Research progress of stimulus-responsive transdermal drug delivery systems / 中国药房

Stimulus-responsive transdermal drug delivery systems can achieve specific drug release and improve drug utilization. According to the different stimulation modes， these preparations can be divided into endogenous stimulus-responsive， exogenous stimulus-responsive and combined stimulus-responsive transdermal drug delivery systems. The endogenous stimulation- responsive transdermal drug delivery system can respond specifically to changes in temperature and pH of the lesion site through carrier materials， so as to deliver drugs to the target site. Exogenous stimulus-responsive transdermal drug delivery system can use light， heat， magnetic， electric and other external stimulation to make the carrier material phase change， so as to achieve drug delivery. The combined stimulus-responsive transdermal drug delivery system is a combination of two or more stimulus-responsive percutaneous drug delivery systems， such as temperature-pH dual-responsive drug delivery system. At present， the relevant studies of stimulus-responsive transdermal drug delivery systems are mostly in the experimental stage， and further evaluation of stability， toxicity and skin irritation is needed in the future to lay a theoretical foundation for clinical application.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Wearable patches for transdermal drug delivery

Transdermal drug delivery systems (TDDs) avoid gastrointestinal degradation and hepatic first-pass metabolism, providing good drug bioavailability and patient compliance. One emerging type of TDDs is the wearable patch worn on the skin surface to deliver medication through the skin. They can generally be grouped into passive and active types, depending on the properties of materials, design principles and integrated devices. This review describes the latest advancement in the development of wearable patches, focusing on the integration of stimulus-responsive materials and electronics. This development is deemed to provide a dosage, temporal, and spatial control of therapeutics delivery.

Development of monolithic matrix type transdermal patches containing cinnarizine: Physical characterization and permeation studies

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated

Transdermal delivery of Chinese herbal medicine extract using dissolvable microneedles for hypertrophic scar treatment

Hypertrophic scars are unfavorable skin diseases characterized by excessive collagen deposition. Although systemic treatments exist in clinic to manage hypertrophic scars, they pose significant side effects and tend to lose efficacy over prolonged applications. Traditional Chinese medicine (TCM) offers as a promising candidate to treat pathological scars. A large number of TCMs have been studied to show anti-scarring effect, however, the natural barrier of the skin impedes their penetration, lowering its therapeutic efficacy. Herein, we reported the use of dissolvable hyaluronic acid (HA) microneedles (MNs) as a vehicle to aid the transdermal delivery of therapeutic agent, a model TCM called shikonin for the treatment of hypertrophic scars. Here, shikonin was mixed with HA to make MNs with adequate mechanical strength for skin penetration, making its dosage controllable during the fabrication process. The therapeutic effect of the shikonin HA MNs was studied

Preparation and Formulation Optimization of Ketoprofen Microemulsion-based Gel / 中国药学杂志

OBJECTIVE: To prepare the ketoprofen microemulsion-based gel in order to expand its drug loading and increase the transdermal permeability. METHODS: The proportion range of oil phase/surfactant in ketoprofen microemulsion were screened by the pseudo-ternary phase diagram. Optimization of formulation for microemulsion gels was conducted by central composite design-response surface methodology with the cumulative permeation quantity across in vitro rat skin and time-lag as evaluation indexes.The transdermal performance of self prepared gel was compared with the commercially available gel. RESULTS: The optimal oil phase, surfactant and cosurfactant of ketoprofen microemulsion were oleic acid, polyoxy ethylene castor oil (EL-35) and ethanol, respectively.The optimal microemulsion formulation was 1.35% oleic acid, 10.8% EL-35, and 9% ethanol by central composite design experiment. The cumulative penetration quantity in 24 h reached 562.82 μg•cm-2 in vitro rat skin was 1.35 times as much as commercially available gel. CONCLUSION: The ketoprofen microemulsion-based gel prepared in this study has good permeability, which lay the foundation for development of the gel.

Preparation of compound liquorice microemulsion gel and its pharmacodynamics evaluation / 中国中药杂志

Based on the previous study of compound liquorice microemulsion, this paper aims to prepare the compound liquorice microemulsion gel and investigate its pharmacodynamics of chronic eczema. The type, dosage and adding method of gel matrix, and formula dosage of humectant were optimized by single factor method to obtain the formula and preparation technique of the gel. With glycyrrhizic acid, glycyrrhetin and oxymatrine used as evaluation indexes, the Franz diffusion cell method was adopted to monitor the in vitro release profile of the gel. Eczema model of delayed-type hypersensitivity in mice was chosen to detect the ear swelling rate, degree of inflammatory cell infiltration of ear pieces, and pathological changes of ear pieces, so as to investigate the therapeutic effect of the microemulsion gel. The preparation process of the compound liquorice microemulsion gel was stable. The release of glycyrrhizin and oxymatrine was most consistent with the Hixcon-Crowell kinetic model, while the release of glycyrrhizic acid was most consistent with the Ritger-Peppas kinetic model. The pharmacodynamics studies proved that compound liquorice microemulsion gel could significantly reduce the ear swelling rate in mice, with good anti-inflammatory effect as well as the ability to resist the pathological changes of chronic eczema and inhibit the infiltration of dermal inflammatory cells. Therefore, the preparation process of compound liquorice microemulsion gel is feasible, with stable drug release and a significant therapeutic effect on chronic eczema.

Studies on high-efficiency loading, sustained-release and permeability as transdermal delivery of graphene oxide to docetaxel composites / 中草药

Objective: To synthetize the new-type GO-DEX-β-CD/DOC and Fe3O4/GO-Na/DOC inclusion compound, and study its high-efficiency loading, sustained-release and permeability as transdermal delivery for docetaxel (DOC) composites. Methods: The concentration of DOC was determined by high efficiency liquid chromatography. The high-efficiency loading, sustained-release and permeability as transdermal delivery of GO-DEX-β-CD/DOC and Fe3O4/GO-Na/DOC were studied, and the encapsulation efficiency and drug loading of them were determined by centrifugation. The GO-DEX-β-CD/DOC and Fe3O4/GO-Na/DOC were applied onto the female mice skin in vitro and in vivo to develop the permeability of them. Results: The encapsulation efficiency and drug loading of Fe3O4/GO-Na/DOC were higher than GO-DEX-β-CD/DOC, and its slow release property and permeability as transdermal delivery were better. The results showed that the accumulation permeation amount was (22.512 ± 0.715) μg after Fe3O4/GO-Na/DOC being applied over 90 h, DOC concentration in skin reached a peak at 15 min by the application of Fe3O4/GO-Na/DOC. After 5 h of administration, DOC concentration in the blood of female mice reached (76.886 ± 1.232) μg/mL. Conclusion: The preparation techniques of Fe3O4/GO-Na/DOC was feasible with better sustained release and transdermal effect, which had a promising application prospect.

Research progress on non-injection administration systems of paclitaxel / 中草药

Paclitaxel (PTX) is a complex secondary metabolite isolated from Taxus brevifolia, which widely used as chemotherapentic agent with a broad spectrum of actinity against cancer in the world. Its water solubility was poor and oral bioavailability was low. Cremophor-EL was used in traditional PTX injections to improve the solubility of PTX, and resulted in several adverse side effects such as severe hypersensitivity. Pre-desensitization treatment was needed before clinical use. Recently, a variety of non-injection drug delivery systems (DDS) of PTX have been developed. In this paper, the research progress of non-parenteral PTX was reviewed, including oral administration systems, vaginal administration systems, transdermal DDS, implantable DDS, transdermal DDS, intranasal administration and inhalation DDS, so as to provide references for future study and clinical applications.

Synthesis of transdermal aloesin loaded zinc oxide nanoparticles and its inhibitory effect on the activity of tyrosinase / 生物医学工程学杂志

Zinc oxide quantum dots (ZnO QDs) were synthesized by gel-sol method and employed as the transdermal aloesin (Alo) carriers. ZnO QDs were surface-functionalized with amino using aminopropyltriethoxysilane (APTES). Alo was covalently bonded on the surface of ZnO QDs via N,N'-carbonyldiimidazole to obtain Alo NPs, which were characterized by transmission electron microscope (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analyzer (TGA). TEM images showed that ZnO QDs were analogously sphere and monodisperse with a reasonably narrow size distribution, of which was around 4 nm. The size of Alo NPs increased to around 8 nm due to the surface modification. The intense bands at around 3 400 cm and 1 200 cm in the FTIR spectrum of Alo NPs from the vibration of -OH indicated the linkage of Alo on the surface of ZnO QDs. The results of TGA analysis showed that the mass ratio of ZnO QDs and Alo were 39.27% and 35.14%, respectively. The penetration of Alo NPs was much higher than raw Alo according to the passive penetration experiments with Franz-type diffusion cells instrument using full-thickness cavy skin, which manifested the improvement of the penetration for Alo delivered by ZnO QDs. The pH-controlled drug release behavior was investigated. At pH 7.4, only a small amount of Alo (1.45% ± 0.21%) had been released after 2 h. In contrast, as incubation at pH 5.0 of which pH was similar to endosomal environment, Alo was released very fast (87.63% ± 0.46% in 2 h) from Alo NPs, confirming that Alo NPs could response to the pH and realize the intracellular drug release. The inhibitory effect of Alo NPs on tyrosinase was in a dose dependent manner. When the concentration of Alo NPs was 12.5 μg/mL, the inhibition rate was up to 40.32% ± 1.57%. All the results show that the Alo NPs hold a great potential in transdermal tyrosinase inhibition.

Preparation of plumbagin transfersomal gel and investigation on its transdermal penetration characteristics in vitro / 中草药

Objective: To prepare plumbagin transfersomal (PBG-T) gel and investigate its transdermal penetration characteristics in vitro. Methods: Plumbagin transfersomes were prepared by film-ultrasonic dispersion method. The optimal prescription condition of PBG-T was selected by central composite design and response surface method. The formula of PBG-T gel was optimized by orthogonal test. The Franz diffusion cell was used to investigate transdermal penetration characteristics of PBG-T gel in vitro. Results: The optimal prescription condition of transfersomes was determined as drug 10.0 mg, phospholipids 700.0 mg, Tween-80 91.5 mg, ultrasonication time 13 min. The optimal prescription condition of transfersomal gel was 1% carbomer 940 as gel matrix, and 5% glycerol as the humectant. According to the optimized prescription, the entrapment efficiency, the mean particle size, and Zeta potential of PBG-T were (79.88 ± 2.26)%, (125.64 ± 4.54) nm, and (-30.97 ± 1.13) mV. The cumulative penetration rate of PBG-T gel was 70.0% at 12 h. Conclusion: The optimal preparation technique is stable and feasible. Transfersomal gel features a sustained release in vitro, the transfersomal gel can increase penetration rate of plumbagin through the skin of rats.

Pharmacokinetic Study of Triptolide Nanoemulsion Gels Based on Simultaneous Skin and Blood Microdialysis / 中国药学杂志

OBJECTIVE: To investigate the pharmacokinetics of triptolide gels, nanoemulsions and nanoemulsion gels by simultaneous skin and blood microdialysis in rats. METHODS: The microdialysis systems include linear probes and vascular probes which are used for measuring the recovery of triptolide in skin and blood, respectively. Linear probe and vascular probe were implanted in SD rats after abdominal hair removal. Triptolide gels, nanoemulsions and nanoemulsion gels were administered to SD rats. The probe was continuously perfused with PBS(pH 7.4) at a flow rate of 3 μL•min-1. Dialysate samples were collected every 30 min and continuously performed for 12 h. The dialysis samples were determined by LC-MS. RESULTS: The AUC0-t(s) of triptolide nanoemulsions and nanoemulsion gels were significantly higher than those of triptolide gels in skin and blood. Moreover, compared with the concentration of triptolide nanoemulsions in skin and blood, triptolide was released more smoothly from nanoemulsion gels, providing a sustained release effect and an improved bioavailability. CONCLUSION: The technique of simultaneous skin and blood microdialysis is able to detect the concentration of drug in the skin and blood of rats, which provides a new method for the pharmacokinetic study of tripolide.

Determination of oxybutynin concentration in rabbit plasma by LC-MS/MS and its application to bioequivalence evaluation / 基础医学与临床

Objective To develop and validate a LC-MS/MS method to quantify oxybutynin in rabbit plasma and evaluate the bioequivalence of self-prepared oxybutynin chloride gel and Gelnique. Methods The plasma sample was submitted to liquid-liquid extraction using methyl t-butyl ether after alkalified by 0.5 mol/L NaOH, with di-phenhydramine as the internal standard. Chromatographic separation was performed on a Kinetex C18column with the mobile phase consisting of 10 mmol/L ammonium acetate(1‰formic acid)-acetonitrile(50 : 50,v/v). Oxy-butynin and diphenhydramine were ionized with an ESI source operated in positive ion mode,and the detected ions were m/z 358→142 (oxybutynin),m/z 256→167(diphenhydramine). The validated method was then applied to the drug determination in rabbit plasma following single dermal topical administration of oxybutynin gel. Results Calibration curve was liner over the concentration range of 1~200 μg/L in rabbit plasma.For quality control samples, the intra-and inter-day precision was in the range of 1.67%~9.79%, and accuracy was within 92.9% to 103%. Self-prepared oxybutynin chloride gel and Gelnique were proved to be bioequivalent. Conclusions It was validated that the LC-MS/MS method is simple,strong specificity and high sensitivity,which could be successfully applied to pharmacokinetic study and bioequivalence evaluation of transdermal oxybutynin formulations in rabbit.

Effects of Frankincense and Myrrh essential oil on transdermal absorption of ferulic acid in Chuanxiong / 中国中药杂志

The aim of this paper was to explore the effects of Frankincense and Myrrh essential oil on transdermal absorption, and investigate the mechanism of permeation on the microstructure and molecular structure of stratum corneum. Through the determination of stratum corneum/medium partition coefficient of ferulicacid in Chuanxiong influenced by Frankincense and Myrrh essential oil, the effects of volatile oil of frankincense and Myrrh on the the microscopic and molecular structure of stratum corneum were explored by observation of skin stratum corneum structure under scanning electron microscopy, and investigation of frankincense and myrrh essential oil effects on the molecular structure of keratin and lipids in stratum corneum under Fourier transform infrared spectroscopy. The results showed that the oil could enhance the distribution of ferulic acid in the stratum corneum and medium, and to a certain extent damaged the imbricate structure of stratum corneum which was originally regularly, neatly, and closely arranged; some epidermal scales turned upward, with local peeling phenomenon. In addition, frankincense and myrrh essential oil caused the relative displacement of CH2 stretching vibration peak of stratum corneum lipids and amide stretching vibration peak of stratum corneum keratin, indicating that frankincense and myrrh essential oil may change the conformation of lipid and keratin in the stratum corneum, increase the bilayer liquidity of the stratum corneum lipid, and change the orderly and compact structure to increase the skin permeability and reduce the effect of barrier function. It can be concluded that Frankincense and Myrrh essential oil can promote the permeation effect by increasing the distribution of drugs in the stratum corneum and changing the structure of the stratum corneum.

Quality Evaluation and Transdermal Study of Matrine Microemulsion-based Hydrogel / 中国药师

Objective: To study the quality and transdermal properties of matrine microemulsion-based hydrogel (MBH) to provide basis for the development of the preparation.Methods: The stability of MBH was observed at 4 ℃ for 3 months and the changes of particle appearance, viscosity, pH and matrine content were observed.The transdermal permeation of MBH was investigated by a dual chamber permeation and diffusion device with excised mouse skin as the barrier.Taking rabbits as the experimental subjects, the irritation of MBH to the normal skin and damaged skin was investigated.Results: The appearance, viscosity, pH and matrine content of MBH at 4 ℃ in 3 months did not change significantly.In vitro transdermal test showed that MBH had a good penetration rate on mouse skin, and no skin irritation occurred after single or multiple administrations.Conclusion: MBH has good stability and high rate of transdermal penetration without skin irritation, which is a promising drug delivery system of matrine with good application prospects.

Enhanced transdermal delivery of dihydrotestosterone using the combination strategy of iontophoresis and prodrug / 国际药学研究杂志

Objective To enhance the transdermal delivery of dihydrotestosterone(DHT)and to make the delivery controlla?ble,which would enable personalized administration of DHT to pediatric patients. Methods A hydrosoluble,ionizable prodrug of DHT,dihydrotestosterone dimethylglycine ester hydrochloride(DHT-DG),was synthesized,characterized and its physicochemical properties were determined. DHT And DHT-DG were formulated into hydrogel,respectively,and the transdermal delivery of each compound across fresh porcine ear skin with or without iontophoresis was evaluated. Results Application of current(0.5 mA/cm2)to 2.5%DHT-DG hydrogel for 8 h enabled(226.91±45.62)nmol/cm2 accumulative amounts of DHT-DG across fresh porcine ear skin, which was much higher than the amount of DHT delivered from 2.5%DHT hydrogel without iontophoresis,(10.45±3.63)nmol/cm2. More than 80%delivered amount of DHT-DG was hydrolyzed into its parent drug DHT. The steady state flux of DHT-DG was found af?ter the application of iontophoresis for 2 h,and the accumulative amounts of DHT-DG could be modulated by drug concentration and current intensity. Conclusion Combination strategy of iontophoresis and prodrug can enable fast controllable transdermal delivery of DHT.

Enhanced transdermal delivery of dihydrotestosterone using the combination strategy of iontophoresis and prodrug / 国际药学研究杂志

Objective To enhance the transdermal delivery of dihydrotestosterone (DHT) and to make the delivery controllable, which would enable personalized administration of DHT to pediatric patients. Methods A hydrosoluble, ionizable prodrug of DHT, dihydrotestosterone dimethylglycine ester hydrochloride (DHT-DG), was synthesized, characterized and its physicochemical properties were determined. DHT And DHT-DG were formulated into hydrogel, respectively, and the transdermal delivery of each compound across fresh porcine ear skin with or without iontophoresis was evaluated. Results Application of current (0.5 mA/cm2) to 2.5% DHT-DG hydrogel for 8 h enabled (226.91 ± 45.62) nmol/cm2 accumulative amounts of DHT-DG across fresh porcine ear skin, which was much higher than the amount of DHT delivered from 2.5% DHT hydrogel without iontophoresis, (10.45±3.63) nmol/cm2. More than 80% delivered amount of DHT-DG was hydrolyzed into its parent drug DHT. The steady state flux of DHT-DG was found after the application of iontophoresis for 2 h, and the accumulative amounts of DHT-DG could be modulated by drug concentration and current intensity. Conclusion Combination strategy of iontophoresis and prodrug can enable fast controllable transdermal delivery of DHT.

Asiatic acid-pectin hydrogel matrix patch transdermal delivery system influences parasitaemia suppression and inflammation reduction in P. berghei murine malaria infected Sprague-Dawley rats

OBJECTIVE@#To report the influence of transdermal delivery of asiatic acid (AA) in Plasmodium berghei-infected Sprague Dawley rats on physicochemical changes, %parasitaemia and associated pathophysiology.@*METHODS@#A topical once-off AA (5, 10, and 20 mg/kg)- or chloroquine (CHQ)-pectin patch was applied on the shaven dorsal neck region of Plasmodium berghei-infected Sprague Dawley rats (90-120 g) on day 7 after infection. Eating and drinking habits, weight changes, malaria effects and %parasitaemia were compared among animal groups over 21 d.@*RESULTS@#AA-pectin patch application preserved food and water intake together with %weight gain. All animals developed stable parasitaemia (15-20%) by day 7. AA doses suppressed parasitaemia significantly. AA 5 mg/kg patch was most effective. AA and CHQ displayed bimodal time-spaced peaks. CHQ patch had a longer time course to clear parasitaemia.@*CONCLUSIONS@#AA influences bio-physicochemical changes and parasitaemia suppression in dose dependent manner. In comparison by dose administered, AA has much better efficacy than CHQ. AA may be a useful antimalarial. AA and CHQ displays bimodal peaks suggesting possible synergism if used in combination therapy.

Asiatic acid-pectin hydrogel matrix patch transdermal delivery system influences parasitaemia suppression and inflammation reduction in P. berghei murine malaria infected Sprague–Dawley rats

Objective To report the influence of transdermal delivery of asiatic acid (AA) in Plasmodium berghei-infected Sprague Dawley rats on physicochemical changes, %parasitaemia and associated pathophysiology. Methods A topical once-off AA (5, 10, and 20 mg/kg)- or chloroquine (CHQ)-pectin patch was applied on the shaven dorsal neck region of Plasmodium berghei-infected Sprague Dawley rats (90–120 g) on day 7 after infection. Eating and drinking habits, weight changes, malaria effects and %parasitaemia were compared among animal groups over 21 d. Results AA-pectin patch application preserved food and water intake together with %weight gain. All animals developed stable parasitaemia (15–20%) by day 7. AA doses suppressed parasitaemia significantly. AA 5 mg/kg patch was most effective. AA and CHQ displayed bimodal time-spaced peaks. CHQ patch had a longer time course to clear parasitaemia. Conclusions AA influences bio-physicochemical changes and parasitaemia suppression in dose dependent manner. In comparison by dose administered, AA has much better efficacy than CHQ. AA may be a useful antimalarial. AA and CHQ displays bimodal peaks suggesting possible synergism if used in combination therapy.

Effects of different penetration enhancers on pharmacokinetics of active components in Xiangfu Siwu transdermal patches / 中国中药杂志

To study the effect of different penetration enhancers on the pharmacokinetic characters of six active components in Xiangfu Siwu transdermal patch (XBW) and optimize the best penetration enhancers. During the experiment, the patches containing different penetration enhancers were stuck on the rat's skin, and then the blood samples were acquired at different time points. Six active components in plasma were determined by UPLC-MS/MS. The main pharmacokinetic parameters were calculated with DAS software package. The total factor scores (F) of the plasma concentrations of six components at every time point in different groups were calculated using principle component analysis, and the areas under F versus time curves (AUCF-t) were employed to be the indexes for selecting penetration enhancers. The results demonstrated that compared with the control group, the AUCF-t from other groups increased prominently and furthermore, 5% menthol manifested the best effect. In this research, 5% menthol could remarkably promote the percutaneous penetration effect of the six active compounds in XBW, and it could provide a scientific basis for the preparation research of XBW.