Development and in vitro evaluation of pressure sensitive adhesive patch for the transdermal delivery of galantamine: Effect of penetration enhancers and crystallization inhibition.
Ameen Dina,Michniak-Kohn Bozena
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
The transdermal route offers an attractive alternative route of drug administration especially for Alzheimer's disease patients through eliminating gastrointestinal side effects and ultimately improving compliance. In this study, we prepared an optimized matrix-type patches for the transdermal delivery of galantamine free base with ex vivo and in vitro evaluation. Four pressure sensitive adhesives with different functional groups, ten penetration enhancers and four drug loadings were tested to determine the optimized patch. The ex vivo permeation of the different formulated patches through human cadaver skin using vertical Franz diffusion cells showed that GELVA GMS 788 was the best pressure sensitive adhesive among the tested polymers. FT-IR and rheological studies done to investigate any potential interactions of the polymer with the drug and/or additives showed the possibility of hydrogen bonding between the drug and pressure sensitive adhesive (PSA), also the additives had a plasticization effect causing increased flexibility of the polymer chains. The optimized formulation had 10%w/w drug loading, 5% w/w limonene as a penetration enhancer, and 5%w/w oleic acid as a crystallization inhibitor. The combination of limonene and oleic acid increased the flux of galantamine by 2.7-fold compared to 1.7-fold when limonene was used alone. The optimized patch exhibited diffusion release kinetics and fitted well to Higuchi's model and yielded a permeation rate of 32.4 ± 1.41 µg/cm/h across human cadaver skin.
10.1016/j.ejpb.2019.04.008
Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization, In Vitro Drug Release, and In Vivo Studies.
Dante Mariane de Cássia Lima,Borgheti-Cardoso Livia Neves,Fantini Marcia Carvalho de Abreu,Praça Fabíola Silva Garcia,Medina Wanessa Silva Garcia,Pierre Maria Bernadete Riemma,Lara Marilisa Guimarães
Journal of pharmaceutical sciences
Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB.
10.1016/j.xphs.2017.10.039
Nanovesicles of nitrendipine with lipid complex for transdermal delivery: pharmacokinetic and pharmacodynamic studies.
Kumar Gaur Praveen,Mishra Shikha,Purohit Suresh
Artificial cells, nanomedicine, and biotechnology
CONTEXT:Vesicular transdermal delivery can enhance the bioavailability of a drug especially affected by first-pass metabolism, e.g. nitrendipine. However effective transdermal delivery employs permeation enhancer, e.g oleic acid (OA) with ceramide 2, stearic acid, behenic acid, and cholesteryl sulfate lipid complex. OBJECTIVE:This study investigated the preparation, characterization of physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential in rats, of nitrendipine-loaded nanovesicles of ceramide 2, stearic acid, behenic acid and cholesteryl sulfate containing oleic acid gel (NOVG). MATERIALS AND METHODS:The nanovesicles were made using film hydration method and characterized for physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential. RESULTS:Nitrendipine-loaded nanovesicles of ceramide-2 containing oleic acid (NOV-5) have shown fluxes in the range of 4.88-24.72 μg/cm(2)/h nitrendipine oral suspension (NOS) at equal dose. NOVG-5 has shown almost 33% reduction in blood pressure in the first hour and a further decrease of 25% in the second hour to restore the normal pressure. DISCUSSION:The permeation increases with increase in OA content. OA gets integrated in vesicle wall and enhances its permeability, whereas ceramide content makes sure that skin does not become damaged even after permeation. CONCLUSION:NOVG-5 has shown the most favorable physicochemical properties and good permeation through skin providing good management of hypertension during crucial initial hours.
10.3109/21691401.2015.1080170
Transcutol® P/Cremophor® EL/Ethyl Oleate-Formulated Microemulsion Loaded into Hyaluronic Acid-Based Hydrogel for Improved Transdermal Delivery and Biosafety of Ibuprofen.
Zhang Yongtai,Zhang Kai,Wang Zhi,Hu Hongmei,Jing Qian,Li Yanyan,Guo Teng,Feng Nianping
AAPS PharmSciTech
In the present study, a novel transdermal delivery system was developed and its advantages were demonstrated. Ibuprofen is a commonly used anti-inflammatory, antipyretic, and analgesic drug; however, because of its short biological half-life, it must be frequently administered orally and is highly irritating to the digestive tract. To prepare a novel transdermal delivery system for ibuprofen, a microemulsion was used as a drug carrier and dispersed in a hyaluronic acid-based hydrogel (ME/Gel) to increase percutaneous drug absorption while avoiding gastrointestinal tract irritation. The prepared microemulsion had a droplet size of ~ 90 nm, and the microemulsion had good stability in the hydrogel. Rheological tests revealed that the ME/Gel is a pseudoplastic fluid with decreased viscosity and increased shear rate. It displayed a certain viscoelasticity, and the microemulsion distribution displayed minor effects on the rheological characteristics of the hydrogel system. There was no significant difference in the rheology of the ME/Gel at 25°C and 32°C (normal skin surface temperature), which is beneficial for clinical application. Drug transdermal flux was significantly higher than that of the hydrogel and commercial cream groups (p < 0.01). The 24-h cumulative drug permeation amount was 1.42-fold and 2.52-fold higher than that of the hydrogel and cream groups, respectively. By loading into the ME/Gel, the cytotoxicity of the drug to HaCaT cells was reduced. These results indicate that the prepared ME/Gel can effectively improve transdermal ibuprofen delivery and the biosafety of the drug and could therefore have applicability as a drug delivery system.
10.1208/s12249-019-1584-8
Gel-like TPGS-Based Microemulsions for Imiquimod Dermal Delivery: Role of Mesostructure on the Uptake and Distribution into the Skin.
Telò Isabella,Favero Elena Del,Cantù Laura,Frattini Noemi,Pescina Silvia,Padula Cristina,Santi Patrizia,Sonvico Fabio,Nicoli Sara
Molecular pharmaceutics
The aim of this work was to develop an innovative microemulsion with gel-like properties for the cutaneous delivery of imiquimod, an immunostimulant drug employed for the treatment of cutaneous infections and neoplastic conditions. A pseudoternary phase diagram was built using a 1/1 TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate)/Transcutol mixture as surfactant system, and oleic acid as oil phase. Eight microemulsions-selected from the 1.25/8.75 oil/surfactants ratio, along the water dilution line (from 20 to 56% w/w)-were characterized in terms of rheological behavior, optical properties via polarized microscopy, and supramolecular structure using X-ray scattering. Then, these formulations were loaded with imiquimod and the uptake and distribution into the skin was evaluated on full-thickness porcine skin. X-ray scattering experiments revealed the presence of disconnected drops in the case of microemulsion with 20% water content. Diluting the system up to 48% water content, the structure turned into an interconnected lamellar microemulsion, reaching a proper disconnected lamellar structure for the highest water percentages (52-56%). Upon water addition, also the rheological properties changed from nearly Newtonian fluids to gel-like structures, displaying the maximum of viscosity for the 48% water content. Skin uptake experiments demonstrated that formulation viscosity, drug loading, and surfactant concentration did not play an important role on imiquimod uptake into the skin, while the skin penetration was related instead to the microemulsion mesostructure. In fact, drug uptake became enhanced by locally lamellar interconnected structures, while it was reduced in the presence of disconnected structures, either drops or proper lamellae. Finally, the data demonstrated that mesostructure also affects the drug distribution between the epidermis and dermis. In particular, a significantly higher dermal accumulation was found when disconnected lamellar structures are present, suggesting the possibility of tuning both drug delivery and localization into the skin by modifying microemulsions composition.
10.1021/acs.molpharmaceut.7b00348
Transdermal delivery of tadalafil using a novel formulation.
Baek Jong-Suep,Cho Cheong-Weon
Drug delivery
The aim of this work was to investigate the transdermal gel loaded with tadalafil, a practically insoluble selective phosphodiesterase-5 inhibitor (PDE5) in order to improve the solubility and bioavailability. The solubility of tadalafil in mixed solution of hydroxypropyl-β-cyclodextrin (HPCD), polyethylene glycol (PEG) 400 and tween 80 (T2 solution) was 260.8 ± 4.3 µg/mL and that of tadalafil in modified T2 (M-T2) solution, which tadalafil was dissolved in 20% (w/v) HPCD at first and then mixture solutions of PEG 400 and tween 80 were added, was increased to 344.9 ± 30.6 µg/mL. Four gel formulae were prepared, subsequently in vitro and in vivo skin permeation studies were carried out. Interestingly, tadalafil gel in M-T2 and oleic acid (OA) (F3) could promote the percutaneous absorption of tadalafil by 179.4% in vitro and increase AUC by 223% in vivo compared with tadalafil gel in the absence of M-T2 and OA (F1). Also, there was a finding that tadalafil gel in M-T2 and OA did not cause dermal irritations in an experimental animal.
10.3109/10717544.2015.1077291
Fatty Acid Esters of G-(Propyl Ether Imine) Dendron as Bicephalous Heterolipids for Permeation Enhancement in Transdermal Drug Delivery.
Chaudhari Kapil S,Akamanchi Krishnacharya G
ACS biomaterials science & engineering
The objective of the present study was to synthesize, evaluate, and explore the potential of a new class of bicephalous heterolipids (BHLs) as chemical permeation enhancers (CPEs) with emphasis on investigation of the influence of variable chain lengths of BHLs with the G-PETIM (poly(propyl ether imine)) dendron as a headgroup on skin permeation efficiency using diclofenac sodium (DS) as a model drug. These BHLs were synthesized, and chemical structures were confirmed by FT-IR, H NMR, C NMR, and ESI-MS. All BHLs were assessed for cytotoxicity and skin irritation studies that revealed their dermal safety. All respective DS gels with loaded BHLs were evaluated for skin permeation at varied concentrations, where gels with 1% concentration showed a significant increase in steady state flux (ER) as compared to the control gel and oleic acid loaded gel. The mechanism of enhanced skin permeation using BHL-loaded DS gels was examined using transepithelial electrical resistance (TEER), attenuated total reflection infrared (ATIR), and histomorphology, which showed significant reduction in the barrier integrity, alterations in the stratum corneum (SC), and compromising of the SC. These observations were concurrent with skin permeation results indicating that BHL enhancers could have wide scope as semisynthetic CPEs for transdermal drug delivery.
10.1021/acsbiomaterials.8b00953
Solubility-physicochemical-thermodynamic theory of penetration enhancer mechanism of action.
Haq Anika,Chandler Mark,Michniak-Kohn Bozena
International journal of pharmaceutics
The hypothesis for the investigation was that the overall mechanism of action of skin penetration enhancers is best explained by the Solubility-Physicochemical-Thermodynamic (SPT) theory. To our knowledge, this is the first report of the application of SPT theory in transdermal/topical/enhancer research. The SPT theory puts forward the concept that the mode of action of enhancers is related to solubility parameters, physicochemical interactions and thermodynamic activity. This paper discusses these concepts by using experimentally derived permeation data, various physicochemical and solubility parameters (ingredient active gap (IAG), ingredient skin gap (ISG), solubility of active in the formulation (SolV) and the formulation solubility in the skin (SolS)) generated by using FFE (Formulating for Efficacy™ - ACT Solutions Corp) software. These studies suggest that there is an inverse relationship between measured flux and IAG values given that there is an optimum ingredient skin gap, SolV and SolS ratio. The study demonstrated that the flux is actually proportional to a gradient of thermodynamic activity rather than the concentration and maximum skin penetration and deposition can be achieved when the drug is at its highest thermodynamic activity.
10.1016/j.ijpharm.2019.118920
Formulation and evaluation of transdermal drug delivery of topiramate.
Cherukuri Suneetha,Batchu Uma Rajeswari,Mandava Kiranmai,Cherukuri Vidhyullatha,Ganapuram Koteswara Rao
International journal of pharmaceutical investigation
BACKGROUND:Transdermal drug delivery system (TDDS) was designed to sustain the release and improve the bioavailability of drug and patient compliance. Among the various types of transdermal patches, matrix dispersion type systems disperse the drug in the solvent along with the polymers and solvent is allowed to evaporate forming a homogeneous drug-polymer matrix. The objective of the present study was to design and formulate TDDS of topiramate (TPM) and to evaluate their extended release and . MATERIALS AND METHODS:In the present study, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising TPM with different ratios of hydrophilic and hydrophobic polymeric combinations using solvent casting technique. RESULTS:The physicochemical compatibility of the drug and the polymers was studied by Fourier transform infrared spectroscopy. The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The patches were further subjected to various physical evaluations along with the permeation studies using pig ear skin. CONCLUSIONS:On the basis of results obtained from the physical evaluation and studies the patches containing the polymers, that is, Eudragit L 100 and polyvinylpyrrolidone, with oleic acid as the penetration enhancer were considered as the best formulations for the transdermal delivery of TPM.
10.4103/jphi.JPHI_35_16
Follicular Penetration of Caffeine from Topically Applied Nanoemulsion Formulations Containing Penetration Enhancers: In vitro Human Skin Studies.
Abd Eman,Benson Heather A E,Roberts Michael S,Grice Jeffrey E
Skin pharmacology and physiology
BACKGROUND/AIMS:This study aimed to investigate transfollicular delivery enhancement of caffeine from nanoemulsion formulations incorporating oleic acid (OA) and eucalyptol (EU) as chemical penetration enhancers. METHODS:Caffeine permeation was evaluated from nanoemulsions containing OA or EU and an aqueous control solution through excised human full-thickness skin with hair follicles opened, blocked, or left untreated. Differential tape stripping was performed, followed by cyanoacrylate skin surface biopsies to determine the amount of caffeine in the hair follicles, and skin extraction to determine the retention of caffeine in the skin. RESULTS:Nanoemulsions significantly increased caffeine permeation through open and untreated skin over control (untreated: 36- and 42-fold for OA and EU, respectively; open: 40- and 49-fold). The follicular route contributed 53.7% of caffeine permeation for the OA nanoemulsion and 51% for EU when follicles were opened. Nanoemulsions promoted 4- and 3.4-fold increases in caffeine retention in open follicles, for OA and EU, respectively. Retention of caffeine in the stratum corneum and skin was almost equal in all cases. CONCLUSIONS:This study demonstrated effective delivery of caffeine as a hydrophilic model drug into and through hair follicles and showed that follicles and surrounding regions may be targeted by optimised formulations for specific treatments.
10.1159/000489857
Gellified Emulsion of Ofloxacin for Transdermal Drug Delivery System.
Jagdale Swati,Pawar Saylee
Advanced pharmaceutical bulletin
Ofloxacin is a fluoroquinolone with broad-spectrum antibacterial action, used in treatment of systemic and local infections. Ofloxacin is BCS class II drug having low solubility, high permeability with short half-life. The present work was aimed to design, develop and optimize gellified emulsion of Ofloxacin to provide site targeted drug delivery. Transdermal drug delivery will enhance the bioavailability of the drug giving controlled drug release. Transdermal drug delivery system was designed with gelling agent (Carbopol 940 and HPMC K100M), oil phase (oleic acid) and emulsifying agent (Tween 80: Span 80). Effect of concentration of gelling agent on release of drug from transdermal delivery was studied by 3 factorial design. Emulgel was evaluated for physical appearance, pH, drug content, viscosity, spreadability, antimicrobial activity, in- vitro diffusion study and ex-vivo diffusion study. FE-SEM study of the emulsion batch B5 has revealed formation of emulsion globules of approximately size 6-8 µm with -11.2 mV zeta potential showing good stability for the emulsion. Carbopol 940 had shown greater linear effect on drug release and viscosity of the formulations due to its high degree of gelling. In-vitro diffusion study through egg membrane had shown 88.58±1.82 % drug release for optimized batch F4. Ex-vivo diffusion study through goat skin indicated 76.68 ± 2.52% drug release. Controlled release Ofloxacin emulgel exhibiting good in-vitro and ex-vivo drug release proving good antimicrobial property was formulated.
10.15171/apb.2017.028
Formulation, characterization, and in vitro/ex vivo evaluation of quercetin-loaded microemulsion for topical application.
Kajbafvala Azar,Salabat Alireza,Salimi Anayatollah
Pharmaceutical development and technology
The aim of this study was to develop a new microemulsion formulation for topical application of poorly soluble drug named quercetin. In order to design suitable microemulsion system, the pseudo-ternary phase diagrams of microemulsion systems were constructed at different surfactant/co-surfactant ratios using tween 80 as surfactant, transcutol P as a co-surfactant and oleic acid as an oil phase. Some physicochemical properties such as droplet size, density, refractive index, electrical conductivity, pH, surface tension, and viscosity of the microemulsion systems were measured at 298.15 K. The average hydrodynamic droplet size of the optimized microemulsions was obtained by dynamic light scattering method. Morphology assessment of the optimized quercetin-loaded microemulsion by transmission electron microscopy analysis indicated that the particles have the size of about 25 nm and spherical with narrow size distribution. Equilibrium solubility, in vitro drug release at a 24 h time period, release kinetic evaluation as well as ex vivo permeation and retention of quercetin-loaded microemulsions through rat skin has been investigated. The obtained results showed a slow release behavior without any transdermal delivery. Most of the formulations fitted best with zero-order kinetic model with a non-Fickian mechanisms. This study illustrated that the proposed QU-microemulsion has a good potential for use in sunscreen formulations. [Formula: see text].
10.1080/10837450.2016.1263995
Prominent efficiency in skin delivery of resveratrol by novel sucrose oleate microemulsion.
Yutani Reiko,Komori Yuka,Takeuchi Atsuko,Teraoka Reiko,Kitagawa Shuji
The Journal of pharmacy and pharmacology
OBJECTIVES:To achieve an efficient skin delivery of resveratrol using sucrose fatty acid ester microemulsions and to clarify the mechanism of enhanced penetration. METHODS:Skin delivery of resveratrol using different sucrose fatty acid ester microemulsions was examined in vitro. Vehicle-skin interaction was assessed by applying blank microemulsions to skin. Skin incorporation of microemulsion components was also assessed. KEY FINDINGS:The microemulsion consisting of sucrose oleate (SO), ethanol, isopropyl myristate (IPM) and water (MESO-E) showed a prominent increase in the amount of skin incorporation of resveratrol, which was more than 5-fold higher than those of all microemulsions we previously examined. Using MESO-E, resveratrol was rapidly incorporated into skin and mainly located in the dermis. When applied in the concentration range of 5-55 mm, the amount of skin incorporation of resveratrol increased with the applied concentration up to 30 mm, whereas skin incorporation efficiency was inversely proportional to the concentration. The microemulsion-skin interaction seemed to be involved in the enhanced skin delivery process of resveratrol by MESO-E. Stratum corneum modification due to the penetration of IPM, ethanol and SO is also involved in this interaction. CONCLUSIONS:MESO-E would be a promising vehicle for the efficient skin delivery of resveratrol, especially when applied at a low concentration.
10.1111/jphp.12497
Optimization of nanostructured lipid carriers for topical delivery of nimesulide using Box-Behnken design approach.
Moghddam Seyedeh Marziyeh Mahdavi,Ahad Abdul,Aqil Mohd,Imam Syed Sarim,Sultana Yasmin
Artificial cells, nanomedicine, and biotechnology
OBJECTIVE:The aim of the present study was to develop and optimize topically applied nimesulide-loaded nanostructured lipid carriers. MATERIALS AND METHODS:Box-Behnken experimental design was applied for optimization of nanostructured lipid carriers. The independent variables were ratio of stearic acid: oleic acid (X), poloxamer 188 concentration (X) and lecithin concentration (X) while particle size (Y) and entrapment efficiency (Y) were the chosen responses. Further, skin penetration study, in vitro release, confocal laser scanning microscopy and stability study were also performed. RESULTS AND DISCUSSION:The optimized nanostructured lipid carriers of nimesulide provide reasonable particle size, flux, and entrapment efficiency. Optimized formulation (F9) with mean particle size of 214.4 ± 11 nm showed 89.4 ± 3.40% entrapment efficiency and achieved mean flux 2.66 ± 0.09 μg/cm/h. In vitro release study showed prolonged drug release from the optimized formulation following Higuchi release kinetics with R value of 0.984. Confocal laser scanning microscopy revealed an enhanced penetration of Rhodamine B-loaded nanostructured lipid carriers to the deeper layers of the skin. The stability study confirmed that the optimized formulation was considerably stable at refrigerator temperature as compared to room temperature. CONCLUSION:Our results concluded that nanostructured lipid carriers are an efficient carrier for topical delivery of nimesulide.
10.3109/21691401.2016.1167699
Development and characterization of nanostructured lipid carrier-based gels for the transdermal delivery of donepezil.
Mendes I T,Ruela A L M,Carvalho F C,Freitas J T J,Bonfilio R,Pereira G R
Colloids and surfaces. B, Biointerfaces
Donepezil is one of the main compounds used in the therapy of Alzheimer's disease. Oral administration of this drug presents many drawbacks, resulting in treatment non-adherence among patients. Thus, the development of transdermal formulations for donepezil delivery is important. The aim of this study was to prepare and to evaluate nanostructured lipid carrier-based gels (NLC gel) able to improve the skin delivery of donepezil free base (DPB). The components of nanostructured lipid carriers (NLCs) were selected after evaluating their enhancing effects using in vitro DPB skin delivery assays. DPB-loaded NLC were prepared by a microemulsion technique, by employing stearic acid as a solid lipid, oleic acid as a liquid lipid, lecithin as a surfactant, and sodium taurodeoxycholate as a co-surfactant. The DPB-NLC dispersions were characterized morphologically using atomic force microscopy and physicochemically using dynamic light scattering and surface charge measurements. These data along, with the encapsulation studies, indicated that uniformly nano-sized particles with high drug encapsulation were fabricated. In vitro skin permeation assays were performed, and the results indicated that drug skin permeation from DPB-NLC gel was increased, not only by the enhancing effect of their components, but the lipid nanocarriers also presented an additional enhancing effect to increase drug flux across the skin. Therefore, DPB-NLC gel is an interesting formulation for the enhanced treatment of Alzheimer's disease.
10.1016/j.colsurfb.2019.02.007
Clotrimazole Loaded Ufosomes for Topical Delivery: Formulation Development and In-Vitro Studies.
Bolla Pradeep Kumar,Meraz Carlos A,Rodriguez Victor A,Deaguero Isaac,Singh Mahima,Yellepeddi Venkata Kashyap,Renukuntla Jwala
Molecules (Basel, Switzerland)
Global incidence of superficial fungal infections caused by dermatophytes is high and affects around 40 million people. It is the fourth most common cause of infection. Clotrimazole, a broad spectrum imidazole antifungal agent is widely used to treat fungal infections. Conventional topical formulations of clotrimazole are intended to treat infections by effective penetration of drugs into the stratum corneum. However, drawbacks such as poor dermal bioavailability, poor penetration, and variable drug levels limit the efficiency. The present study aims to load clotrimazole into ufosomes and evaluate its topical bioavailability. Clotrimazole loaded ufosomes were prepared using cholesterol and sodium oleate by thin film hydration technique and evaluated for size, polydispersity index, and entrapment efficiency to obtain optimized formulation. Optimized formulation was characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). Skin diffusion studies and tape-stripping were performed using human skin to determine the amount of clotrimazole accumulated in different layers of the skin. Results showed that the optimized formulation had vesicle size <250 nm with ~84% entrapment efficiency. XRD and DSC confirmed the entrapment of clotrimazole into ufosomes. No permeation was observed through the skin up to 24 h following the permeation studies. Tape-stripping revealed that ufosomes led to accumulation of more clotrimazole in the skin compared to marketed formulation (Perrigo). Overall, results revealed the capability of ufosomes in improving the skin bioavailability of clotrimazole.
10.3390/molecules24173139
Colloidal nanocarriers for the enhanced cutaneous delivery of naftifine: characterization studies and in vitro and in vivo evaluations.
Erdal M Sedef,Özhan Gül,Mat M Cem,Özsoy Yıldız,Güngör Sevgi
International journal of nanomedicine
In topical administration of antifungals, the drugs should pass the stratum corneum to reach lower layers of the skin in effective concentrations. Thus, the formulation of antifungal agents into a suitable delivery system is important for the topical treatment of fungal infections. Nanosized colloidal carriers have gained great interest during the recent years to serve as efficient promoters of drug penetration into the skin. Microemulsions are soft colloidal nanosized drug carriers, which are thermodynamically stable and isotropic systems. They have been extensively explored for the enhancement of skin delivery of drugs. This study was carried out to exploit the feasibility of colloidal carriers as to improve skin transport of naftifine, which is an allylamine antifungal drug. The microemulsions were formulated by construction of pseudoternary phase diagrams and composed of oleic acid (oil phase), Kolliphor(®) EL or Kolliphor(®) RH40 (surfactant), Transcutol(®) (cosurfactant), and water (aqueous phase). The plain and drug-loaded microemulsions were characterized in terms of isotropy, particle size and size distribution, pH value, refractive index, viscosity, and conductivity. The in vitro skin uptake of naftifine from microemulsions was studied using tape stripping technique in pig skin. The drug penetrated significantly into stratum corneum from microemulsions compared to its marketed cream (P<0.05). Moreover, the microemulsion formulations led to highly significant amount of naftifine deposition in deeper layers of skin than that of commercial formulation (P<0.001). Microemulsion-skin interaction was confirmed by attenuated total reflectance - Fourier transformed infrared spectroscopy data, in vitro. The results of the in vivo tape stripping experiment showed similar trends as the in vitro skin penetration study. Topical application of the microemulsion on human forearms in vivo enhanced significantly the distribution and the amount of naftifine penetrated into the stratum corneum as compared to the marketed formulation (P<0.05). The relative safety of the microemulsion formulations was demonstrated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability test. This study indicated that the nanosized colloidal carriers developed could be considered as an effective and safe topical delivery system for naftifine.
10.2147/IJN.S96243
Potential of Non-aqueous Microemulsions to Improve the Delivery of Lipophilic Drugs to the Skin.
Carvalho Vanessa F,de Lemos Debora P,Vieira Camila S,Migotto Amanda,Lopes Luciana B
AAPS PharmSciTech
In this study, non-aqueous microemulsions were developed because of the challenges associated with finding pharmaceutically acceptable solvents for topical delivery of drugs sparingly soluble in water. The formulation irritation potential and ability to modulate the penetration of lipophilic compounds (progesterone, α-tocopherol, and lycopene) of interest for topical treatment/prevention of skin disorders were evaluated and compared to solutions and aqueous microemulsions of similar composition. The microemulsions (ME) were developed with BRIJ, vitamin E-TPGS, and ethanol as surfactant-co-surfactant blend and tributyrin, isopropyl myristate, and oleic acid as oil phase. As polar phase, propylene glycol (MEPG) or water (MEW) was used (26% w/w). The microemulsions were isotropic and based on viscosity and conductivity assessment, bicontinuous. Compared to drug solutions in lipophilic vehicles, MEPG improved drug delivery into viable skin layers by 2.5-38-fold; the magnitude of penetration enhancement mediated by MEPG into viable skin increased with drug lipophilicity, even though the absolute amount of drug delivered decreased. Delivery of progesterone and tocopherol, but not lycopene (the most lipophilic compound), increased up to 2.5-fold with MEW, and higher amounts of these two drugs were released from MEW (2-2.5-fold). Both microemulsions were considered safe for topical application, but MEPG-mediated decrease in the viability of reconstructed epidermis was more pronounced, suggesting its higher potential for irritation. We conclude that MEPG is a safe and suitable nanocarrier to deliver a variety of lipophilic drugs into viable skin layers, but the use of MEW might be more advantageous for drugs in the lower range of lipophilicity.
10.1208/s12249-016-0643-7
Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics.
Calatayud-Pascual María Aracely,Sebastian-Morelló María,Balaguer-Fernández Cristina,Delgado-Charro M Begoña,López-Castellano Alicia,Merino Virginia
Pharmaceutics
The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm² were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm² were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical enhancer because it allowed faster delivery of the drug. The DPK method was sufficiently sensitive to detect subtle vehicle-induced effects on the skin permeation of propranolol. The shorter duration of these experiments and their ability to provide mechanistic information about partition between vehicle and skin and diffusivity through skin place them as practical and potentially insightful approach to quantify and, ultimately, optimize topical bioavailability.
10.3390/pharmaceutics10040265
Liposomal hydrogel formulation for transdermal delivery of pirfenidone.
Jose Anup,Mandapalli Praveen Kumar,Venuganti Venkata Vamsi Krishna
Journal of liposome research
CONTEXT:Pirfenidone (PFD) is an anti-fibrotic and anti-inflammatory agent indicated for the treatment of idiopathic pulmonary fibrosis (IPF). The current oral administration of PFD has several limitations including first pass metabolism and gastrointestinal irritation. OBJECTIVE:The aim of this study is to investigate the feasibility of transdermal delivery of PFD using liposomal carrier system. MATERIALS AND METHODS:PFD-loaded liposomes were prepared using soy phosphatidylcholine (SPC) and sodium cholate (SC). Encapsulation efficiency (EE) of PFD in liposomes was optimized using different preparation techniques including thin film hydration (TFH) method, direct injection method (DIM) and drug encapsulation using freeze-thaw cycles. In vitro drug release study was performed using dialysis membrane method. The skin permeation studies were performed using excised porcine ear skin model in a Franz diffusion cell apparatus. RESULTS AND DISCUSSION:The average particle size and zeta-potential of liposomes were 191 ± 4.1 nm and -40.4 ± 4.5 mV, respectively. The liposomes prepared by TFH followed by 10 freeze-thaw cycles showed the greatest EE of 22.7 ± 0.63%. The optimized liposome formulation was incorporated in hydroxypropyl methyl cellulose (HPMC) hydrogel containing different permeation enhancers including oleic acid (OA), isopropyl myristate (IPM) and propylene glycol (PG). PFD-loaded liposomes incorporated in hydrogel containing OA and IPM showed the greatest flux of 10.9 ± 1.04 μg/cm(2)/h across skin, which was 5-fold greater compared with free PFD. The cumulative amount of PFD permeated was 344 ± 28.8 μg/cm(2) with a lag time of 2.3 ± 1.3 h. CONCLUSION:The hydrogel formulation containing PFD-loaded liposomes can be developed as a potential transdermal delivery system.
10.3109/08982104.2015.1060611
Enhanced skin permeation of Methotrexate from penetration enhancer containing vesicles: In vitro optimization and in vivo evaluation.
Sadarani Bhakti,Majumdar Anuradha,Paradkar Shalaka,Mathur Anupam,Sachdev Satbir,Mohanty Bhabani,Chaudhari Pradip
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Low dose Methotrexate (MTX) therapy is considered a gold standard for Rheumatoid Arthritis (RA). Transdermal drug delivery is hypothesized as an alternative to conventional therapies to alleviate its adverse effects. In our study, MTX was entrapped in deformable liposomes and loaded in a hydroxyethyl cellulose gel. This system was evaluated by the Box Behnken statistical design for optimization. The effect of formulation variables on particle size, entrapment and ex vivo skin permeation was studied. The MTX nanogel was evaluated for its dermal toxicity (acute and repeat dose safety), in vivo biodistribution (using I radio-labelled MTX) and therapeutic efficacy (collagen induced arthritis [CIA] model). The optimized formulation demonstrated appreciable nanosize (110 ± 20 nm), drug entrapment (42 ± 1.9%) and high ex vivo transdermal flux (17.37 ± 1.5 μg/cm2/hr). In the dermal toxicity studies, nanogel formulation did not show any signs of irritation or toxicity, whereas in the biodistribution study, the MTX nanogel formulation depicted sustained systemic delivery up to 48 h with low accumulation in its organs of toxicity such as the liver, kidneys and gut. In the CIA model, the MTX nanogel significantly ameliorated hind paw swelling, reduced arthritic score, joint damage (histological, radiological examination) and attenuated the rise in serum cytokines such as TNF-ɑ and IL-6. In conclusion, the optimized MTX nanogel formulation displayed skin biocompatibility, sustained systemic delivery, safety as well as therapeutic efficacy.
10.1016/j.biopha.2019.108770
[Dexamethasone acetate microemulsions: formulation and effect on skin permeability].
Mei Fen,Zeng Wei-dong,Wan Tao,Huang Jie-wei,Luo Shuang-hui,Wu Chuan-bin,Xu Yue-hong
Yao xue xue bao = Acta pharmaceutica Sinica
The present project was designed to optimize the microemulsion (ME) formulation of oil in water (O/W) for dexamethasone acetate (DA), and examine its impact on DA percutaneous permeation. The saturated solubility of DA in different oils, surfactants and co-surfactants was tested. The ratio of surfactant to co-surfactant was selected by constructing pseudo three phase diagrams to investigate the maximal microemulsion area. In vitro permeation studies of DA from microemulsion and suspension were performed to optimize the formulation further. Differential scanning calorimetry(DSC) and attenuated total reflection flourier transformed infrared spectroscopy (ATR-FTIR) were performed to investigate the mechanism of microemulsion action on skin. The optimized formulation was composed of oleic acid/Labrasol/propylene glycol/water with 8/45/15/32 (w/w), and the DA loading was 0.75% (w/w). The permeation enhancement of microemusion was 6.00-fold as that of suspension, and the DA from microemulsion retained in the skin was 4.79-fold as that of suspension. DSC and ATR-FTIR results suggested that microemulsion could affect the intercellular lipid lamellae and keratin of the stratum corneum. The barrier function of stratum corneum was disordered by the microemulsion so that the dermal drug delivery was enhanced. Therefore, the optimized microemulsion enhanced DA percutaneous permeation significantly through the interaction of microemulsion with skin, microemulsion is a promising approach for DA percutaneous delivery.
Self-Assembling Organogels Based on Pluronic and Lecithin for Sustained Release of Etodolac: In Vitro and In Vivo Correlation.
Mohammed Ahmed Mohammed,Faisal Walid,Saleh Khaled Ismail,Osman Shaaban Khalaf
Current drug delivery
BACKGROUND:Etodolac, a member of non steroidal anti-inflammatory drugs (NSAIDs), has a poor aqueous solubility. Long term administration of etodolac causes severe gastrointestinal disturbances such as peptic ulcer and bleeding. These disturbances could be overcome by alternative routes such as a topical administration. METHOD:In the present study, pluronic lecithin organogels (PLOs) were prepared by simple mixing of pluronic solution with lecithin solution. Etodolac was loaded into the prepared gels or added during the gel formation. The physicochemical properties of the modified organogels were investigated by different analysis including visual inspection, pH determination, viscosity, spreadability and extrudability. Also, the in vitro release studies of etodolac in the presence of different penetration enhancers were carried out. The anti-inflammatory behavior of the prepared etodolac organogel was investigated using carrageenan induced paw edema test. RESULTS:The results indicated that the prepared organogels showed good physicochemical properties. The organogels, containing a combination of tween 80 and oleic acid as penetration enhancers, showed the highest percentage of drug release. CONCLUSION:All tested organogels showed a significant oedema inhibition compared with oral indomethacin ® and Voltaren® as a topical marketed anti-inflammatory drug. Moreover, the increase of drug concentration from 1% to 5% w/w is accompanied with a longer duration of action up to 12 hrs. Therefore, the formulated organogels are considered as a promising vehicle for controlled topical delivery of etodolac.
10.2174/1567201813666160902151514
Design of a Drug-in-Adhesive Transdermal Patch for Risperidone: Effect of Drug-Additive Interactions on the Crystallization Inhibition and In Vitro/In Vivo Correlation Study.
Weng Wei,Quan Peng,Liu Chao,Zhao Hanqing,Fang Liang
Journal of pharmaceutical sciences
The purpose of this work was to develop and design an appropriate drug-in-adhesive patch for transdermal delivery of risperidone (RISP). Various formulation factors were investigated by in vitro permeation study using excised rabbit skin. Increasing the drug concentration in the pressure sensitive adhesive (PSA) was used to enhance the drug permeation. To overcome the high crystallization tendency of the patch, several crystallization inhibitors such as PVP, PEG, and surfactants and fatty acids were evaluated by microscopy study. The mechanism of crystallization inhibition was investigated by differential scanning calorimetry, nuclear magnetic resonance spectrometer, and FT-IR studies. RISP and its active metabolite were determined after topical application of the optimized transdermal patch, and the in vivo pharmacokinetic parameters were compared with the intravenous administration group. The microscopy study indicated that fatty acid greatly inhibited the crystallization of RISP in PSA. The inhibition was attributed to the drug-additive interaction between amino group of RISP and the carboxyl group of fatty acid which was further confirmed by (1)H-NMR and FT-IR studies. The optimal permeation profile was obtained with the patches containing 5% RISP and 5% oleic acid in Duro-Tak(®) 87-2287. The in vivo pharmacokinetic study exhibited a sustained absorption and metabolism profile and well correlated with the in vitro permeation data.
10.1016/j.xphs.2016.07.003
Formulation and in vitro/in vivo evaluation of chitosan-based film forming gel containing ketoprofen.
Drug delivery
The film forming gel, adhered to skin surfaces upon application and formed a film, has an advantage onto skin to provide protection and continuous drug release to the application site. This study aimed to prepare a chitosan-based film forming gel containing ketoprofen (CbFG) and to evaluate the CbFG and film from CbFG (CbFG-film). CbFG were prepared with chitosan, lactic acid and various skin permeation enhancers. The physicochemical characteristics were evaluated by texture analysis, viscometry, SEM, DSC, XRD and FT-IR. To identify the mechanism of skin permeation, in vitro skin permeation study was conducted with a Franz diffusion cell and excised SD-rat and hairless mouse dorsal skin. In vivo efficacy assessment in mono-iodoacetate (MIA)-induced rheumatoid arthritis animal model was also conducted. CbFG was successfully prepared and, after applying CbFG to the excised rat dorsal skin, the CbFG-film was also formed well. The physicochemical characteristics of CbFG and CbFG-film could be explained by the grafting of oleic acid onto chitosan in the absence of catalysts. In addition, CbFG containing oleic acid had a higher skin permeation rate in comparison with any other candidate enhancers. The in vivo efficacy study also confirmed significant anti-inflammatory and analgesic effects. Consequently, we report the successful preparation of chitosan-based film forming gel containing ketoprofen with excellent mechanical properties, skin permeation and anti-inflammatory and analgesic effects.
10.1080/10717544.2017.1346001
Microemulsion and Microporation Effects on the Genistein Permeation Across Dermatomed Human Skin.
Chen Li,Annaji Manjusha,Kurapati Sharmila,Ravis William R,Jayachandra Babu R
AAPS PharmSciTech
This study reports the microemulsion (ME) effects on the permeation of genistein across normal (intact) and microporated human skin. The genistein formulation was optimized to know the stable ME region in the pseudo-ternary phase diagrams and to maximize the skin permeation and retention of genistein. The phase diagrams were constructed with different oil phases, surfactants, and their combinations. The influence of formulation factors on the permeation through intact and microporated human skin was determined. Based on its wide ME region, as well as permeation enhancement effects, oleic acid was used as an oil phase with various surfactants and co-surfactants to further maximize the ME region and skin permeation. The water content in the formulation played an important role in the ME stability, droplet size, and flux of genistein. For example, the ME with 20% water exhibited 4- and 9-fold higher flux as compared to the ME base (no water) and aqueous suspension, respectively. Likewise, this formulation had demonstrated 2- and 4-fold higher skin retention as compared to the ME base (no water) and aqueous suspension, respectively. The skin microporation did not significantly increase the skin permeation of genistein from ME formulations. The ME composition, water content, and to a lesser extent the ME particle size played a role in improving the skin permeation and retention of genistein.
10.1208/s12249-018-1150-9
Formation of stable nanoemulsions by ultrasound-assisted two-step emulsification process for topical drug delivery: Effect of oil phase composition and surfactant concentration and loratadine as ripening inhibitor.
Sarheed Omar,Shouqair Douha,Ramesh K V R N S,Khaleel Taha,Amin Muhammad,Boateng Joshua,Drechsler Markus
International journal of pharmaceutics
Nanoemulsions are very interesting systems as they offer capacity to encapsulate both hydrophilic and lipophilic molecules in a single particle, as well as the controlled release of chemical moieties initially entrapped in the internal droplets. In this study, we propose a new two-step modified ultrasound-assisted phase inversion approaches-phase inversion temperature (PIT) and self-emulsification, to prepare stable o/w nanoemulsions from a fully water-dilutable microemulsion template for the transdermal delivery of loratadine (a hydrophobe and as Ostwald ripening inhibitor). Firstly, the primary water-in-oil microemulsion concentrate (w/o) was formed using loratadine in the oil phase (oleic acid or coconut oil) and Tween 80 in the aqueous phase and by adjusting the PIT around 85 °C followed by stepwise dilution with water at 25 °C to initiate the formation the nanoemulsions (o/w). To assure the long-term stability, a brief application of low frequency ultrasound was employed. Combining the two low energy methods resulted in nanoemulsions prepared by mixing constant surfactant/oil ratios above the PIT with varying water volume fraction (self-emulsification) during the PIT by stepwise dilution. The kinetic stability was evaluated by measuring the droplet size with time by dynamic light scattering (DLS). The droplet size ranged 15-43 nm and did not exceed 100 nm over the period of 6 months indicating the system had high kinetic stability. Cryo-TEM showed that the nanoemulsions droplets were monodispersed and approaching micellar structure and scale. All nanoemulsions had loratadine crystals formed within 20 days after preparation, which tended to sediment during storage. Nanoemulsions improved the in vitro permeation of loratadine through porcine skin up to 20 times compared to the saturated solution.
10.1016/j.ijpharm.2019.118952
Formulation Optimization and In-vitro and In-vivo Evaluation of Lornoxicam Ethosomal Gels with Penetration Enhancers.
Li Keke,Gao Shanshan,Tian Baocheng,Shi Yanan,Lv Qingzhi,Han Jingtian
Current drug delivery
BACKGROUND:Ethosomes, a novel type of percutaneous drug delivery carrier with a lipid bilayer structure, penetrate the skin barrier due to their deformability and malleability, and presence of ethanol that fluidizes lipids in the skin. In order to further enhance the delivery of drugs through the skin, penetration enhancers are widely used. OBJECTIVE:The objective of this work was to develop an optimized formulation of lornoxicam ethosomal gels, investigate skin permeability with the addition of penetration enhancers, and evaluate the invivo pharmacodynamics of these formulations. METHODS:Lornoxicam ethosomes were prepared by the ethanol injection method and optimized using the orthogonal design method. Lornoxicam ethosomal gels with enhancers were prepared and optimized using in-vitro transdermal delivery experiments. Experiments on lornoxicam ethosomal gels containing various enhancers such as azone, menthol, lauryl alcohol, and oleic acid were conducted using vertical Franz diffusion cells to measure the percutaneous permeability of the different formulations. Furthermore, the in-vivo analgesic effects of the optimized lornoxicam ethosomal gels were examined using the hot-plate and acetic acid-induced writhing tests. Anti-inflammatory activity was investigated using the dimethylbenzene-induced mouse ear swelling method. RESULTS:The results showed that compared to other formulations, the optimized lornoxicam ethosomal gels with 5 % menthol significantly increased transdermal penetration. Meanwhile, the optimized lornoxicam ethosomal gels showed remarkably anti-nociceptive and anti-inflammatory activity compared with the plain lornoxicam gels. CONCLUSION:These results suggest that the optimized ethosomal gel formulated in this study is a promising lornoxicam carrier in transdermal delivery systems to enhance anti-nociceptive and antiinflammatory efficiency.
10.2174/1567201815666171207163010
Ex-Vivo percutaneous absorption of enrofloxacin: Comparison of LMOG organogel vs. pentravan cream.
Kirilov Plamen,Tran Van Hung,Ducrotté-Tassel Alban,Salvi Jean-Paul,Perrot Sébastien,Haftek Marek,Boulieu Roselyne,Pirot Fabrice
International journal of pharmaceutics
The objective of this study was to investigate the percutaneous absorption of enrofloxacin from two base formulations, Pentravan cream and LMOG organogel. Ex-vivo experiments were carried out on pig ear skin. The percutaneous permeation through pig skin of two formulations containing 5 wt% of enrofloxacin was measured and compared using Franz diffusion cells. At appropriate intervals up to 120 h, diffusion samples were taken and analyzed using HPLC assays. Permeation profiles were established and the parameters Tlag and flux values were calculated. In this ex-vivo study, the flux values were 0.35 μgcm(-2)h(-1) for Pentravan and 1.22 μgcm(-2)h(-1) for LMOG organogel, corresponding respectively to 7.9 % and 29.3 % of enrofloxacin absorbed after 120 h by these formulations. The lag time (T lag) of Pentravan and organogel were 6.32 and 0.015 h respectively. The absorption time to reach the antibiotic concentration of enrofloxacin (2 μgmL(-1)) in the receptor was 60 h with Pentravan and 30 h with the organogel, suggesting more effective treatment by the latter. Enrofloxacin contained in organogel could be absorbed through pig ear skin 3.7 times greater than that in Pentravan (commercial formulation). This study demonstrates the perspective of organogel formulations as potential drug delivery systems.
10.1016/j.ijpharm.2015.12.018
Microemulsion-Based Topical Hydrogels of Tenoxicam for Treatment of Arthritis.
Goindi Shishu,Narula Manleen,Kalra Atin
AAPS PharmSciTech
Tenoxicam (TNX) is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, backache and pain. However, prolonged oral use of this drug is associated with gastrointestinal adverse events like peptic ulceration, thus necessitating its development as topical formulation that could obviate the adverse effects and improve patient compliance. The present study was aimed at development of microemulsion-based formulations of TNX for topical delivery at the affected site. The pseudoternary phase diagrams were developed and microemulsion formulations were prepared using Captex 300/oleic acid as oil, Tween 80 as surfactant and n-butanol/ethanol as co-surfactant. Optimized microemulsions were characterized for drug content, droplet size, viscosity, pH and zeta potential. The ex vivo permeation studies through Laca mice skin were performed using Franz diffusion cell assembly, and the permeation profile of the microemulsion formulation was compared with aqueous suspension of drug and drug incorporated in conventional cream. Microemulsion formulations of TNX showed significantly higher (p < 0.001) mean cumulative percent permeation values in comparison to conventional cream and suspension of drug. In vivo anti-arthritic and anti-inflammatory activity of the developed TNX formulations was evaluated using various inflammatory models such as air pouch model, xylene-induced ear edema, cotton pellet granuloma and carrageenan-induced inflammation. Microemulsion formulations were found to be superior in controlling inflammation as compared to conventional topical dosage forms and showed efficacy equivalent to oral formulation. Results suggest that the developed microemulsion formulations may be used for effective topical delivery of TNX to treat various inflammatory conditions.
10.1208/s12249-015-0383-0
Development of a novel human stratum corneum model, as a tool in the optimization of drug formulations.
Shakel Zinaida,Nunes Cláudia,Costa Lima Sofia A,Reis Salette
International journal of pharmaceutics
Transdermal delivery represents a very attractive administration route that provides various advantages over other methods of administration, including enhanced patient compliance via non-invasive, painless and simple application and reduced side effects. Thereby, the research on suitable drugs for this route continues to increase. However, most of drug candidates face the challenges of low drug permeability across the skin's biologically active barrier - the stratum corneum (SC). In this context, a low cost, simple screening tool to evaluate penetration of drug candidates in a human SC barrier model was developed. The in vitro model is based on a modified phospholipid vesicle-based permeation assay (PVPA) with a lipid composition close to human SC layer. The new SC PVPA model can be stored up to 2 weeks at -20 °C, withstand a pH range from 2.0 to 8.0 and the presence of co-solvents (DMSO, oleic acid and cremophor®) without losing their integrity. The human mimicking SC PVPA model was able to detect calcein permeability differences when different drugs, applied in the therapy of skin-related diseases, were present. The obtained data correlated well with the well accepted pig ear model, which highlights the potential of this new human SC model.
10.1016/j.ijpharm.2019.118571
Predicting drug permeability through skin using molecular dynamics simulation.
Lundborg Magnus,Wennberg Christian L,Narangifard Ali,Lindahl Erik,Norlén Lars
Journal of controlled release : official journal of the Controlled Release Society
Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.
10.1016/j.jconrel.2018.05.026
Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation.
Farghaly Dalia Ali,Aboelwafa Ahmed A,Hamza Manal Y,Mohamed Magdy I
Journal of liposome research
The aim of this study was to investigate microemulsion (ME) based topical delivery system for fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. ME was prepared by the water titration method using oleic acid as oil phase, tween 80 as a surfactant and propylene glycol as a cosurfactant. Oleic acid was selected as oil phase due to its good solubilizing capacity. ME existence region was determined using pseudo-ternary phase diagrams for preparing different formulations. Six different formulations were selected with various values of oil (25-68%), water (2-3%), and the mixture of surfactant and cosurfactant (1:1) (24-67%). The selected ME formulae were characterized for optical birefringence, transmission electron microscopy (TEM), pH, % transmittance, electronic conductivity, drug content, droplet size, rheological properties and stability evaluation. In vitro release study of FPCa from ME s through the synthetic membrane and hairless rat skin were evaluated. The optimized formula ME5 consisting of 5% w/w FPCa, 60% w/w oleic acid as oil phase, 3% w/w aqueous phase, and 32% w/w of surfactant phase containing Tween 80 and propylene glycol (1: 1) showed the highest transdermal flux and highest skin permeation rate. Finally, the % inhibition of carrageenan-induced rat paw edema of the optimized formula ME5 was highly significant (p < 0.001) as compared to plain gel of FPCa. In conclusion, ME is a promising technique for topical delivery of FPCa.
10.1080/08982104.2017.1281951
A novel transdermal delivery system for the anti-inflammatory lumiracoxib: influence of oleic acid on in vitro percutaneous absorption and in vivo potential cutaneous irritation.
Moreira Tailane Sant'Anna,de Sousa Valéria Pereira,Pierre Maria Bernadete Riemma
AAPS PharmSciTech
Transdermal delivery of non-steroidal anti-inflammatory drugs may be an interesting strategy for delivering these drugs to the diseased site, but it would be ineffective due to low skin permeability. We investigated whether oleic acid (OA), a lipid penetration enhancer in poloxamer gels named poloxamer-based delivery systems (PBDS), can improve lumiracoxib (LM) delivery to/through the skin. The LM partition coefficient (K) studies were carried out in order to evaluate the drug lipophilicity grade (K(octanol/buffer)), showing values >1 which demonstrated its high lipophilicity. Both in vitro percutaneous absorption and skin retention studies of LM were measured in the presence or absence of OA (in different concentrations) in PBDS using porcine ear skin. The flux of in vitro percutaneous absorption and in vitro retention of LM in viable epidermis increased in the presence of 10.0% (w/w) OA in 25.0% (w/w) poloxamer gel. In vivo cutaneous irritation potential was carried out in rabbits showing that this formulation did not provide primary or cumulative cutaneous irritability in animal model. The results showed that 25.0% poloxamer gel containing 10.0% OA is potential transdermal delivery system for LM.
10.1208/s12249-010-9420-1
Mechanisms of imiquimod skin penetration.
Telò Isabella,Pescina Silvia,Padula Cristina,Santi Patrizia,Nicoli Sara
International journal of pharmaceutics
Imiquimod (IMQ) ia an immunostimulating drug used for the treatment of neoplastic skin diseases, such as actinic keratosis (AK) and superficial basal cell carcinoma (sBCC), and as adjuvant for vaccination. Imiquimod formulation and skin delivery is highly challenging because of its very low solubility in most pharmaceutical excipients and poor penetration properties. Objectives of the work were: (1) to evaluate IMQ solubility in different solvents and pharmaceutical excipients; (2) to evaluate IMQ skin retention after the application of simple saturated solutions; (3) to evaluate the role of stratum corneum and solvent uptake on IMQ skin retention and (4) to formulate IMQ in microemulsions - prepared using previously investigated components - and compare them with the commercial formulation. The results show that IMQ solubility is not related to the solubility parameter of the solvents considered. The highest solubility was found with oleic acid (74mg/ml); in the case of PEGs, the solubility increased linearly with MW (PEG 200: 1.9mg/ml; PEG 400 7.3mg/ml, PEG 600 12.8mg/ml). Imiquimod skin retention from saturated solutions (Tween 80, oleic acid, propylene glycol, PEG 200, PEG 400, PEG 600, Transcutol, 2-pyrrolidone, DMSO) resulted relatively similar, being 1.6μg/cm(2) in case of oleic acid (solubility 74mg/ml) and 0.18μg/cm(2) in case of propylene glycol (solubility 0.60mg/ml). Permeation experiments on stripped skin (no stratum corneum) and isolated dermis as well as uptake experiments on isolated stratum corneum sheets demonstrated that IMQ accumulation is related to skin solvent uptake. Finally, microemulsions (MEs) prepared with the above-studied components demonstrated a very good performance. In particular, a ME composed of 10% oleic acid, 35% Transcutol, 35% Tween 80 and 20% water is able to accumulate the same amount of drug as the commercial formulation but with far more efficiency, since its concentration was 12 times lower.
10.1016/j.ijpharm.2016.07.043
Liquid Crystalline Nanodispersions Functionalized with Cell-Penetrating Peptides for Topical Delivery of Short-Interfering RNAs: A Proposal for Silencing a Pro-Inflammatory Cytokine in Cutaneous Diseases.
Petrilli R,Eloy J O,Praça F S G,Del Ciampo J O,Fantini M A C,Fonseca M J V,Bentley M V L B
Journal of biomedical nanotechnology
Short-interfering RNAs (siRNAs) are a potential strategy for the treatment of cutaneous diseases. In this context, liquid crystalline nanoparticles functionalized with specific proteins and peptide-transduction domains (PTDs), which act as penetration enhancers, are a promising carrier for siRNA delivery through the skin. Herein, hexagonal phase liquid crystal nanoparticles based on monoolein (MO) and/or oleic acid (OA) containing (or lacking) the cationic polymer polyethylenimine (PEI) and the cationic lipid oleylamine (OAM) were functionalized with the membrane transduction peptides transcriptional activator (TAT) or penetratin (PNT). These nanoparticles were complexed with siRNA and characterized by particle size, polydispersity, zeta potential, complexation efficiency and siRNA release. The formulations containing cationic agents presented positive zeta potentials, sizes on the nanometer scale, and complexed siRNAs at concentrations of 10 μM; these agents were successfully released in a heparin competition assay. Cell culture studies demonstrated that nanoparticles composed of MO:OA:PEI functionalized with TAT were the most efficient at transfecting L929 cells, and the uptake efficiency was enhanced by TAT peptide functionalization. Thereafter, the selected formulations were evaluated for in vivo skin irritation, penetration and in vivo efficacy using a chemically induced inflammatory animal model. These nanoparticles did not irritate the skin and provided higher siRNA penetration and delivery into the skin than control formulations. Additionally, efficacy studies in the animal model showed that the association of TAT with the nanodispersion provided higher suppression of tumor necrosis factor (TNF)-α. Thus, the development of liquid crystalline nanodispersions containing TAT may lead to improved topical siRNA delivery for the treatment of inflammatory skin diseases.
Sustained release of piroxicam from solid lipid nanoparticle as an effective anti-inflammatory therapeutics in vivo.
Peng Li-Hua,Wei Wei,Shan Ying-Hui,Chong Yee-Song,Yu Lian,Gao Jian-Qing
Drug development and industrial pharmacy
This study aims to investigate the solid lipid nanoparticle (SLN) as a novel vehicle for the sustained release and transdermal delivery of piroxicam, as well as to determine the anti-inflammation effect of piroxicam-loaded SLN. SLN formulation was optimized and the particle size, polydispersity index, zeta potential (ZP), encapsulation efficiency, drug release, and morphological properties were characterized. The transdermal efficiency and mechanism of the piroxicam-loaded SLNs were investigated in vitro. With the inflammation induced edema model in rat, the anti-inflammatory efficiency of piroxicam-enriched SLNs (Pir-SLNs) was evaluated. The SLN formulation was optimized as: lecithin 100 mg, glycerin monostearate 200 mg, and Tween (1%, w/w). The particle size is around 102 ± 5.2 nm with a PDI of 0.262. The ZP is 30.21 ± 2.05 mV. The prepared SLNs showed high entrapment efficiency of 87.5% for piroxicam. There is no interaction between piroxicam and the vehicle components. The presence of polymorphic form of lipid with higher drug content in the optimized Pir-SLNs enables the Pir-SLNs to release the drug with a sustained manner. Pir-SLNs with oleic acid as enhancer can radically diffuse into both the stratum corneum and dermal layer, as well as penetrate through the hair follicles and sebaceous glands with significantly higher density than the other control groups. Pir-SLNs promptly inhibited the inflammation since the 3rd hour after the treatment by decreasing the PGE level. SLN was demonstrated to be a promising carrier for encapsulation and sustained release of piroxicam. Pir-SLN is a novel topical preparation with great potential for anti-inflammation application.
10.1080/03639045.2016.1220563
Development of microemulsions of suitable viscosity for cyclosporine skin delivery.
Benigni Marta,Pescina Silvia,Grimaudo Maria Aurora,Padula Cristina,Santi Patrizia,Nicoli Sara
International journal of pharmaceutics
Psoriasis is a widespread chronic disease affecting 2-4% of the population in Western countries. Its mild-to-moderate form, representing approximately 80% of the total cases, is treated by topical application, with corticosteroid being the standard treatment. However, in case of psoriasis, no single treatment works for every patient and optimizing topical therapy is a key aspect. A possible alternative is represented by cyclosporine, an immunosuppressant cyclic peptide administered orally in the treatment of the severe form. Its topical application could avoid the problems related to systemic immunosuppression, but the unfavourable physico-chemical properties (MW: 1202 Da; LogP ≈ 3) hinder its permeation across the stratum corneum. The aim of the paper was the preparation, characterization and ex-vivo evaluation of cyclosporine loaded microemulsions using oleic acid as oil phase, either Tween80 or a soluble derivative of vitamin E (TPGS) as surfactants and either Transcutol, propylene glycol or 1,3 propanediol as co-surfactants. The issue of formulation viscosity was also addressed 1) by evaluating the thickening of Tween80-based microemulsions by direct addition of different rheological modifiers, 2) by building pseudo-ternary phase diagrams using TPGS, to identify the water/oil/surfactants proportions resulting in viscous self-gelifying systems. Nine formulations (five Tween80-based and four TPGS-based) were selected, characterized in terms of droplets size (low viscosity systems) or rheological properties (high viscosity systems), loaded with 6 mg/g cyclosporine and applied ex-vivo on porcine skin for 22 h. A relevant skin accumulation was obtained either with a low-viscosity Tween80-based microemulsion (9.78 ± 3.86 µg/cm), or with a high viscosity TPGS-based microemulsion (18.3 ± 5.69 µg/cm), with an increase of about 3 and 6 times respectively for comparison with a control cyclosporine solution in propylene glycol. The role of water content, surfactant, co-surfactant and viscosity was also addressed and discussed. The kinetic of skin uptake from the best performing formulation was finally evaluated, highlighting a relatively quick skin uptake and the achievement, after 2 h of contact, of potentially therapeutic cyclosporine skin concentrations.
10.1016/j.ijpharm.2018.04.049
Development of Microemulsions and Microemulgels for Enhancing Transdermal Delivery of Kaempferia parviflora Extract.
Rangsimawong Worranan,Wattanasri Paisit,Tonglairoum Prasopchai,Akkaramongkolporn Prasert,Rojanarata Theerasak,Ngawhirunpat Tanasait,Opanasopit Praneet
AAPS PharmSciTech
The purpose of this research was to develop microemulsions (ME) and microemulgels (MG) for enhancing transdermal delivery of Kaempferia parviflora (KP) extract. The methoxyflavones were used as markers. Various formulations of ME and MG containing 10% w/v KP extract were prepared, and the in vitro skin permeation and deposition were investigated. The potential ME system containing oleic acid (5% w/v), Tween 20 (20% w/v), PG (40% w/v), and water (35% w/v) was successfully formulated. ME with 10% w/v limonene (ME-L10%) showed higher methoxyflavones flux than ME-L5%, ME-L1%, ME without limonene, and KP extract in water, respectively. ME-L10% was selected for adding a gelling agent to form microemulgels (MG-L10%). However, the high viscosity of the gel formulation might control the diffusion of the compound from gel layer into the skin. Therefore, the liquid formulation provided potential ME droplets to deliver KP extract through the skin. Limonene also plays an effective role on the skin permeation, in which the histological image of the skin treated with ME-L10% exhibited larger space of each flattened keratinocyte layer in the stratum corneum compared to the skin treated with KP extract in water. Moreover, ME-L10% showed good stability. Therefore, ME-L10% was a potential formulation for improving transdermal delivery of KP extract.
10.1208/s12249-018-1003-6
Effects of chemical and physical enhancement techniques on transdermal delivery of 3-fluoroamphetamine hydrochloride.
Puri Ashana,Murnane Kevin S,Blough Bruce E,Banga Ajay K
International journal of pharmaceutics
The present study investigated the passive transdermal delivery of 3-fluoroamphetamine hydrochloride (PAL-353) and evaluated the effects of chemical and physical enhancement techniques on its permeation through human skin. In vitro drug permeation studies through dermatomed human skin were performed using Franz diffusion cells. Passive permeation of PAL-353 from propylene glycol and phosphate buffered saline as vehicles was studied. Effect of oleic acid, maltose microneedles, ablative laser, and anodal iontophoresis on its transdermal permeation was investigated. Infrared spectroscopy, scanning electron microscopy, calcein imaging, confocal laser microscopy, and histology studies were used to characterize the effects of chemical and physical treatments on skin integrity. Passive permeation of PAL-353 (propylene glycol) after 24h was found to be 1.03±0.17μg/cm. Microneedles, oleic acid, and laser significantly increased the permeation to 7.35±4.87μg/cm, 38.26±5.56μg/cm, and 523.24±86.79μg/cm (p<0.05), respectively. A 548-fold increase in drug permeation was observed using iontophoresis as compared to its passive permeation from phosphate buffered saline (p<0.05). The characterization studies depicted disruption of the stratum corneum by microneedles and laser treatment. Overall, transdermal permeation of PAL-353 was significantly enhanced by the use of chemical and physical enhancement techniques.
10.1016/j.ijpharm.2017.06.041
Skin Delivery and Irritation Potential of Phenmetrazine as a Candidate Transdermal Formulation for Repurposed Indications.
Jiang Ying,Murnane Kevin S,Bhattaccharjee Sonalika A,Blough Bruce E,Banga Ajay K
The AAPS journal
Phenmetrazine, a selective dopamine and norepinephrine releaser, previously available as an oral anorectic, is prone to be abused. This study aimed to assess the feasibility of delivering phenmetrazine via the transdermal route for a new indication, while also minimizing its abuse potential. The passive permeation of phenmetrazine through dermatomed human cadaver skin was evaluated using static Franz diffusion cells at 10 mg/mL for the fumarate salt, and at 20, 40, and 80 mg/mL for the free base in propylene glycol for 24 h. Further, oleic acid (5% w/w), oleyl alcohol (5% and 10% w/w), and lauric acid (10% w/w) were investigated as chemical permeation enhancers to enhance the delivery. Skin irritation potential was assessed using EpiDerm™ in vitro reconstructed human epidermal model. The free base showed superior 24-h delivery (8.13 ± 4.07%, 10.6 ± 2.5%, and 10.4 ± 1.4% for groups with 20, 40, and 80 mg/mL of the free base, respectively) to phenmetrazine fumarate salt (undetectable). The successful screening of effective chemical enhancers, oleyl alcohol (5% and 10% w/w), oleic acid (5% w/w), and lauric acid (10% w/w) resulted in significant enhancement of delivery. The calculated therapeutic relevant flux for the potential indication, attention deficit hyperactivity disorder, 20 μg/cm/h was met, where a 24-mg daily dose from a 50-cm patch was projected to be delivered to a 60-kg individual. Irritation study results suggest that formulations with therapeutically relevant delivery are likely to be non-irritant. In conclusion, it is feasible to deliver therapeutically relevant amounts of phenmetrazine via the transdermal route.
10.1208/s12248-019-0335-9
Microemulsion Formulations for the Transdermal Delivery of Lapachol.
Tabosa Maria Alice Maciel,de Andrade Ana Rosa Brissant,Lira Ana Amélia Moreira,Sarmento Victor Hugo Vitorino,de Santana Davi Pereira,Leal Leila Bastos
AAPS PharmSciTech
This project was carried out to investigate the feasibility of using microemulsions for transdermal delivery of lapachol. From the screening of surfactants and oils, a range of microemulsions were developed using oleic acid, a mixture of Cremophor EL and Tween 20 and water. The solubility of lapachol was determined in these ingredients and in the formulated microemulsions. The microemulsions were characterised using cross-polarising light microscopy, their electrical conductivity, pH, zeta potential and rheology were analysed, and they were also investigated using small-angle X-ray scattering and differential scanning calorimetry. Ex vivo studies were performed using porcine ear skin and Franz diffusion cells to investigate the permeation and retention of lapachol. Systems containing different concentrations of Cremophor EL (8.4-41.6%), Tween 20 (5.4-41.6%) and oleic acid (12-31.9%) are able to form microemulsions. Lapachol was delivered more effectively through the skin from all of the microemulsions tested than by the control (oleic acid). These studies indicated that microemulsions incorporating lapachol were formed successfully and that these enhanced drug delivery and retention in the skin. Microemulsion systems may, therefore, provide promising vehicles for percutaneous delivery of lapachol.
10.1208/s12249-018-0995-2
Enhancement in the Transdermal and Localized Delivery of Honokiol Through Breast Tissue.
Gao Xinyi,Patel Meera Gujjar,Bakshi Pooja,Sharma Dipali,Banga Ajay K
AAPS PharmSciTech
Honokiol is a natural phenolic anti-cancer compound isolated from an extract of seed cones from Magnolia grandiflora. This study investigated the transdermal delivery of honokiol using various enhancement methods and to explore the potential of honokiol to treat breast cancer directly via delivery through mammary papilla. Poration of dermatomed human skin with microneedles significantly increased the delivery of honokiol by nearly 3-fold (97.81 ± 18.96 μg/cm) compared with passive delivery (32.56 ± 5.67 μg/cm). Oleic acid was found to be the best chemical penetration enhancer, increasing the delivery almost 27-fold (868.06 ± 100.91 μg/cm). Addition of oleic acid also resulted in better retention of drug in the porcine mammary papilla (965.41 ± 80.26 μg/cm) compared with breast skin (294.16 ± 8.49 μg/cm). Anti-cancer effect of honokiol was demonstrated with the decrease in the release of cytokine IL-6 and further suppression of Ki-67 proliferative protein. In addition, the topical honokiol formulation investigated was found to be safe and non-irritant. In summary, both microneedles and chemical enhancers can improve the absorption of honokiol through skin. Directly applying honokiol on mammary papilla is a potential administration route which can increase localized delivery into breast tissue.
10.1208/s12249-018-1158-1
Development of Betamethasone Dipropionate-Loaded Nanostructured Lipid Carriers for Topical and Transdermal Delivery.
Hanna Pierre A,Ghorab Mamdouh M,Gad Shadeed
Anti-inflammatory & anti-allergy agents in medicinal chemistry
INTRODUCTION:Betamethasone dipropionate is a highly effective corticosteroid anti-inflammatory. However, the main drawback of its topical use is the limited skin penetration into deeper skin layers. Also, its systemic use has shown many side effects. OBJECTIVE:The goal of this research was to formulate betamethasone dipropionate in nanostructured lipid carriers (NLC) formulae that contain oleic acid to aid its penetration to deeper skin layers and to aid absorption to local regions upon topical application. METHODS:NLC formulae were prepared by high shear homogenization then sonication. Formulae were characterized for their particle size, size distribution, electric potential, occlusion factor, entrapment efficiency, drug loading, transmission electron microscopy, in vitro drug release, and ex vivo skin penetration. Compatibility of ingredients with drug was tested using differential scanning calorimetry. Formulae were shown to have appropriate characteristics. NLC formulae were superior to traditional topical formulation in drug release. RESULTS:Upon testing ex vivo skin penetration, betamethasone dipropionate prepared in NLC formulae was shown to penetrate more efficiently into skin layers than when formulated as a traditional cream. NLC formulation that contained higher percentage of oleic acid showed higher penetration and higher amount of drug to pass through skin. CONCLUSION:In general, NLC with lower oleic acid percentage was shown to deliver betamethasone dipropionate more efficiently into deeper skin layers while that of a higher oleic acid percentage was shown to deliver the drug more efficiently into deeper skin layers and through the skin, transdermally.
10.2174/1871523017666181115104159
Effects of solvents and penetration enhancers on transdermal delivery of thymoquinone: permeability and skin deposition study.
Drug delivery
Thymoquinone (TQ) is a quinone-based phytochemical that was first identified in 1963 in Nigella sativa (black cumin seed) by El-Dakhakhany. Based on the ideal characteristics of transdermal delivery, TQ is potentially an attractive candidate for transdermal drug delivery. The aim of this study was to investigate the feasibility of transdermal delivery of TQ and to assess the effect of an ethanol and propylene glycol donor solvent system along with various compositions of receptor solvents. The effects of penetration enhancers on the in vitro skin permeation and TQ skin absorption were studied using human cadaver skin in Franz diffusion cells. The permeation of saturated solutions of TQ was investigated with 5% v/v of each of the following enhancers: Azone (laurocapram), Transcutol® P (Tc), oleic acid, ethanol, Polysorbate 80 (Tween 80), and N-methyl-pyrrolidone (NMP). The results indicated that Azone, oleic acid, and Tc were able to provide adequate TQ flux and may be the agents of choice for use in a novel transdermal formulation of TQ. These penetration enhancers were also able to generate TQ reservoirs in the skin that may be useful to provide sustained release of TQ from the stratum corneum over longer periods of time.
10.1080/10717544.2018.1523256
Fatty acid vesicles acting as expanding horizon for transdermal delivery.
Kumar Lalit,Verma Shivani,Kumar Sanjeev,Prasad Deo Nandan,Jain Amit Kumar
Artificial cells, nanomedicine, and biotechnology
The body is protected against the external environment by the skin due to its physical barrier nature. Stratum corneum composed of corneocytes surrounded by lipid region performs a major barrier function as it lies in the uppermost area of skin. Alteration in barrier function, increase in permeability, and disorganization of stratum corneum represent diseased skin. Drugs applied to the diseased skin should induce a local effect at the site of application or area close to it along with cutaneous absorption rather than percutaneous absorption. Conventional formulations like ointments, gels, and creams suffer from the drawback of limited local activity. For the enhancement of drug penetration and localization of the drug at the site of action approaches explored are liposomes, niosomes, ethosomes microparticles, and solid lipid nanoparticles. Vesicles composed of fatty acids like oleic acid and linoleic acid represent the new approach used for transdermal penetration and localization. In this review article, our major aim was to explore the applications of fatty acid vesicles for transdermal delivery of various bioactives.
10.3109/21691401.2016.1146729
Ion-pair formation combined with a penetration enhancer as a dual strategy to improve the transdermal delivery of meloxicam.
Jiang Qikun,Wang Jin,Ma Panqin,Liu Cuiru,Sun Mengchi,Sun Yinghua,He Zhonggui
Drug delivery and translational research
The aim of the study was to develop a novel drug-in-adhesive patch for transdermal delivery of meloxicam (MLX). The formulation involved a strategy to combine a chemical enhancer with an ion-pair agent. Diethylamine (DETA) was selected as the counter ion to form the ion-pair agent MLX-DETA. MLX-DETA was characterized by nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). The ion-pair lifetime (T ) of MLX-DETA was 164.1 μs. The water solubility of MLX-DETA was increased nearly 9.3-fold, compared with that of MLX. Oleic acid (OA) was selected as the chemical enhancer, and the optimized formulation consisted of 5% (w/w) MLX-DETA, 5% (w/w) oleic acid, and DURO-TAK® 87-4098 adhesive as the pressure-sensitive adhesive matrix. The permeation study in vitro showed that both the counter ion and chemical enhancer were effective in improving the skin permeation of MLX. Tissue distribution studies demonstrated that higher accumulation of MLX following application of the MLX-DETA patch to the skin could be obtained in rats compared with the MLX-patch group. In conclusion, to increase the skin absorption and obtain a sustained release for the transdermal delivery of MLX, preparation of a drug-in-adhesive patch by combining an ion pair (MLX-DETA) with a permeation enhancer (OA) is a suitable strategy.
10.1007/s13346-017-0434-z
Using Raman Spectroscopy in Studying the Effect of Propylene Glycol, Oleic Acid, and Their Combination on the Rat Skin.
Atef Eman,Altuwaijri Njoud
AAPS PharmSciTech
The permeability enhancement effect of oleic acid (OA) and propylene glycol (PG) as well as their (1:1 v/v) combined mixture was studied using rat skin. The percutaneous drug administration is a challenge and an opportunity for drug delivery. To date, there is limited research that illustrates the mechanism of penetration enhancers and their combinations on the skin. This project aims to explore the skin diffusion and penetration enhancement of PG, OA, and a combination of PG-OA (1:1 v/v) on rat skin and to identify the potential synergistic effect of the two enhancers utilizing Raman spectroscopy. Dissected dorsal skin was treated with either PG or OA or their combination for predetermined time intervals after which the Raman spectra of the treated skin were collected with the enhancer. A spectrum of the wiped and the washed skin were also collected. The skin integrity was tested before and after exposure to PG. The skin histology proved that the skin integrity has been maintained during experiments and the results indicated that OA disrupted rat skin lipid as evident by changes in the lipid peak. The results also showed that PG and OA improved the diffusion of each other and created faster, yet reversible changes of the skin peaks. In conclusion, Raman spectroscopy is a potential tool for ex vivo skin diffusion studies. We also concluded that PG and OA have potential synergistic reversible effect on the skin.
10.1208/s12249-017-0800-7
Synthesis of an oleic acid based pH-responsive lipid and its application in nanodelivery of vancomycin.
Mhule Danford,Kalhapure Rahul S,Jadhav Mahantesh,Omolo Calvin A,Rambharose Sanjeev,Mocktar Chunderika,Singh Sanil,Waddad Ayman Y,Ndesendo Valence M K,Govender Thirumala
International journal of pharmaceutics
Stimuli-responsive nano-drug delivery systems can optimize antibiotic delivery to infection sites. Identifying novel lipids for pH responsive delivery to acidic conditions of infection sites will enhance the performance of nano-drug delivery systems. The aim of the present investigation was to synthesize and characterize a biosafe novel pH-responsive lipid for vancomycin delivery to acidic conditions of infection sites. A pH-responsive solid lipid, N-(2-morpholinoethyl) oleamide (NMEO) was synthesized and used to prepare vancomycin (VCM)-loaded solid lipid nanoparticles (VCM_NMEO SLNs). The particle size (PS), polydispersity index (PDI), zeta potential (ZP) and entrapment efficiency (EE) of the formulation were 302.8 ± 0.12 nm, 0.23 ± 0.03, -6.27 ± 0.017 mV and 81.18 ± 0.57% respectively. The study revealed that drug release and antibacterial activity were significantly greater at pH 6.0 than at pH 7.4, while the in silico studies exposed the molecular mechanisms for improved stability and drug release. Moreover, the reduction of MRSA load was 4.14 times greater (p < 0.05) in the skin of VCM_NMEO SLNs treated mice than that of bare VCM treated specimens. Thus, this study confirmed that NMEO can successfully be used to formulate pH-responsive SLNs with potential to enhance the treatment of bacterial infections.
10.1016/j.ijpharm.2018.08.025
Investigation of Fucoidan-Oleic Acid Conjugate for Delivery of Curcumin and Paclitaxel.
Phan Uyen T,Nguyen Khanh T,Vo Toi V,Duan Wei,Tran Phuong H L,Tran T D
Anti-cancer agents in medicinal chemistry
Nanoparticles for a specific delivery are likely to be designed for cancer therapeutic effectiveness and improvement. In this study, a fucoidan-oleic acid conjugate was prepared and investigated in terms of loading capacity for poorly water-soluble anti-cancer drugs to maximize effectiveness of the treatment. Fucoidan was used as a hydrophilic portion of an amphiphilic structure for improving cancer therapeutic effects. Paclitaxel and curcumin were chosen as other model drugs loaded in the conjugates. The results showed that self-assembled nanoparticles with different sizes and morphologies could be prepared with two different concentrations of oleic acid as hydrophobic portion. Moreover, loading efficiency and release patterns of these drugs were mainly dependent on the hydrophobic interaction between drugs and oleic acid. It was also revealed that fucoidan and curcumin were released higher at pH 4.5 than at the physiological condition (pH 7.4), thus, facilitating the delivery and maximizing effects of the anticancer agents on cancer cells. On the contrary, paclitaxel from fucoidan nanoparticles was released faster at pH 7.4. The exploration of fucoidan-oleic acid conjugate could be considered as promising nanomedicines for cancer therapeutics.
10.2174/1567201810666131124140259
Pro-apoptotic activity of nano-escheriosome based oleic acid conjugate against 7,12-dimethylbenz(a)anthracene (DMBA) induced cutaneous carcinogenesis.
Khan Azmat Ali
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
AIM:2,6-Diisopropylphenol-oleic acid (2,6P-OLA) is an ester conjugate of oleic acid that has displayed a strong anticancer activity on different types of cancer cell lines (Khan et al., 2012). The present study is focused on the development of a nano-liposome-based approach for the delivery of 2,6P-OLA on 7,12-dimethylbenz(a)anthracene (DMBA) induced cutaneous papilloma in experimental mice. For effective and specific delivery of the conjugate to the tumor site, it was incorporated into escheriosome (EC); an Escherichia coli lipid nanoparticle. MATERIALS AND METHODS:I determined the size, zeta-potential, entrapment and release efficacy of 2,6P-OLA-EC nano-formulation. The consequence of 2,6P-OLA-EC treatment was initially analyzed by regression in tumor volume, inhibition of cutaneous papilloma and survival of treated mice. Its anticancer activity was further examined by histopathology, fluorescence microscopy, flow cytometry and electroblot-immuno assay of apoptotic factors. RESULTS:Distinct disperse circular shaped EC nanoparticles showed slow and sustained release of therapeutic concentration of 2,6P-OLA in the surrounding milieu. 2,6P-OLA-EC significantly reduced tumor volume and inhibited onset of new papilloma. Treatment with nano-formulation revealed induced caspase-9 activity and noteworthy apoptotic response as visualized by fluorescence microscopy and TUNEL assay. Electroblot-immuno analysis revealed significant modulation of p53wt and p53mut expression levels. CONCLUSION:The results suggest the therapeutic potential of 2,6P-OLA entrapped in nano-escheriosomes against cutaneous papilloma and can become a promising system against various forms of cancer as well.
10.1016/j.biopha.2017.03.061
Skin permeation, biocompatibility and antitumor effect of chloroaluminum phthalocyanine associated to oleic acid in lipid nanoparticles.
Almeida Ellen Denise P,Dipieri Lívia V,Rossetti Fábia C,Marchetti Juliana M,Bentley Maria Vitória L B,Nunes Rogéria de S,Sarmento Víctor Hugo V,Valerio Mário Ernesto G,Rodrigues Júnior José Joatan,Montalvão Monalisa M,Correa Cristiane B,Lira Ana Amélia M
Photodiagnosis and photodynamic therapy
The objective of this study was to develop and characterize lipid nanoparticles (LNs) containing chloroaluminum phthalocyanine (ClAlPc) to reduce the aggregation of the drug and improve its skin penetration and its antitumor effect. LNs were prepared and characterized by using stearic acid (SA) as solid lipid and oleic acid (OA) as liquid lipid in different proportions. in vitro and in vivo skin penetration was evaluated using modified Franz diffusion cells and fluorescence microscopy, respectively. in vitro biocompatibility and Photodynamic Therapy (PDT) were performed using L929-fibroblasts cell line and A549 cancer cell line and melanoma BF16-F10, respectively. OA promoted the increase in the encapsulation efficiency and drug loading, reaching values of 95.8% and 4%, respectively. The formulation with 40% OA (NLC 40) showed a significantly higher (p < 0.01) amount of drug retained in the skin compared to other formulations. All formulations developed were considered biocompatible. PDT evidenced the antitumor efficacy of NLC 40 with reduced cell viability for approximately 10% of cancer cells, demonstrating that the presence of OA in the NLC seems to potentialize this antitumor effect. PDT in BF16-F10 melanoma using NLC 40 resulted in a reduction in mean cell viability of approximately 99%. According to the results obtained, the systems developed may be promising for the incorporation of ClAlPc in the treatment of skin cancer by photodynamic therapy.
10.1016/j.pdpdt.2018.10.002
Large-Scale, Facile Transfer of Oleic Acid-Stabilized Iron Oxide Nanoparticles to the Aqueous Phase for Biological Applications.
Cai Jing,Miao Yu Qing,Yu Bao Zhi,Ma Pei,Li Li,Fan Hai Ming
Langmuir : the ACS journal of surfaces and colloids
FeO nanoparticles synthesized via thermal decomposition in the organic phase have attracted tremendous research interest because of their unique morphology, size dispersion, and crystallinity. However, their poor water dispersibility strongly limited their development in biomedical applications. Therefore, a phase-transfer strategy through which hydrophobic nanoparticles with good performance in the aqueous phase can be obtained is an extremely critical issue. Herein, we present a large-scale, facile, highly efficient strategy for the phase transfer of oleic acid-coated FeO nanoparticles via a reverse-micelle-based oxidative reaction. The reverse micelle system improves the efficiency of the interface oxidative reaction and prevents the aggregation of nanoparticles during the reaction, facilitating the transfer of FeO nanoparticles from the organic phase to the aqueous phase. The transferred FeO nanoparticles are used as a T contrast agent to perform magnetic resonance imaging of CNE2 cells (nasopharyngeal carcinoma cell line). In addition, the free carboxyl groups on the surface of transferred nanoparticles can also be programmed to permit the conjugation of other molecules, in turn allowing nanoparticles to be extended in biological targeting or biological recognition applications. Therefore, this strategy offers a promising platform for the large-scale, highly efficient phase transfer of oleic acid-capped nanoparticles and may become a new paradigm to promote the development of diverse nanoparticles for widespread biomedical applications.
10.1021/acs.langmuir.6b03360