severity index (MASI). Side effects were documented. Mean MASI score decreased from 15.51 ± 3.00 before treatment to 10.02 ± 4.39 3 months after the final treatment (P < 0.01). Side effects were few and transient. High-density coverage fractional QSRL combined with sonophoresis on levorotatory vitamin C is safe and effective for the treatment of melasma in Chinese patients.

Fractional radiofrequency combined with sonophoresis to facilitate skin penetration of 5-aminolevulinic acid.

Ablative fractional technology has been used to improve transdermal drug delivery. However, there have been few previous in vivo investigations of the relative potency and methodology of fractional radiofrequency (RF) combined with sonophoresis. The purpose of this study was to investigate the effects of fractional RF combined with sonophoresis on 5-aminolevulinic acid (ALA) penetration of the skin. Three male domestic swine were used. The skin of the pigs was exposed to fractional RF and/or sonophoresis, followed by topical ALA application. Fluorescence intensity (FI) of porphyrin fluorescence was measured. In both the epidermis and the dermis, FI increased after fractional RF and increased additionally with the addition of sonophoresis. Fractional RF with sonophoresis effectively enhanced ALA skin penetration. Pre-fractional RF followed by posttreatment with sonophoresis can be used for ALA-photodynamic therapy to achieve higher ALA uptake.

Effect of ultrasound and heat on percutaneous absorption of l-ascorbic acid: human in vitro studies on Franz cell and Petri dish systems.

OBJECTIVE: Percutaneous absorption of l-ascorbic acid (LAA) is limited due to its high hydrophilicity and low stability. Here, we investigated the effect of post-dosing sonophoresis (329 kHz, 20 mW cm-2 ) and heat (36°C) on transdermal delivery of LAA. METHODS: Ultrasound/heat, heat and control treatments were applied on skin surface for 2 and 5 min after topical application of C14-labelled LAA aqueous solution. After 15 min post-exposure, radioactivity was measured in tape-striped stratum corneum (TS-SC), epidermis, dermis and receptor fluid. As Franz diffusion cell model may have different acoustic response than in vivo human tissues, a novel Petri dish model was developed and compared with Franz cell model on the effects of ultrasound/heat treatment on the skin permeability. RESULTS: Five-min ultrasound/heat treatment significantly accelerated skin absorption/penetration of LAA; 2-min treatment showed no enhancement effect on Franz diffusion cell model at the end of experiment. The use of Petri dish model significantly increased LAA concentrations in epidermis after 5 min of ultrasound/heat treatment, compared to the results of Franz cell model. CONCLUSION: Combination of ultrasound (329 kHz, 20 mW cm-2 ) and heat (36°C) significantly enhanced LAA transdermal penetration, when the time of treatment was sufficient (5 min). As Petri dish model was designed to simulate acoustic respond of dense human tissue to ultrasound, the difference between Franz cell and Petri dish models suggests that the enhancement effect of ultrasound/heat on skin penetration in vivo may be greater than that determined on in vitro Franz cell model.

Influence of sonophoresis and chemical penetration enhancers on percutaneous transport of penbutolol sulfate.

The effect of ultrasound and chemical penetration enhancers on transcutaneous flux of penbutolol sulfate across split-thickness porcine skin was investigated. Penbutolol sulfate is a potent, noncardioselective beta-blocker, which is used for the management of hypertension. The drug is one of the most lipid soluble of the ß-adrenoceptor antagonists used clinically. It has an n-octanol/pH 7.4 buffer partition coefficient of 179 compared to a value of 22 for propranolol. The amount of penbutolol sulfate transported across the skin is low. In this project, we studied the effect of sonophoresis and chemical penetration enhancers on transdermal delivery of penbutolol sulfate. Low-frequency sonophoresis at a frequency of 20 kHz increased transcutaneous flux of penbutolol sulfate by 3.5-fold (27.37 ± µg cm-2 h-1) compared to passive delivery (7.82 ± 1.72 µg cm-2 h-1). We also investigated the effect of 50% ethanol, 1% limonene and 2% isopropyl myristate (IPM) on transcutaneous permeation of penbutolol sulfate. IPM, ethanol and limonene at the concentration of 1%, 50% and 2%, respectively, increased the steady-state flux values of penbutolol sulfate 2.2- (17.07 ± 3.24 µg cm-2 h-1), 2.6 - (19.40 ± 6.40 µg cm-2 h-1) and 3.4-times (26.38 ± 5.01 µg cm-2 h-1) compared to passive delivery (7.76 ± 2.9 µg cm-2 h-1). The results demonstrate that although there were slight increases in flux values, ultrasound, ethanol, limonene and IPM did not significantly enhance the transdermal delivery of penbutolol sulfate. Future studies will examine ways of optimizing sonophoretic and chemical enhancer parameters to achieve flux enhancement.

Quantitative evaluation of sonophoresis efficiency and its dependence on sonication parameters and particle size.

Transdermal drug delivery makes a critical contribution to medical practice and some advantages over conventional oral administration and hypodermic injection. Enhancement of percutaneous absorption or penetration of therapeutic agents (ie, drugs and macromolecules) by ultrasound, termed sonophoresis, has been applied and studied for decades. In this study, the penetration percentage through porcine ear skin specimens was determined quantitatively by measuring the fluorescence from nanoparticles of 60, 220, and 840 nm in size in a receptor chamber at different sonication parameters (ie, duty cycle, 20%-100%; acoustic intensity, 0.3-1.0 W/cm(2); duration, 7-30 minutes; and frequency, 1 MHz). In general, the sonophoresis efficiency increased with the acoustic intensity, duty cycle, and sonication duration but decreased with the particle size (mean ± SD, 62.6% ± 5.4% for 60-nm versus 11.9% ± 1.1% for 840-nm polystyrene nanospheres after 30 minutes of sonication at 0.5 W/cm(2) and a 100% duty cycle; P < .05). On scanning electron microscopy the pore size remained the same (≈100 µm), but more flakes were observed with the progress of sonication. In summary, sonophoresis efficiency is dependent on the ultrasound parameters and particle size. Sufficient sonication would lead to satisfactory penetration of even submicrometer objects through the pores.

Topical anesthesia.

Topical anesthetics are being widely used in numerous medical and surgical sub-specialties such as anesthesia, ophthalmology, otorhinolaryngology, dentistry, urology, and aesthetic surgery. They cause superficial loss of pain sensation after direct application. Their delivery and effectiveness can be enhanced by using free bases; by increasing the drug concentration, lowering the melting point; by using physical and chemical permeation enhancers and lipid delivery vesicles. Various topical anesthetic agents available for use are eutectic mixture of local anesthetics, ELA-max, lidocaine, epinephrine, tetracaine, bupivanor, 4% tetracaine, benzocaine, proparacaine, Betacaine-LA, topicaine, lidoderm, S-caine patch™ and local anesthetic peel. While using them, careful attention must be paid to their pharmacology, area and duration of application, age and weight of the patients and possible side-effects.

Sonophoresis mediated diffusion of caffeine loaded Transcutol® enriched cerosomes for topical management of cellulite.

The goal of this research was to augment the deposition of caffeine loaded Transcutol® enriched cerosomes (TECs) gel for efficient topical treatment of cellulite utilizing the sonophoresis technique. Caffeine-loaded TECs were prepared using thin film hydration method applying 23 factorial design to study the impact of different factors, each with two levels on the entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of the formulated TECs. The studied factors were cetyl trimethyl ammonium bromide (CTAB) amount (mg) (X1), phosphatidylcholine (PC) amount (mg) (X2), and Transcutol® amount (mg) (X3). Design-Expert® software was utilized to determine the optimum TECs formulation. Afterward, the optimum TECs formulation was loaded into a gel and subjected to extra investigations. The optimum TECs formulation was (TEC5) which was prepared using 10 mg of CTAB, 150 mg of PC, and 10 mg of Transcutol®. TEC5 presented EE% of 87.44 ± 0.14 %, PS of 308.60 ± 13.38 nm, PDI of 0.455 ± 0.030, and ZP of 50.20 ± 1.55 mV. TEC5 had a fiber-like morphology, with elongated tubules of ceramide. Further, the optimum TECs formulation showed a high stability profile. Moreover, an in vivo dermatokinetic study showed superior deposition of caffeine from TEC5 gel coupled with the sonophoresis on rat skin compared to TEC5 gel and caffeine gel. Moreover, the histopathological study of TEC5 on rat skin confirmed the non-irritant nature of TEC 5 gel mediated by ultrasonic waves through the skin. Overall, the outcomes exposed the obvious superiority of sonophoresis delivered TECs-gel for topical delivery of caffeine for cellulite management.