Ulya Badilli

Microparticulate Based Topical Delivery System of Clobetasol Propionate

Psoriasis is a chronic, autoimmune skin disease affecting approximately 2% of the worlds population. Clobetasol propionate which is a superpotent topical corticosteroid is widely used for topical treatment of psoriasis. Conventional dosage forms like creams and ointments are commonly prefered for the therapy. The purpose of this study was to develop a new topical delivery system in order to provide the prolonged release of clobetasol propionate and to reduce systemic absorption and side effects of the drug. Clobetasol propionate loaded-poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared by oil-in-water emulsion–solvent evaporation technique. Particle size analysis, morphological characterization, DSC and XRD analyses and in vitro drug release studies were performed on the microparticle formulations. Emulgel formulations were prepared as an alternative for topical delivery of clobetasol propionate. In vitro drug release studies were carried out from the emulgel formulations containing pure drug and drug-loaded microspheres. In addition, the same studies were performed to determine the drug release from the commercial cream product of clobetasol propionate. The release of clobetasol propionate from the emulgel formulations was significantly higher than the commercial product. In addition, the encapsulation of clobetasol propionate in the PLGA microspheres significantly delayed the drug release from the emulgel formulation. As a result, the decrease in the side effects of clobetasol propionate by the formulation containing PLGA microspheres is expected.

Quality by design case study 1: Design of 5-fluorouracil loaded lipid nanoparticles by the W/O/W double emulsion - Solvent evaporation method.

With Quality by Design (QbD), a systematic approach involving design and development of all production processes to achieve the final product with a predetermined quality, you work within a design space that determines the critical formulation and process parameters. Verification of the quality of the final product is no longer necessary. In the current study, the QbD approach was used in the preparation of lipid nanoparticle formulations to improve skin penetration of 5-Fluorouracil, a widely-used compound for treating non-melanoma skin cancer. 5-Fluorouracil-loaded lipid nanoparticles were prepared by the W/O/W double emulsion - solvent evaporation method. Artificial neural network software was used to evaluate the data obtained from the lipid nanoparticle formulations, to establish the design space, and to optimize the formulations. Two different artificial neural network models were developed. The limit values of the design space of the inputs and outputs obtained by both models were found to be within the knowledge space. The optimal formulations recommended by the models were prepared and the critical quality attributes belonging to those formulations were assigned. The experimental results remained within the design space limit values. Consequently, optimal formulations with the critical quality attributes determined to achieve the Quality Target Product Profile were successfully obtained within the design space by following the QbD steps.

Topical emulgel formulation containing inclusion complex of calcipotriol with cyclodextrin

Psoriasis is a relatively common, chronic, inflammatory disease that affects the skin, scalp, and joints. Calcipotriol is one of the most commonly used topical agents for the treatment of psoriasis. However, it is a water-insoluble active substance and frequently leads to skin irritation in patients. Cyclodextrins (CDs) are cyclic oligosaccharides consisting of (α-1,4-)-linked d-glucopyranose units. CD molecules have a hydrophilic outer surface and a lipophilic central cavity, and they are able to form inclusion complexes in aqueous solutions with many drugs. They can increase bioavailability, aqueous solubility, and stability and also reduce the side effects of the drugs. The aim of this study was to develop a new topical drug delivery system of calcipotriol in order to improve the solubility and dissolution characteristics of the drug and reduce the undesirable side effects. For this purpose, an inclusion complex of calcipotriol with Captisol® was prepared, and complex formation was confirmed. The inclusion complex and pure drug were formulated separately in an emulgel base. Dissolution profiles of calcipotriol from emulgel formulations were compared with a commercial product of the drug. The drug release was significantly increased with the emulgel formulations compared to the commercial cream product.

Development of a HILIC method for the determination of 5-fluorouracil from nano drug delivery systems and rat skin extracts

HIGHLIGHTSFirst hydrophilic interaction liquid chromatography with diode array detection study for stability indicating determination of 5‐Fluorouracil.5‐Fluorouracil loaded solid lipid nanoparticle and nano lipid carrier formulations were developed.Developed method has sufficient sensitivity for the estimation of 5‐Fluorouracil in raw materials, marketed formulation and rat skin extracts.Ex‐vivo Penetration/Permeation Studies with rat skin indicated that higher dermal accumulation of 5‐Fluorouracil was obtained with nano lipid carrier formulation. ABSTRACT This is the first report in literature using hydrophilic interaction liquid chromatography (HILIC) in combination with diode array detector (DAD) for stability indicating determination of 5‐Fluorouracil (5‐FU) from its bulk form, pharmaceutical preparations, developed solid lipid nanoparticle (SLN) and nano structured lipid carrier (NLC) drug delivery systems as well as the rat skin extracts. The separation was performed at 45°C, on Sequant Zic HILIC (250mm×4.60mm ID, 5&mgr;m, 200Ao), peek HPLC column. Mobile phase is consisting of a mixture of acetonitrile: buffer containing 5mM ammonium acetate (95:5; v/v). The pH of the mobile phase was adjusted to 7.0 using 1M NaOH. The analysis was carried out at 0.75mLmin−1 flow rate with a detection wavelength of 265nm and the injection volume was arranged as 10&mgr;L. The developed method was fully validated in accordance with the International Council on Harmonization (ICH) Guidelines. Specificity of this method was demonstrated by forced degradation studies. As a result of calibration studies, the calibration curve was found linear in the concentration range of 1–250&mgr;gmL−1 (R2=0.999). The precision of this technique calculated within the frame of intra‐day and inter‐day based on a percentage of relative standard deviation (RSD%) values (<2%). The limits of detection and quantification were 11 and 37ngmL−1 respectively. On the other hand, 5‐FU loaded SLN and NLC formulations with average particle size of 370nm were also developed and compared in order to increase the permeation of drug into the rat skin. Ex‐vivo Penetration/Permeation Studies indicated that higher dermal accumulation of 5‐FU was obtained with NLC formulation. As a conclusion, the present work expressed the optimization and the validation of a selective, simple, precise and accurate fully validated HILIC method with sufficient sensitivity for the estimation of 5‐FU in raw materials, marketed formulation and rat skin extract after applying both of the commercial product and newly developed nanoparticulate drug delivery systems on to the rat skins with high percentage recoveries.

Development Of Etofenamate-Loaded Semisolid Sln Dispersions And Evaluation Of Anti-Inflammatory Activity For Topical Application

Dermal application of various active substances is widely preferred for topical or systemic delivery. SLNs consist of biocompatible and non-toxic lipids and have a great potential for topical application in drugs. In this study, semisolid SLN formulations were successfully prepared by a novel one-step production method as a topical delivery system of etofenamate, an anti-inflammatory drug. Compritol 888 ATO and Precirol ATO 5 were chosen as lipid materials for the fabrication of the formulations. In-vitro evaluation of the formulations was performed in terms of encapsulation efficiency, particle size, surface charge, thermal behavior, rheological characteristics, in vitro drug release profile, kinetics, mechanisms, stability, and anti-inflammatory activity. The colloidal size and spherical shape of the particles were proved. According to the results of the rheological analysis, it was demonstrated that the semisolid SLN formulations have a gel-like structure. Stability studies showed that semisolid SLNs were stable at 4°C for a six month period. Zero order release was obtained with Precirol ATO 5, while Compritol 888 ATO followed the square root of time (Higuchis pattern) dependent release. Semisolid SLNs showed higher inhibitory activity of COX in comparison with pure etofenamate. In conclusion, etofenamate-loaded semisolid SLN formulations can be successfully prepared in a novel one-step production method and useful for topical application.

Lipid-based nanoparticles for dermal drug delivery

Abstract Dermal drug application is commonly used for the local treatment of skin diseases. However, the uppermost layer of the skin, stratum corneum, plays an effective role as a physical barrier against to the penetration of compounds into skin. The physicochemical properties of the active agents and vehicles are major limiting factors for the skin penetration of the drugs. In recent years, nanoparticulate drug delivery systems, especially lipid nanoparticles, attract considerable interest in providing enhanced skin penetration and to ensure site-specific skin targeting of drugs. Solid-lipid nanoparticles, nanostructured lipid carriers and lipid nanocapsules are manufactured using biocompatible and biodegradable lipids that have various advantages for dermal administration, such as controlled release of active agents, increasing the chemical stability of sensitive drugs, enhancing the penetrated amount of active substances into skin, and drug targeting to different skin layers. In this chapter, an overview of lipid-based nanoparticles as dermal drug delivery systems will be presented, preparation techniques and in vitro/in vivo characterization methods of lipid nanoparticles and their assays will be reviewed. Analytical studies related to the drug-loaded lipid nanoparticles, their characterization, and quantitation are also discussed and summarized as details.

Novel Drug Delivery System For Dermal Uptake Of Etofenamate: Semisolid SLN Dispersion

BACKGROUND Semisolid SLNs are novel strategy for dermal drug administration instead of incorporating the SLN dispersions into conventional semisolids. Etofenamate loaded semisolid SLNs were successfully prepared and in vitro characterization of formulations were performed in our previous study. The present study is an attempt to evaluate the dermal behavior of the semisolid SLNs selected on the basis of previous research and investigate the properties in terms of the convenience for topical applications. OBJECTIVE The objective of this study is to evaluate the skin penetration characteristics of semisolid SLN formulations. The occlusive and mechanical properties of semisolid SLNs were also evaluated because of their impression on the dermal behavior of the formulations. METHOD The occlusive properties were investigated by in vitro occlusion test. Texture analysis was performed to define the hardness, compressibility, adhesiveness, cohesiveness and elasticity of the formulations. Rat skin was chosen to evaluate the ex vivo penetration of etofenamate loaded semisolid SLNs and commercial gel product. Coumarin-6 was used to visualize the dermal distribution of the semisolid SLN formulations. For monitorizing the penetration of coumarin-6 into the skin samples Confocal Laser Scanning Microscopy was employed. RESULTS The occlusive and mechanical properties of C1 coded semisolid SLN formulation were found more favorable in comparison with P1. The cumulative etofenamate amount in skin samples was found to be 39.88 ± 1.50 μg/cm2 for C1 and 30.56 ± 2.10 μg/cm2 for P1 coded formulations. According to CLSM images, greater fluorescence intensities and deeper skin penetrations were obtained with both of the semisolid SLNs in comparison to plain Carbopol gel. CONCLUSION It can be concluded that the semisolid SLNs are promising alternative dermal drug delivery systems to the conventional dosage forms.

Skin Localization of Lipid Nanoparticles (SLN/NLC): Focusing the Influence of Formulation Parameters

BACKGROUND In this study, fluorescein labeled SLN and NLC formulations were prepared for improving the dermal distribution of the hydrophilic active ingredients and for enhancing the skin penetration. METHODS To determine skin distribution of the lipid nanoparticles ex-vivo penetration/ permeation experiments were performed using full thickness rat skin by means of Franz diffusion cells. Studies on the localization of fluorescence labeled nanoparticles were performed by confocal laser scanning microscopy (CLSM). Cellular uptake studies were performed on human keratinocyte cell line (HaCaT) and visualized by fluorescence microscope. Both tissue and cell uptake were also quantitatively determined by means of fluorimetric method in the skin extract or cell extract. RESULTS Both imaging and quantification studies suggest that the dermal localization of the lipid nanoparticles depends on their dimensions and particle size distribution. The CLSM images clearly show that the Tripalmitin based lipid nanoparticles have higher accumulation in the skin. It is possible to overcome the stratum corneum barrier function with T-NLC05 coded lipid nanoparticle formulation. Additionally cellular uptake of this NLC formulation is time dependent. Conclusıon: It can be concluded that this formulation is promising for treating local skin disorders without systemic side effects. On the other hand obtained results suggest that optimum formulation (T-NLC05) might be an interesting option even for novel cosmetic products.

Calcipotriol–captisol inclusion complex and corticosteroid in a novel fixed dose combination: evaluation on human epidermal keratinocyte cells

Psoriasis is a common chronic inflammatory dermatological disorder. Calcipotriol (CAL) and super potent corticosteroids are often used for the topical treatment of this disease. Because these active substances have serious and dose-dependent side effects, the application of combination therapies are preferred. By combination therapy, decreasing of the side effects of both active agents and increasing of the efficiency is provided. However, it is not possible to combine these two drugs in one formulation containing an aqueous phase since these substances show pH-dependent incompatibility. Therefore, for combination therapy, commercial products of corticosteroids and CAL are usually applied separately at different times of a day. The aim of this study was to prepare a fixed-dose combination of cyclodextrin complex of CAL and microspheres of clobetasol propionate in an aqueous semisolid vehicle for once daily application and to evaluate the in vitro antipsoriatic efficacy of this combination formulation on human epidermal keratinocyte cell line. The effect of fixed dose combination on the proinflammatory cytokine levels and keratinocyte proliferation were determined. It may be concluded that our new aqueous based fixed dose combination could be proposed as an alternative to the combination therapy which have been currently adopted in clinical practice.