Promising Transdermal Delivery System Research Articles

Improving the stability and transdermal permeability of phycocyanin loaded cubosomes

Instability and low transdermal permeability of protein antioxidants are major obstacles to resist oxidative stress in transdermal drug delivery system. To overcome these shortcomings, cubosomes were developed as an advanced transdermal delivery system to improve stability and transdermal absorption of the model antioxidant phycocyanin in this study. Glyceryl monooleate and poloxamer 407 (P407) were used to prepare cubosomes as carrier matrix and stabilizer, respectively. Phycocyanin loaded cubosomes (PC-cubosomes) were prepared by the emulsification and homogenization method. A 33 full factorial design was used to optimize the cubosome formulations. The final optimal PC-cubosomes possessed an average particle size of 183.2 ± 0.5 nm and a negative surface charge as well as achieved a high encapsulation efficiency of 87.2% ± 2.7%. PC-cubosomes appeared as nano-sized and well-shaped spheres with highly ordered cubical structures. The residual amount of phycocyanin in PC-cubosomes was 3-fold higher than that in the free drug solution after 10 days ultraviolet radiation exposure. In vitro release kinetics of phycocyanin from PC-cubosomes fitted to the Higuchi kinetic model, indicating that phycocyanin released from cubosomes mainly attributed to drug diffusion and dissolution. PC-cubosomes also exhibited higher permeability (39.79 μg⋅cm−2⋅hour−1) across the rat skin than phycocyanin solution (16.33 μg⋅cm−2⋅hour−1). Furthermore, PC-cubosomes were easily taken up by keratinocytes, thereby achieving a prolonged anti-oxidative stress effect. These results therefore suggested that cubosomes could be a promising transdermal delivery system to improve the stability and transdermal permeability of phycocyanin.

State of the Art in Constructing Gas-Propelled Dissolving Microneedles for Significantly Enhanced Drug-Loading and Delivery Efficiency.

Dissolving microneedles (MNs) have emerged as a promising transdermal delivery system, as they integrate the advantages of both injection and transdermal preparations. However, the low drug-loading and limited transdermal delivery efficiency of MNs severely hinder their clinical applications. Microparticle-embedded gas-propelled MNs were developed to simultaneously improve drug-loading and transdermal delivery efficiency. The effects of mold production technologies, micromolding technologies, and formulation parameters on the quality of gas-propelled MNs were systematically studied. Three-dimensional printing technology was found to prepare male mold with the highest accuracy, while female mold made from the silica gel with smaller Shore hardness could obtain a higher demolding needle percentage (DNP). Vacuum micromolding with optimized pressure was superior to centrifugation micromolding in preparing gas-propelled MNs with significantly improved DNP and morphology. Moreover, the gas-propelled MNs could achieve the highest DNP and intact needles by selecting polyvinylpyrrolidone K30 (PVP K30), polyvinyl alcohol (PVA), and potassium carbonate (K2CO3): citric acid (CA) = 0.15:0.15 (w/w) as the needle skeleton material, drug particle carrier, and pneumatic initiators, respectively. Moreover, the gas-propelled MNs showed a 1.35-fold drug loading of the free drug-loaded MNs and 1.19-fold cumulative transdermal permeability of the passive MNs. Therefore, this study provides detailed guidance for preparing MNs with high productivity, drug loading, and delivery efficiency.

QBD based Design and Characterization of Proniosomal Transdermal Delivery of Atenolol and Glibenclamide Combination: An Innovative Approach

There are numerous circumstances where chronic disease is associated with other disorders, especially in diseases like diabetes with noncommunicable disease risk factors, such as hypertension. This study shows a novel and innovative combinational proniosomal delivery of combination to beat the reactions by complex therapeutic regimen, and to improve patient compliance after controlling combinational transdermal delivery of Glibenclamide (GLB) and Atenolol (ATN) which have not been tried actually. To achieve the above reason, proniosomes were prepared and optimized utilizing Box-Behnken design. The ideal formulation was chosen by a point prediction method and formulation showed vesicle size of 562 ± 1.223 nm, entrapment efficiency of GLB & ATN 97.037 ± 1.43% and 96.230 ± 1.62% respectively which were found in concurrence with the predicted value. The optimized combinational proniosomal gel (OCPG) formulation was additionally assessed for in vitro drug release, In vitro drug permeation, and in vivo pharmacokinetic study. The OCPG formulation shows the greatest flux over the rabbit skin (128.609 ± 2.24 mg/cm2/h and 322.054 ± 1.53 mg/ cm2/h) of GLB and ATN respectively. The results indicated desired release and permeation profiles. OCPG showed significantly (p < 0.001) pharmacokinetic contemplate exhibited that transdermal proniosomal formulation demonstrated improvement in bioavailability of two drugs 129.30 and 174.62 times respectively as that of the oral formulation. Overall the results show that controlled release GLB and ATN provesicles offer a useful and promising transdermal delivery system for the treatment of type II diabetes and hypertension by using design. Henceforth this may be an achievement in treating diabetic hypertensive patient.

Design and optimization of nano invasomal gel of Glibenclamide and Atenolol combination: in vitro and in vivo evaluation

BackgroundThere are many circumstances where chronic disease is associated with other disorders, especially in diseases such as diabetes with noncommunicable disease risk factors, such as hypertension. The current therapies for treating such chronic comorbid diseases are limited and challenging due to the difficulties in overcoming the side effects from complex therapeutic treatment regimen. The present study is aimed to develop and optimize the combinational nano invasomal gel of Glibenclamide (GLB) and Atenolol (ATN) as a novel combination therapy for comorbid treatment of diabetic hypertensive patients. The developed formulations were characterized for various parameters, including in-vitro skin permeation, skin irritation, in-vivo antidiabetic, and antihypertensive activities.ResultsOCNIG showed that the % entrapment efficiency of GLB is 96.67 ± 0.65% and % entrapment efficiency of ATN is 93.76 ± 0.89%, flux of GLB (240.43 ± 1.76 μg/cm2/h), and flux of ATN (475.2 ± 1.54 μg/cm2/h) which was found to conform to the expected value. The results indicated desired release and permeation profiles. Optimized formulation showed significant pharmacokinetic properties, which shows improvement in bioavailability by 134.30% and 180.32% respectively for two drugs, when compared to marketed oral preparation. Pharmacodynamic studies showed improved and prolonged management of diabetes and hypertension in Wistar rats, compared to oral and drug-loaded nano invasomes formulations.ConclusionOverall, the results showed that nano invasomal gel was found to be a useful and promising transdermal delivery system for the treatment of concurrent diseases.

Central composite design for the development of carvedilol-loaded transdermal ethosomal hydrogel for extended and enhanced anti-hypertensive effect

BackgroundCarvedilol, the anti-hypertensive drug, has poor bioavailability when administered orally. Ethosomes-mediated transdermal delivery is considered a potential route of administration to increase the bioavailability of carvedilol. The central composite design could be used as a tool to optimize ethosomal formulation. Thus, this study aims to optimize carvedilol-loaded ethosomes using central composite design, followed by incorporation of synthesized ethosomes into hydrogels for transdermal delivery of carvedilol.ResultsThe optimized carvedilol-loaded ethosomes were spherical in shape. The optimized ethosomes had mean particle size of 130 ± 1.72 nm, entrapment efficiency of 99.12 ± 2.96%, cumulative drug release of 97.89 ± 3.7%, zeta potential of − 31 ± 1.8 mV, and polydispersity index of 0.230 ± 0.03. The in-vitro drug release showed sustained release of carvedilol from ethosomes and ethosomal hydrogel. Compared to free carvedilol-loaded hydrogel, the ethosomal gel showed increased penetration of carvedilol through the skin. Moreover, ethosomal hydrogels showed a gradual reduction in blood pressure for 24 h in rats.ConclusionsTaken together, central composite design can be used for successful optimization of carvedilol-loaded ethosomes formulation, which can serve as the promising transdermal delivery system for carvedilol. Moreover the carvedilol-loaded ethosomal gel can extend the anti-hypertensive effect of carvedilol for a longer time, as compared to free carvedilol, suggesting its therapeutic potential in future clinics.

PRONIOSOMAL GEL MEDIATED TRANSDERMAL DELIVERY OF GLIBENCLAMIDE AND ATENOLOL COMBINATION: EXVIVO AND PHARMACODYNAMIC STUDIES

Objective: The objective of the present work was to develop an optimized dosage form for treating comorbidity in combination and evaluate it for its pharmacodynamic performance in male Wistar albino rats.&#x0D; Methods: Transdermal proniosomal gel for Combination of Glibenclamide (GLB) and Atenolol (ATN) was developed and optimized by Box Behnken design. This optimized combinational proniosomal gel (OCPG), which was selected by a point prediction method, was evaluated for its ex vivo, skin irritation studies and pharmacodynamic activities of both drugs in rats in comparison with its oral therapy.&#x0D; Results: The ex-vivo permeation behavior through different skins was studied and the findings were also confirmed by the values of the steady-state flux (Jss). The OCPG observed an increase of more than twice in the cumulative amount of impregnated drugs compared to pure drug films. The study on skin irritation revealed the non-irritability of the developed OCPG applied. OCPG significantly showed sustained hypoglycemic activity in rats (p&lt;0.001), when compared to orally treat animals up to 24 h. Systolic blood pressure (SBP) lowering effect of OCPG was found to be significant (p&lt;0.02), when compared to orally treat rats up to 24 h. However, the reduction was slow and sustained in the case of OPCG where a significant response was observed in the performed studies.&#x0D; Conclusion: Overall, the results show that controlled release GLB and ATN proniosomes offer a useful and promising transdermal delivery system. Henceforth this may be an achievement in treating the diabetic hypertensive patient.

Curcumin-Loaded Nanoemulsion for Better Cellular Permeation

Curcumin nanoemulsion was prepared using coconut oil, Tween 80 (surfactant) and polyethylene glycol (co-solvent) with the addition of honey and glycerol as additives. The nanoemulsion was optimized and systematically characterized for transdermal delivery. Small particle size (15.92 nm), low polydispersity index (0.17) and slight acidic (pH 4.18) curcumin nanoemulsion was obtained without any chemical degradation based on the Fourier transform infrared (FTIR) spectrum. The incorporation of curcumin inside nanoglobul improved curcumin stability and skin permeability. Its high permeability can be seen from Nile dyed curcumin in different layers of skin through fluorescent imaging. The release kinetic of curcumin followed the Higuchi model, which explains why the skin permeation was a Fickian diffusion-controlled process because the Korsmeyer constant was proven to be 0.3 (&lt;0.5). Nanoencapsulation slightly decreased the antioxidant capacity of curcumin for about 7.9% compared to its free counterpart. It showed low cytotoxicity (EC50 2.3552 µg/mL) to human skin fibroblasts. Cell death was noticed at a high concentration (2.5 µg/mL) of treatment. Curcumin was also found to promote wound closure at low concentration 0.1563 µg/mL and was comparable with the performance of ascorbic acid based on scratch assay. Therefore, this nutritious curcumin nanoemulsion is a promising transdermal delivery system for topical application.

RETRACTED: Pluronic® F127 stabilized reduced graphene oxide hydrogel for transdermal delivery of ondansetron: Ex vivo and animal studies

Ondansetron which is used to manage vertigo, nausea and vomiting suffer from the major limitations of low oral bioavailability (60 %) and short half-life (3-4 h), which affects the routine life style of patients (noncompliance due to multiple dosing). The present work aim to developed ondansetron loaded Pluronic® F127 stabilized reduced graphene oxide hydrogel (2 % Carbopol 940 base) as a promising transdermal delivery system, capable of sustaining and tailoring the drug release profile. The fourier transform infrared spectroscopy, raman spectroscopy, and X-ray diffraction reports confirm the attachment of Pluronic® F127 on the reduced graphene oxide. The scanning electron microscopy image showed the wrinkled and flattened nano-sheet surface with the presence of Pluronic F127 micelles. The hydrogel showed sufficient mechanical properties (texture analysis) for topical application. The ex vivo permeation data suggest that the flux decreased proportionally (due to π- π stacking interaction) with increase in the level of graphene oxide in the hydrogel, which indicate that the drug release rate can be tailored by changing the level of graphene oxide in the hydrogel. The high area under the curve, mean residence time and 2.89 fold increased in the bioavailability (rat model) suggest the potential of ondansetron loaded Pluronic® F127-graphene oxide hydrogel to sustain the release of ondansetron to manage vertigo, nausea and vomiting.

Amifostine-loaded armored dissolving microneedles for long-term prevention of ionizing radiation-induced injury

Amifostine is a cytoprotective agent against the hematopoietic damage induced by ionizing radiation, although the intravenous injection of amifostine is a unique administration method with strict dosing time limitation. Hence, the fields of application of amifostine are greatly limited. Here, we developed an amifostine-loaded armored microneedle (AAMN) with long-term prevention of hematopoietic injury induced by ionizing radiation. First, amifostine-loaded hyaluronic acid microneedles (AMNs) were fabricated, and the AMNs were then dipped in an N-vinyl-2-pyrrolidone (NVP) solution followed by ultraviolet (UV) photocuring to obtain AAMNs. AAMNs were nail-shaped with much higher mechanical strength compared to the conical shape and weak strength of AMNs, which was verified by their in silico simulation. In the in vitro release experiment, more than 55% of amifostine was released from AAMNs within 10 min, and 95% was released in 60 min. Drug skin permeation of AAMNs was also high, at twice that of AMNs. AAMNs provided long-term protection of the hematopoietic system from radiation within 3−7 h pre-radiation compared to the unique amifostine injection 0.5 h pre-radiation because topical application of AAMNs led to the long-term maintenance of the in vivo effective drug concentration. More importantly, AAMNs led to the survival of all irradiated mice due to intravenous amifostine. AAMNs are a promising transdermal delivery system of amifostine for long-term protection against ionizing radiation-induced injury. Statement of SignificanceAn amifostine-loaded dissolving armored microneedle (AAMN) patch is developed for long-term prevention of ionizing radiation-induced injury. High drug loads in microneedles (MNs) with adequate mechanical strength is a challenge. We fabricated armors on the surface of high amifostine-loaded hyaluronic acid microneedles (AMNs) by dipping the tips of AMNs in N-vinyl-2-pyrrolidone (NVP) solutions and then subjecting them to UV irradiation, and high-strength armored AMNs (AAMNs) were obtained. AAMNs show deeper skin insertion and much higher drug permeation than AMNs. The controlled drug release from AAMNs in the mouse skins provides a long-term protection of radiation-induced injury with 3−7 h administration pre-radiation compared to the merely 0.5-h point of amifostine injection.

Amifostine-Loaded Dissolving Armored Microneedles for Long-Term Prevention of Ionizing Radiation-Induced Injury

Amifostine is a cytoprotective agent against ionizing radiation-induced hematopoietic damages although the intravenous injection of amifostine is the unique way and the administration time is strictly restricted. Here we developed an amifostine-loaded dissolving armored microneedle (AAMN) patch with long-term prevention of ionizing radiation-induced injury. Amifostine-loaded hyaluronic acid microneedles (AMNs) were fabricated, dipped in N-vinyl-2-pyrrolidone (NVP) solutions and then UV irradiated to obtain AAMNs. The nail-shaped AAMNs had much higher mechanical strength than the conically shaped AMNs, which was confirmed by in silico simulation. Amifostine rapidly released from AAMNs with 95% of the cumulative release in 60 min at 37 °C due to the dissolving property of AAMNs. The drug cutaneous permeation ability of AAMNs was about two times that of AMNs due to the deeper skin insertion of the former. The controlled drug permeation of AAMNs in the skin and the long-term in vivo drug exposure provided much longer effective protection of the hematopoietic system within 3−7 h administration pre-radiation compared to the merely 0.5-h point of amifostine injection. Survival rates were ensured by AAMNs within the effective time range. Therefore, dissolving AAMNs are a promising transdermal delivery system of amifostine for long-term protection of ionizing radiation-induced injury.

Transdermal Delivery of Ondansetron Hydrochloride via Bilosomal Systems: In Vitro, Ex Vivo, and In Vivo Characterization Studies.

Ondansetron hydrochloride (OND) is commonly used for management of postoperative and chemotherapeutic-induced nausea and vomiting. It suffers from low bioavailability (60%) and rapid elimination (t1/2; 3-4h). The current work aimed to develop OND-loaded bilosomes as a promising transdermal delivery system capable of surmount drug limitations. The variables influencing the development of OND-loaded bilosomes and niosomes (18 systems) via the thin film hydration technique were investigated, including surfactant type (Span®60 or Span®80), surfactant/cholesterol molar ratio (7:0, 7:1, or 7:3), and sodium deoxycholate (SDC) concentration (0, 2.5, or 5%, w/v). The systems were characterized for particle size, polydispersity index, zeta potential, drug entrapment efficiency (EE%), and in vitro permeation. Based on factorial analysis (32·21) and calculations of desirability values, six systems were further subjected to ex vivo permeation through excised rat skin, differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), and transmission electron microscopy. Histopathological and in vivo permeation studies in rats were conducted on the best achieved system (B6) in comparison to drug solution. Higher desirability values were achieved with Span® 60-based bilosomes, surfactant/cholesterol molar ratio of 7:1, and SDC concentration of 2.5% w/v with respect to small vesicle size, polydispersity index and high zeta potential, EE%, and cumulative drug permeation. OND was dispersed in amorphous state as revealed from DSC and PXRD studies. No marked effect was observed in rat skin following application of B6 system while higher ex vivo and in vivo cumulative permeation profiles were revealed. Bilosomal systems were considered as safe and efficient carriers for the transdermal delivery for OND.

Dry Gel Containing Optimized Felodipine-Loaded Transferosomes: a Promising Transdermal Delivery System to Enhance Drug Bioavailability.

Felodipine has a very low bioavailability due to first-pass metabolism. The aim of this study was to enhance its bioavailability by transdermal application. Felodipine-loaded transferosomes were prepared by thin-film hydration using different formulation variables. An optimized formula was designed using statistical experimental design. The independent variables were the used edge activator, its molar ratio to phosphatidylcholine, and presence or absence of cholesterol. The responses were entrapment efficiency of transferosomes, their size, polydispersity index, zeta potential, and percent drug released after 8h. The optimized formula was subjected to differential scanning calorimetry studies and its stability on storage at 4°C for 6months was estimated. This formula was improved by incorporation of different permeation enhancers where ex vivo drug flux through mice skin was estimated and the best improved formula was formulated in a gel and lyophilized. The prepared gel was subjected to in vivo study using Plendil® tablets as a reference. According to the calculated desirability, the optimized transferosome formula was that containing sodium deoxycholate as edge activator at 5:1M ratio to phosphatidylcholine and no cholesterol. The thermograms of this formula indicated the incorporation of felodipine inside the prepared vesicles. None of the tested parameters differed significantly on storage. The lyophilized gel of labrasol-containing formula was chosen for in vivo study. The relative bioavailability of felodipine from the designed gel was 1.7. In conclusion, topically applied lyophilized gel containing felodipine-loaded transferosomes is a promising transdermal delivery system to enhance its bioavailability.

5-Aminolevulinic acid loaded ethosomal vesicles with high entrapment efficiency for in vitro topical transdermal delivery and photodynamic therapy of hypertrophic scars.

Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an alternative therapy for hypertrophic scars (HS), which destroys human hypertrophic scar fibroblasts (HSF). However, the poor permeability of ALA both in HS tissue and HSF significantly restricts the PDT of HS. To overcome these barriers, ALA-loaded ethosomal vesicles (ALA-ES) were developed by a pH gradient active loading method and characterized by morphology, entrapment efficiency (EE) and stability. Results show that prepared ALA-ES are homogenous spherical lamellar vesicles, 53 ± 7 nm in size, 50.6 ± 2.3% in EE and have excellent stability. In vitro transdermal delivery studies through HS tissue were carried out by using Franz diffusion cells. Compared to the traditional ALA hydroalcoholic solution (ALA-HA), ALA-ES achieve higher drug retention in less administration time, and fluorescence microscopy showed that ALA-ES penetrate into the deeper dermis of HS in a shorter time, indicating that ALA-ES can enhance the penetration of ALA into HS. Additionally, ALA-ES was visualized in HS tissue for the first time by transmission electron microscopy (TEM). The irregular and collapsed ALA-ES suggest that they can squeeze through narrow spaces to the target area and release ALA into HS. Taking HSF as the target, the transcellular delivery of ALA-ES into HSF cells was investigated by intracellular protoporphyrin IX (PpIX) accumulation. The efficiency of PDT for HSF cells, including the formation of reactive oxygen species (ROS) and cell apoptosis, were also well investigated. Furthermore, the detailed changes of HSF were observed by TEM. The results strongly indicate that ALA-ES can facilitate ALA penetration into HSF cells, and can cause a higher level of cell apoptosis or necrosis than ALA-HA. ALA-ES with high EE is therefore a promising transdermal delivery system for topical ALA administration and has great potential in ALA-PDT of HS.

Improved anti-melanoma effect of a transdermal mitoxantrone ethosome gel

Melanomas are malignant tumors characterized by early metastasis, rapid development, poor prognosis and high mortality. A highly effective and convenient method is necessary for long-term treatment of melanomas. Mitoxantrone (MTO) was topically applied for melanoma therapy using an MTO ethosome gel. Firstly, an ethosome was prepared from MTO, phospholipids, ethanol and water followed by addition of hydroxypropyl methylcellulose to obtain an ethosome gel. The ethosome was characterized. The cytotoxicity on B16 melanoma cells was evaluated on an electrical cell-substrate impedance sensing system with a novel modified chip. In vivo anti-melanoma effect of the ethosome gel was explored. Immunohistochemical and flow cytometric investigations were done. The MTO ethosomes had the size of 78nm and the zeta potential of -55mV. The ethosomes were flexible vesicles and showed much higher in vitro permeability across the rat skin than MTO aqueous solutions. The ethosomes had significant cytotoxicity and higher in vivo anti-melanoma effect than MTO solutions. The calreticulin membrane translocation of B16 cells was improved by the MTO ethosomes and the cell uptake of MTO was confirmed. The MTO ethosome gel is a promising transdermal delivery system for melanoma therapy with the advantages of non-invasion and no significant side effects.

Transfersomal lyophilized gel of buspirone HCl: formulation, evaluation and statistical optimization

Context: Buspirone HCl has very low oral bioavailability (4%) due to deactivation by extensive first pass effect. It also has very limited transdermal permeation due to its high hydrophilicity.Objective: The aim of this study was to increase the transdermal permeation of buspirone HCl utilizing a stable dosage form.Methods: Transfersomes were prepared using Tween-80 as a flexibility imparting agent to the vesicular walls. Oleic acid and/or ethanol, with different percentages, were utilized as a permeation enhancer. Formulations were characterized by analyzing particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release and ex vivo drug permeation. Factorial design (32) was planned for the optimization of formulations using Design-Expert® software. Lyophilized transfersomal gel of the optimized formulation was prepared using hydroxypropyl methylcellulose (HPMC) K100, carboxymethyl cellulose or sodium alginate with or without mannitol as a cryoprotectant. Physical characterization of the transfersomes and the lyophilized gel were carried out using transmission and scanning electron microscopy, respectively.Results: The optimized formulation (T7), containing 35% oleic acid, had the highest desirability value (0.658) with high ex vivo drug flux (43.40 µg/h/cm2) through rat skin when compared with the aqueous drug solution and formula T1 (without oleic acid). The T7 transfersomal gel containing HPMC K100 (G2) had the highest desirability value (0.640) among the lyophilized gel formulations with decreased ex vivo drug flux (38.98 µg/h/cm2) in comparison with the original transfersomal formula (T7).Conclusions: Lyophilized transfersomal gel containing oleic acid was considered as a promising transdermal delivery system for hydrophilic drugs.

Design and evaluation of a bioadhesive film for transdermal delivery of propranolol hydrochloride

The objective of the study was to develop a suitable trans-dermal delivery system for propranolol hydrochloride (PPL) via employing chitosan as a film former. Drug concentration uniformity, thickness, moisture uptake capacity and skin bioadhesion of the films were characterized. The effects of chitosan and PPL concentration and different penetration enhancers on the release and permeation profiles from the films were investigated. Skin irritation of the candidate film was evaluated. Chitosan film (PPL 2 mg cm(-2), chitosan 2%, m/m, cineol 10%, m/m) was found nonirritant and achieved 88.2% release after 8 hours in phosphate buffer. Significant high (p < 0.001) permeation of PPL through rat skin was obtained using this film compared to the film without enhancer (about 8 times enhancement factor), making it a promising trans-dermal delivery system for PPL.