Nanosized ethosomes bearing ketoprofen for improved transdermal delivery

The potential of ethosomes for delivering ketoprofen via skin was evaluated. The ethosomes were prepared, optimized and characterized. Vesicular shape, size and entrapment efficiency were determined by transmission electron microscopy, dynamic light scattering and minicolumn centrifugation technique, respectively. Vesicle sizes varied from 120.3±6.1 to 410.2±21.8 nm depending on the concentrations of soya phosphatidyl choline (SPC) and ethanol. Entrapment efficiency increased with concentrations of SPC and ethanol. The formulations exhibited entrapment efficiencies of 42–78%. In vitro release through cellophane membrane showed sustained release of drug from ethosomal formulations in contrast to hydroalcoholic drug solution (HA), which released most of the drug within 2–3 h. In vitro drug permeation across human skin revealed improved drug permeation and higher transdermal flux with ethosomal formulations compared to hydroethanolic drug solution. Kinetics of in vitro skin permeation showed zero order drug release from formulations. Based on in vitro transdermal flux, the estimated steady state in vivo plasma concentration from ethosomes attained therapeutic drug levels whereas hydroalcoholic drug solution exhibited sub therapeutic drug concentration with a patch size of 50 cm². Skin permeation of ethosomal formulations assessed by confocal microscopy revealed enhanced permeation of Rhodamine 123 loaded formulation in comparison to the hydroalcoholic solution.     

酮洛芬贴片体外透皮释放方法学研究

目的:建立酮洛芬贴片体外透皮释放方法学。方法 :采用HPLC法测定释放液中酮洛芬的含量,测定条件:DiamonsilC18色谱柱(150 mm×4.6 mm,5μm),流动相为pH 3.5磷酸盐缓冲液-乙腈-水(2∶53∶45),检测波长为253 nm,流速为1.0mL.min-1,柱温25℃。以裸鼠皮肤为实验皮肤,采用Frans扩散池方法进行三批酮洛芬贴片样品的体外透皮实验。结果:在该HPLC条件下,酮洛芬与其他杂质分离良好,进样量在0.509~40.72μg.mL-1时,酮洛芬浓度与峰面积呈良好的线性关系(r=0.999 9),回收率为101.09%,RSD为1.23%。三批酮洛芬贴片样品的透皮释放速率分别为18.157,17.973,20.001μg.cm-2.h-1,药物透皮释放符合零级动力学过程。结论:本文建立的酮洛芬贴片体外透皮释放方法简便,重现性好,可以用于控制产品质量。     

Microdialysis assessment of percutaneous penetration of ketoprofen after transdermal administration to hairless rats and domestic pigs

The study was performed to evaluate the percutaneous penetration of ketoprofen after transdermal administration using a microdialysis technique in pigs, in comparison with rats. Ketoprofen release from patches was determined by analysis of the remaining drug content after application to hairless rats and pigs. Skin and knee joint penetration of ketoprofen was tested by microdialysis, and recovery was determined by retrodialysis. Residual rates in hairless rats and pigs were 68.1 ± 1.6% and 81.7 ± 4.4%, respectively, at 10 h. The average recoveries of ketoprofen over 480 min in the skin and knee joint cases were 72.0 ± 3.4% and 9.8 ± 6.2% in rats and 72.3 ± 2.5% and 57.6 ± 3.1% in pigs, respectively. In rats, ketoprofen was rapidly absorbed with transdermal administration, with C_max values of 191.7 ± 76.2 and 35.5 ± 21.7 ng/mL and AUC_0-8h values of 918.2 ± 577.5 and 195.9 ± 137.1 ng h/mL, respectively, for the skin and knee joint. The C_max values for the pig were 20.9 ± 18.5 and 3.7 ± 3.0 ng/mL, with AUC_0-8h values of 73.1 ± 69.2 and 16.1 ± 16.1 ng h/mL. Ketoprofen concentrations within skin and knee joint of non-application sites in rats and pigs were less than 0.8 ng/mL. Transdermal administration of ketoprofen significantly reduced prostaglandin E2 levels in the skin of the application site and showed a tendency for inhibition in the knee joint. We thus demonstrated that topical patches containing ketoprofen can deliver the drug through the skin and knee joint of pigs and rats via direct diffusion, and microdialysis data with the pig may be useful for the prediction of human tissue penetration of drugs with transdermal administration.     

Cremophor RH40-PEG 400 microemulsions as transdermal drug delivery carrier for ketoprofen

The aim of this study was to prepare novel microemulsion for transdermal drug delivery of ketoprofen (KP). The microemulsion composed of ketoprofen as model drug, isopropyl myristate (IPM) as oil phase, surfactant mixture consisting of polyoxyl 40 hydrogenated castor oil (Cremophor RH40) as surfactant and polyethylene glycol 400 (PEG400) as co-surfactant at the ratio 1:1, and water were prepared. The viscosity, droplet size, pH, conductivity of microemulsions, and skin permeation of KP through shed snake skin were evaluated. The particle size, pH, viscosity and conductivity of microemulsions were in the range of 114-210 nm, 6.3-6.8, 124-799 cPs and 1-45 μS/cm, respectively. The ratio of IPM, and surfactant mixture played the important role in the skin permeation of KP microemulsions. As the amount of surfactant mixture and IPM increased, the skin permeation of KP decreased. The formulation composed of 30% IPM, 45% surfactant mixture and 25% water showed the highest skin permeation flux. The incorporation of terpenes in the 2.5% KP microemulsions resulted in significant enhancement in skin permeation of KP. The rank order of enhancement ratio for skin permeation enhancement of terpenes was α-pinene > limonene > menthone. The results suggested that the novel microemulsion system containing IPM, water, Cremophor RH40:PEG400 and terpenes can be applied for using as a transdermal drug delivery carrier.     

Correlation between the transdermal permeation of ketoprofen and its solubility in mixtures of a pH 6.5 phosphate buffer and various solvents

The passage of a drug through the skin is directly proportional to the concentration of the drug in the donor phase and to the permeability coefficient constant Kp. Kp is determined essentially by two factors: the dissolution of the drug in the stratum corneum (measured by the partition coefficient P) and the diffusion in the same stratum (measured by the diffusion constant D). In our study, several saturated solutions of ketoprofen in mixtures of a pH 6.5 phosphate buffer and various co-solvents were studied to find correlations between the solubility of the ketoprofen in the mixtures and its permeation parameters in in vitro permeation studies with Franz cells. The results show that D does not change in the different mixtures; the diffusion of the drug into the stratum corneum is not influenced by the presence of the co-solvents, whereas the partition coefficient is strongly influenced. In particular, Kp and P were found to be inversely proportional to solubility, meaning that when the co-solvent increases the solubility, the partition of the drug and consequently Kp decrease. These findings were confirmed in some developed gels, and the developed gels were found to enhance the ketoprofen permeation with respect to the formulation in a commercial Fastum gel.     

Enhancement of the transdermal delivery of zidovudine by pretreating the skin with two physical enhancers: microneedles and sonophoresis

BackgroundZidovudine (AZT) has been the most widely used drug for antiretroviral therapy. In order to improve the therapy with this drug, different alternatives have been proposed, such as the transdermal administration. The use of permeation enhancers is necessary to favor the passage of this drug through the skin, due to its physicochemical properties and to the natural permeation barrier imposed by the skin. ObjectivesTo evaluate the effect of two permeation enhancers, sonophoresis and microneedles, on the permeability of AZT through the skin.MethodsPermeation studies with an AZT solution were performed using pigskin clamped in Franz-type cells. Sonophoresis was applied under different conditions (i.e., amplitude, duty cycle and application time), selected according to an experimental design, where the response variables were the increase in temperature of the skin surface and the increase in transepidermal water loss. ATR-FTIR was also used to demonstrate the effect of enhancers on membrane components. ResultsThe permeability of AZT through intact skin was very poor, with a very long lag time. Pretreatment of the skin with sonophoresis increased AZT transport significantly, reducing the lag time. The maximum flux (27.52 µgcm⁻² h⁻¹) and the highest total amount permeated (about 624 µg/cm²) were obtained when applying sonophoresis in continuous mode, with an amplitude of 20%, and an application time of 2 min. Sonophoresis appears to have an impact on stratum corneum proteins. The use of microneedles further increased the flux (30.41 µgcm⁻² h⁻¹) and the total amount permeated (about 916 µg/cm²), relative to sonophoresis. ConclusionThe results are encouraging in terms of promoting AZT transport through the skin using sonophoresis or microneedles as permeation enhancers.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s40199-021-00402-y.     

Low-frequency sonophoresis: current status and future prospects

Application of ultrasound enhances skin permeability to drugs, a phenomenon referred to as sonophoresis. Significant strides have been made in sonophoresis research in recent years, especially under low-frequency conditions (20 kHz相似文献   

Transdermal delivery system of triamcinolone acetonide from a gel using phonophoresis

Triamcinolone acetonide (TA) is a corticosteroid that is used in the systemic and topical treatment of many inflammatory diseases. In this study, a phonophoretic drug delivery system was designed to enhance the TA permeability and the influence of ultrasound was examined. In order to establish the transdermal delivery system for TA, a hydrophilic carbopol gel containing TA was prepared after adopting phonophoresis. A permeation study through mouse skin was performed at 37 degrees C using a Franz diffusion cell, and the ultrasound treatment was carried out for 10 h. The level of TA permeation through the skin was evaluated under various ultrasound conditions including the frequency (1.0, 3.0 MHz), intensity (1.0, 2.5 W/cm2), and duty cycle (continuous, pulse mode) using a 0.5% TA gel. The highest permeation was observed under the ultrasound treatment conditions of low frequency, high intensity, and in continuous mode.     

Effect of microneedle on the pharmacokinetics of ketoprofen from its transdermal formulations

Non-invasive transdermal delivery using microneedle arrays was recently introduced to deliver a variety of large and hydrophilic compounds into the skin, including proteins and DNA. In this study, a microneedle array was applied to the delivery of a hydrophobic drug, ketoprofen, to determine if transdermal delivery in rats can be improved without the need for permeation enhancers. The ability of a microneedle to increase the skin permeability of ketoprofen was tested using the following procedure. A microneedle array was inserted into the lower back skin of a rat using a clip for 10 min. Subsequently, 24 mg/kg of a ketoprofen gel was loaded on the same site where the microneedle had been applied. Simultaneously, the microneedle was coated with 24 mg/kg of a ketoprofen gel, and inserted into the skin using a clip for 10 min. As a negative control experiment, only 24 mg/kg of the ketoprofen gel was applied to the shaved lower back of a rat. Blood samples were taken at the indicated times. The plasma concentration (C_p) was obtained as a function of time (t), and the pharmacokinetic parameters were calculated using the BE program. The group loaded with the microneedle coated with ketoprofen gel showed a 1.86-fold and 2.86-fold increase in the AUC and C_max compared with the ketoprofen gel alone group. These results suggest that a microneedle can be an ideal tool for transdermal delivery products.     

The influence of guaifenesin and ketoprofen on the properties of hot-melt extruded polyethylene oxide films

Films containing polyethylene oxide (PEO) and a model drug, either guaifenesin (GFN) or ketoprofen (KTP), were prepared by hot-melt extrusion. The thermal properties of the hot-melt extruded films were investigated using differential scanning calorimetry (DSC). Scanning electron microscopy (SEM) was used to examine the surface morphology of the films, and wide angle X-ray diffraction (XRD) was used to investigate the crystalline properties of the polymer, drugs and physical mixtures as well as the solid state structure of the films. The stability of the polymer was studied using gel permeation chromatography. The mechanical properties, including percent elongation and tensile strength of the films, were determined on an Instron according to American Society for Testing Materials (ASTM) procedures. The Hansen solubility parameter was calculated using the Hoftyzer or van Krevelen method to estimate the likelihood of drug–polymer miscibility. Both GFN and KTP were stable during the extrusion process. Melting points corresponding to the crystalline drugs were not observed in the films. Crystallization of GFN on the surface of the film was observed at all concentrations studied, however KTP crystallization did not occur until reaching the 15% level. Guaifenesin and ketoprofen were found to decrease drive load, increase PEO stability and plasticize the polymer during extrusion. The Hansen solubility parameters predicted miscibility between PEO and KTP and poor miscibility between PEO and GFN. The predictions of the solubility parameters were in agreement with the XRD and SEM results. The percent elongation decreased with increasing GFN concentrations and significantly increased with increasing levels of KTP. Both GFN and KTP decreased the tensile strength of the extruded film.     

Preparation and evaluation of ketoprofen floating oral delivery system

A sustained release system for ketoprofen designed to increase its residence time in the stomach without contact with the mucosa was achieved through the preparation of floating microparticles by the emulsion-solvent diffusion technique. Four different ratios of Eudragit S100 (ES) with Eudragit RL (ERL) were used to form the floating microparticles. The drug retained in the floating microparticles decreased with increase in ERL content. All floating microparticle formulations showed good flow properties and packability. Scanning electron microscopy and particle size analysis revealed differences between the formulations as to their appearance and size distribution. X-ray and DSC examination showed the amorphous nature of the drug. Release rates were generally low in 0.1 N HCl especially in presence of high content of ES while in phosphate buffer pH 6.8, high amounts of ES tended to give a higher release rate. Floating ability in 0.1 N HCl, 0.1 N HCl containing 0.02% Tween 20 and simulated gastric fluid without pepsin was also tested. The formulation containing ES:ERL1:1 (FIII) exhibited high percentage of floating particles in all examined media.     

Gastroresistant microcapsules: new approaches for site-specific delivery of ketoprofen

Ketoprofen is a potent non-steroidal anti-inflammatory drug (NSAID) that has been widely used in the treatment of rheumatoid arthritis and other related conditions. However, it carries the risk of undesirable systemic side effects and gastrointestinal irritation at the usual dose of oral administration. The aim of this study was to prepare and evaluate gastroresistant microcapsules containing ketoprofen. Microcapsules were obtained by a spray-drying process starting from an O/A emulsion in the presence of different pH-dependent materials (Eudragit^® L100, Eudragit^® S100, and stearic acid) dissolved in the external phase. The influence of formulation factors (oily phase employed for drug solubilization, type of coating) on the morphology, particle size distribution, drug loading capacity, in-vitro release, and ex-vivo permeation characteristics were investigated. Drug loading capacity was very high for all the microcapsules prepared. Formulation factors did not significatively influence the mean particle size, but modified microcapsule in-vitro and ex-vivo behavior.     

Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.

Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.

What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods.

Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.     

丹皮酚经皮给药系统的研究

目的 以脂溶性药物丹皮酚为模型药物,制备载药传递体,评价其质量并进行小鼠经皮渗透体外研究.方法 采用薄膜分散-超声法制备丹皮酚传递体;以改进的Franz扩散池进行体外小鼠经皮渗透实验,比较不同处方组成对丹皮酚经皮渗透的影响.结果 丹皮酚传递体为乳白色、近透明的胶体溶液.脂质传递体、普通脂质体和丹皮酚水醇混悬液8 h时的累积渗透率分别为81.22%、49.66%、42.22%.结论 丹皮酚传递体制备工艺简单可行,所制传递体的粒径较小且均匀,并可促进丹皮酚的经皮转运.     

Singlet oxygen mediated DNA damage induced phototoxicity by ketoprofen resulting in mitochondrial depolarization and lysosomal destabilization

Ketoprofen (KP) is a widely used nonsteroidal anti-inflammatory drug for the treatment of osteoarthritis and various rheumatic diseases. Currently, KP is applied topically on skin as gel to treat symptoms of pain and inflammation. We have studied the photomodification of KP under natural environmental conditions. KP generates reactive oxygen species (ROS) like ¹O₂ through Type-II photodynamic reaction. ¹O₂ mediated 2′-dGuO photodegradation, single and double strand breakage were significantly induced by photosensitized KP under sunlight/UV-R exposure. Significant intracellular ROS generation was measured through DCF-DA fluorescence. Linoleic acid photoperoxidation and role of ¹O₂ were substantiated by using specific quencher like sodium azide. KP induced cell cycle arrest in G2/M phase and cell death through MTT assay. We found apoptosis as the pattern of cell death which was confirmed through caspase-3 activation, cytochrome-c release from mitochondria, up-regulation of Bax protein and phosphatidylserine translocation. Our RT-PCR result strongly supports our view point of apoptotic cell death through up-regulation of p21 and pro-apoptotic Bax genes expression. Mitochondrial depolarization and lysosomal destabilization were also parallel to apoptotic process. Therefore, much attention should be paid to the topical application of KP and sunlight exposure in the light of skin related photosensitivity and cancers.     

Sorbitan monopalmitate-based proniosomes for transdermal delivery of chlorpheniramine maleate

A proniosomal gel for transdermal drug delivery of chlorpheniramine maleate (CPM) was developed based on Span 40 and extensively characterized in vitro. The system was evaluated for the effect of composition of formulation, type of surfactants and alcohols on the drug loading, rate of hydration, vesicle size, polydispersity, entrapment efficiency, and drug release across cellulose nitrate dialysis membrane. The stability studies were performed at 4°C and at room temperature. The results showed that lecithin produced more stable and larger vesicles with higher loading efficiency but lower dissolution efficiency than cholestrol (chol) and dicethyl phosphate (DCP). The type of alcohol had no significant effect on the stability of vesicles, but ethanol produced larger vesicles (≈44 μm) and entrapped a greater amount of drug. Drug release from vesicles of lecithin followed a first-order kinetics whereas those with DCP or without lecithin fit better with a Higuchi model. The proniosomes that contained Span 40/lecithin/chol prepared by ethanol showed optimum stability, loading efficiency, and particle size and release kinetic suitable for transdermal delivery of CPM.     

氟康唑脂质体凝胶的制备及体外透皮实验（英文）

目的制备氟康唑脂质体凝胶,并研究其性质。方法以薄膜分散法制备氟康唑脂质体,透射电镜观察脂质体的形态,粒度分布仪测定粒径,透皮吸收扩散池测定脂质体凝胶的透皮吸收。结果氟康唑脂质体的包封率为47.68%。脂质体粒径均匀,平均粒径为250±8nm。氟康唑脂质体凝胶的累积透过量（25.27%）低于非脂质体凝胶（36.72%）,而脂质体凝胶的药物皮内滞留量（162±15μg·cm^-2于非脂质体凝胶（48±6μg·cm^-2结论氟康唑脂质体凝胶剂可显著提高药物的皮内滞留量,有望成为氟康唑的一种外用新剂型。     

表面活性剂-醇质体增强多烯紫杉醇经皮给药的渗透性研究(英文)

皮肤的屏障作用使大部分药物无法实现透皮给药。本文以改善难溶性大分子模型药物多烯紫杉醇(docetaxel,DTX)的经皮渗透性为主体思路,研制了DTX的表面活性剂-醇质体(surfactant-ethanlic liposomes,SEL)。SEL由磷脂、乙醇、胆酸钠、DTX和磷酸盐缓冲液组成,采用薄膜分散法制备。对SEL的囊泡形态(冷冻蚀刻电镜法)、粒径大小及分布进行了表征,并测定包封率和载药量。采用体外扩散池实验研究了DTX表面活性剂-醇质体的经皮渗透性。结果表明,当磷脂与表面活性剂的比例为85:15时,DTX的稳态透皮速率和累计透皮量均为最高,且优于表面活性剂脂质体、醇质体和普通脂质体。最优处方的粒径分布、形态和载药量均较为稳定。本研究表明,通过将DTX包载于SEL中可显著改善DTX的经皮渗透性。