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The traditional model Franz diffusion cell method has always been the “gold standard” for evaluating the permeability of transdermal drug delivery system （TDDS） drug. However， in the high throughput screening of a large number of drug molecules， it has the disadvantages of low efficiency， high cost， difficulty to obtain isolated skin，poor reliability and large workload. The emergence of parallel artificial membrane permeation assay （PAMPA） model provides reliable pre-prediction data for the evaluation of permeability of TDDS drug. PAMPA model has been widely used in the permeability screening research of TDDS drugs and their preparations such as analgesics， local anesthetics， antioxidants， antipyretics， analgesics and anti-inflammatory drugs， vitamins， cholinesterase inhibitors， active ingredients of natural products， and has the characteristics of high reliability， good selectivity， high efficiency， low cost and data stability. PAMPA model has greatly improved the high throughput screening efficiency of TDDS drug permeability. With the extensive application and gradual maturity of this model， it will become a new and effective evaluation method in addition to the traditional evaluation model.
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Intracerebral delivery of drugs for the treatment of central nervous system disorders is usually limited by the blood-brain barrier (BBB). Transdermal drug delivery systems (TDDS) have the advantage of improving patient compliance and avoiding first-pass effects compared to intravenous, oral and intranasal drug delivery, and are an emerging non-invasive drug delivery route that facilitates long-term drug delivery to patients. The discovery of direct subcutaneous targeting of lymphatic pathways to brain tissue has made TDDS a new brain-targeted drug delivery strategy. At the same time, the development of nano-delivery technology has further facilitated the application of TDDS for targeted drug delivery to the brain. This review summarizes the mechanism of transdermal drug delivery into the brain and the application of TDDS in the treatment of brain diseases, providing new ideas and methods for the treatment of central nervous system diseases.
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Abstract The main aim of transdermal drug delivery (TDD) is to deliver a specific dose of drug across the skin and to reach systemic circulation at a controlled rate. On the other hand skin is the target for topical drug delivery. Mentioned drug delivery systems (DDS) have numerous advantages compared to oral and parenteral routes. Avoidance of first-pass metabolism, prevent drug degradation due to harsh environment of the stomach, allow controlled drug delivery, provide patient compliance, and pain-free administration are a few of them. To achieve all of them, a DDS with suitable polymer is the primary requisite. Based on the recent trends, natural polymers have been more popular in comparison to synthetic polymers because the former possesses favourable properties including nontoxic, biodegradable, biocompatible, low cost, sustainable and renewable resources. In this context polysaccharides, composed of chains of monosaccharides bound together by glycosidic bonds, have been successfully employed to augment drug delivery into and across the skin with various formulations such as gel, membrane, patches, nanoparticles, nanofibres, nanocomposite, and microneedles. In this chapter, various polysaccharides such as cellulose, chitosan, and their semisynthetic derivatives, alginate, pectin, carrageenan etc, were discussed with their diverse topical and TDD applications. In addition, various formulations based on polysaccharides and limitations of polysaccharides were also briefly discussed.
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The new external preparations of tr aditional Chinese medicine （TCM）mainly include transdermal drug delivery preparation and transmucosal drug delivery system. With the development of modern science and technology ，new external preparations of TCM are widely used in internal medicine ，gynecology，pediatrics and other diseases. In order to provide reference for dosage form development of TCM and safe use of drug in clinic ，this paper reviews the research progress of new external preparation technology for TCM （skin penetration method ，carrier encapsulation technology ，etc.），new external dosage forms of TCM（microneedles，gels，patches，film sprays ，suppositories，film agents ，in situ gels ，etc.）. In the future ，the research of new external preparations of TCM should conduct under the guidance of TCM theory ，and pay attention to the new drug delivery system of previous drugs and the development of TCM components of “drug-adjuvant integration ”，strengthen the research on new external preparations of TCM compounds ，and establish an evaluation system in line with the overall characteristics of TCM so as to promote the sustainable development of new external preparations of TCM.
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Proteins and peptides have become a significant therapeutic modality for various diseases because of their high potency and specificity. However, the inherent properties of these drugs, such as large molecular weight, poor stability, and conformational flexibility, make them difficult to be formulated and delivered. Injection is the primary route for clinical administration of protein and peptide drugs, which usually leads to poor patient's compliance. As a portable, minimally invasive device, microneedles (MNs) can overcome the skin barrier and generate reversible microchannels for effective macromolecule permeation. In this review, we highlighted the recent advances in MNs-mediated transdermal delivery of protein and peptide drugs. Emphasis was given to the latest development in representative MNs design and fabrication. We also summarize the current application status of MNs-mediated transdermal protein and peptide delivery, especially in the field of infectious disease, diabetes, cancer, and other disease therapy. Finally, the current status of clinical translation and a perspective on future development are also provided.
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As a novel transdermal drug delivery technology of minimally invasive, safe and efficient, microneedles have received increasing attention. The microchannels formation by microneedles onto the skin is a prerequisite and key for microneedles to deliver drugs. However, there is still a lack of systematic evaluation in skin microchannels. This review summarized influencing factors and evaluation methods in microchannels formation and healing by microneedles, including geometric parameters, materials for preparation, drugs, penetration parameters, differences among the skin of subjects, and presence or absence of occlusion. This review provides reference for other scholars to further study the effectiveness and security of microneedle applications.
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To improve the efficacy of 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT), a fluorocarbon microemulsion-based gel (FMBG) loaded with both 5-ALA and carbon dioxide (CO2) was prepared in this study. Its physical and chemical properties such as particle size, zeta potential, morphology, pH value and viscosity were characterized. Acid-base titration experiment was used to determine the CO2 loading, a fluorescence derivatization method was established to determine the content of 5-ALA, and the confocal laser scanning microscope and Franz diffusion cell method were carried out to investigate its transdermal ability. Through the laser speckle contrast imaging, the CO2-affected blood flow perfusion of skin was measured. Finally, the skin irritation test was tested by hematoxylin-eosin staining (H&E) method. These results showed that the prepared FMBG was a milky white gel, with an average particle size of 202.4 nm, a zeta potential of -25.3 mV, a pH of 6.0, and a viscosity of 1 062.0 mPa·s. It can be stored stably for seven days at room temperature. The 5-ALA content of FMBG was measured to be approximately equal to 20% (w/w). At room temperature and normal pressure, the CO2 loading content of FMBG was 5.016 mg·L-1, which was 1.5 times as much as that of water. The transdermal absorption experiment and blood perfusion results showed that the FMBG can effectively enable the transdermal delivery of 5-ALA and CO2, and significantly increased the blood perfusion of skin. H&E staining results indicated that FMBG had negligible skin irritation (all animal tests were approved by the Ethics Committee of 900 Hospital of the Joint Logistics Team). In this study, a safe and stable FMBG loaded with both 5-ALA and CO2 was successfully prepared. It was suitable for transdermal application, having the potential of enhancing the efficacy of 5-ALA-mediated PDT.
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Triptolide(TP), the main active and toxic component of Tripterygium wilfordii, has the limitations of low bioavailability, poor absorption, low concentration in plasma, and small lethal dose. Microneedle(MN), the hybrid of hypodermic needle and transdermal patch, is a physical penetration-enhancing system. Dissolving microneedles(DMNs) can be tailored to specific needs of degradation rate. In this study, the TP-loaded DMNs(DMNs-TP) were prepared with the two-step centrifugation method. The optimal ratio of PVA to PVP K30, water content in matrix solution, demoulding method, and plasticizer for preparing DMNs were investigated with the indexes of formability and mechanical strength. The drug loading capacity was determined by HPLC and morphological characteristics were observed under an optical microscope. The mechanical properties were investigated by H&E staining and Franz diffusion cell was used to detect the in vitro skin permeation characteristics. Through the experiment, we confirmed that the optimal backing material should be PVA and PVP K30(3∶1) and the optimal ratio of matrix material to water should be 3∶4. The prepared DMNs-TP were pyramidal with smooth surface and length of approximately 550 μm. Each patch(2.75 cm~2) had the drug loading capacity of(153.41±2.29) μg, and TP was located in the upper part of the needle. The results of in vitro skin permeation assay demonstrated that the cumulative penetration of TP in DMNs-TP reached 80% in 24 h, while little TP solution penetrated the skin, which proved that DMNs promoted the transdermal delivery of TP.
Subject(s)
Administration, Cutaneous , Diterpenes , Drug Delivery Systems , Epoxy Compounds , Needles , Phenanthrenes , SkinABSTRACT
Rheumatoid Arthritis (RA) is a chronic, inflammatory auto immune disorder with unknown aetiology. Though various efficacious treatment options are currently available to treat RA, failure to cure is unpredictable. Hence the present study aimed to evaluate Piroxicam (PC) loaded non-ionic surfactant vesicular carrier as transdermal patches. MethodsTransdermal patches of PC- niosomes were formulated by solvent casting method using different polymers. The prepared formulation was examined for physico - chemical and morphological characteristics and drug release studies were performed by Franz diffusion cell method. ResultsThe results of physico-chemical characterizations show that all formulations were with optimum range and morphological characterization shows that the prepared niosomes are spherical in shape. Drug release characteristic of all formulations was performed and the result exhibits that formulation TN4 (PC encapsulated niosomal gel transdermal patch) shows highest % drug release (95.13%) when compared to other formulation. The release data was fitted with release kinetics and results shows zero order with non Fickian diffusion mechanism. ConclusionsPC encapsulated vesicular carrier as transdermal patches is a promising drug delivery system to enhance the solubility of poorly soluble drugs. It also enhances the residence time of drug at absorption site. Hence this approach could be beneficial for the effective management of RA.
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Objective: Medroxyprogesterone Acetate (MPA) using a transdermal drug delivery system for contraception by passive diffusion is limited by the skin barrier properties. Penetration enhancers such as olive oil (fatty acid permeation enhancer) and DMSO (chemical enhancer) can be used. The objective of this study was to overcome MPA penetration problem by using olive oil and DMSO. Methods: An in vitro penetration study using the Franz diffusion cells was performed. The first penetration study used MPA in olive oil (O) and MPA in coconut oil (C) with the concentration 100 μg/ml to each sample and MPA suspension as a control with the same concentration. The second study used MPA in olive oil with the concentration 200.0 μg/ml (A), MPA in olive oil with 0.5% DMSO with the concentration 200.0 μg/ml (B), and MPA in olive oil with 1% DMSO with the concentration 200 μg/ml (C). Results: MPA penetration test for olive oil+0.5% DMSO had flux value 4.24±0.074 μg/cm2. hr and it was not significantly different (t-test, P>0.05) with olive oil+1% DMSO. While the MPA penetration test in only Olive oil had flux value 0.90±0.0087 μg/cm2. hr. Conclusion: This research concluded that olive oil and 0.5% DMSO could improve the penetration of MPA into skin membrane by 4.5 times more than olive oil alone.
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Objective: To prepare Naja atra neurotoxin (NT) loaded dissolving microneedles (DMNs-NT), and investigate the physicochemical properties and in vitro transdermal properties. Methods: DMNs-NT was prepared by a two-step centrifugation method. The ratio of CS and PVP K30, the water content of the matrix solution, and the backing layer material were optimized by the indexes of formability and mechanical strength of the microneedles and flexibility of the backing layer. The drug loading content was determined by HPLC, and the morphological characteristics were observed under an optical microscope, and the stability was also examined. Franz diffusion cell was used to investigate its in vitro skin permeation characteristics. Results: Through the single-factor exploration, we confirmed that the optimal prescription technique for DMNs-NT preparation was a 1:1 ratio of CS and PVP k30, a 5:4 ratio of matrix material and water, with CMC as the backing layer material. The DMNs-NT had a pyramidal shape with a smooth surface and a length of approximately 500 μm. The drug loading content of per tablet was (15.4 ± 0.5) μg. The drug was located in the upper part of the needle. DMNs-NT had good stability within 3 months. The results of in vitro skin permeation assay showed that the cumulative penetration of NT in DMNs-NT could reach 95.8% in 4 h, while NT solution barely penetrated the skin, which proved that it had a good promoting effect on NT transdermal delivery. Conclusion: In this study, DMNs-NT had good mechanical properties and good skin penetration, which realized the transdermal drug delivery of macromolecular drugs.
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OBJECTIVE：To prepare Brucine （shorted for “Bru”）bilayer polymer soluble microneedles ，and to investigate their in vitro transdermal permeation characteristics under different drug loading modes. METHODS ：Taking the degree of difficulty of microneedle film uncovering ，array integrity ，bubble amount ，needle shape ，tip hardness and backing toughness as the indexes ， tip and backing materials were screened. The swelling method and drying method of matrix were screened using the morphology of microneedles as index. The double-layer polymer soluble microneedle was prepared by two-step method ，then it was characterized and evaluated in the safety. The in vitro transdermal permeation characteristics of tip-loaded ，backing-loaded and full-loaded Bru bilayer polymer soluble microneedles were investigated by Franz diffusion cell. The in vitro skin penetration curve was drawn ，and the cumulative permeability amount （Q）and cumulative permeability rate were calculated. RESULTS ：The optimal preparation technology of bilayer polymer soluble microneedles included chondroitin sulfate （CS）and polyvinylpyrrolidone K 30（PVP K 30） （1∶1，m/m）as tip materials ，15％ polyvinyl alcohol （PVA）as backing material ，matrix swelling in the refrigerator at 4 ℃ for 1 h，and drying at room temperature for 24 h in dryer. Prepared microneedle array was complete and had good mechanical properties，and could successfully puncture aluminum foil and rat skin. After microneedle treatment ，the skin could return to its original state within 6 h. The results of in vitro transdermal test showed that microneedle drug delivery could greatly increase the cumulative transdermal permeability amount of GNYL Bru，and the tip material could dissolve and release the drug within 10 min； the tip-loaded microneedle was basically released within 8 h，Q8h was 102.185 μg/cm2 and the cumulative permeability rate reached 94.05％ ； the drug cumulativepermeability rate of backing-loaded and full-loaded microneedlesexceeded 50％ within 8 h and exceeded 90％ within 48 h；Q48h were 840.77 and 1 156.73 μg/cm2，showing sustained-release characteristics. CONCLUSIONS ：Bru bilayer polymer soluble microneedles with hard tip and tough backing material are successfully prepared to achieve effective transdermal delivery and sustained release through full-loaded mode.
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Electrospinning technology opens up a new method for the construction of drug delivery system. The unique fiber structures of drug-loaded electrospinning nanofibers with the characteristics of similar to the extracellular matrix,good air permeability and hygroscopicity are very suitable for transdermal drug delivery systems.In this paper, the definition, characteristics, matrix selection, preparation methods, drug-loaded forms and drug-released profiles of drug-loaded electrospinning nanofibers are summarized and analyzed. Meanwhile, the application of drug-loaded electrospinning nanofbiers in the transdermal drug delivery systems is analyzed. This review is to provide support for the further studies on electrospun nanofiber transdermal drug delivery system.
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Microneedle-based transdermal drug delivery system refers to the use of microneedles piercing the stratum corneum of the skin to form tiny pores, through which drug absorption via the skin is enhanced with minimal pain sensation. As a novel drug delivery method, the microneedle technology can significantly improve the transdermal absorption efficiency of the drugs, especially hydrophilic drugs, as compared with using transdermal drug formulations alone. Thus the scope of applicable drugs for transdermal delivery are remarkably enlarged, the efficacy and bioavailability improved as well. Microneedle technology has developed rapidly in the field of transdermal drug delivery. In this paper, the recent representative literature on microneedle-aided transdermal drug administration home and abroad to present the latest progress in this field that was summarized.
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Transdermal drug delivery has become one of the research focuses in pharmaceutical formulations due to its potential advantages. In order to overcome the natural barrier function of the skin, several physical, chemical and pharmaceutical enhancement strategies have been developed to promote the transdermal permeation and adsorption of drugs. Electret is a kind of functional dielectric material with permanent electric polarization state. The electrostatic filed and microcurrent produced by electret can be used as physical permeation enhancer to improve the transdermal drug delivery. In this article, we reviewed the mechanism, influencing factors and current research progress of electret as one of the physical enhancing permeation strategies.
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Objective To optimize the formulation of paeonol nanostructured lipid carrier (NLC) thermosensitive in situ gel through Box-Behnken response surface method; To investigate its release properties in vitro to provide references for the study of transdermal drug delivery system. Methods Taking mass fraction of poloxamer 407 and poloxamer 188 as the factors, the gelling temperature as the index, the mathematical relationship between the gelling temperature and two factors was established by binomial model and multivariate linear regression model. The Box-Behnken response surface method was used to optimize the formulation of paeonol NLC thermosensitive in situ gel, and the in vitro release characteristics of the preparation was investigated. Results There was a credible quantitative relationship between the gelling temperature and the 2 factors, and the binomial model was more reliable than the multivariate linear model. The best prescriptions of paeonol NLC thermosensitive in situ gel were 22.90% poloxamer 407 and 3.34% poloxamer 188; gelling temperature was (33.4±0.1)℃, and the cumulative release amount of paeonol in situ gel in 24 h was 51.19%. Conclusion This method is suitable for the formulation optimization of paeonol NLC thermosensitive in-situ gel, and the established mathematical model has good predictability. The optimized formulation can provide references for the development of paeonol transdermal preparation.
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Dissolving microneedles carried drug molecules can effectively penetrate the stratum corneum of skin to improve the transdermal drug delivery. The traditional Chinese medicine acupuncture is based on the needle stimulation at a specific location (acupoint) to generate and transmit biochemical and physiological signals which alter the pathophysiological state of patients. However, the pain associated with conventional acupuncture needles and the requirement of highly trained professionals limit the development of acupuncture in non-Asian countries. The purpose of this study is to investigate whether the dissolving microneedles can be utilized as a self-administered painless replacement for acupuncture and locally released drug molecules can achieve expected therapeutic outcomes. Immunosuppressive rats were treated with acupuncture at Zusanli (ST36) acupoint using microneedles containing thymopentin. The immune functions and psychological mood of the immunosuppressed animals were examined. The proliferation of splenocytes was examined by CCK-8 assay. CD4 and CD8 expression patterns in spleen cells were detected by flow cytometry. The current study showed that use of either microneedles containing thymopentin or conventional acupuncture both resulted in immune cell proliferation, which was confirmed by flow cytometry. Furthermore, either conventional acupuncture or microneedles were able to effectively mitigate the anxiety caused by immune-suppression when applied on the ST36.
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Compared with traditional oral administration and parenteral administration, transdermal administration has such fea-tures as convenient application, high local drug concentration and strong security. This paper reviewed the composition, characteristics and applications of new carriers ( microemulsions, ethosomes, transfersomes, niosomes, proliposomes, gels and so on) in transdermal drug delivery system with increased drug transdermal transport efficiency in recent years. The advantages of the new transdermal drug delivery carriers make them possess high research value and broad development space.
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Microneedle is a painless and minimally invasive transdermal drug delivery. It can enhance the permeability of skin for macromolecular drugs by puncturing and creating a micron-level drug delivery channel in the skin. The biodegradable microneedles aim to solve the problem that nondegradable-material microneedles may break under skin and cause adverse reaction. This article pro?vides an overview of the characteristics of biodegradable microneedles,the biodegradable materials used,its recent research progress, the development status and the tendency.
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Objective: To review the application of polymeric micelles as the vehicles in transdermal delivery systems.Methods: Based on the recently published papers, the researches of preparation, penetration mechanism, drug release and application of polymeric micelles in transdermal delivery systems were classified and summarized.Results: Polymeric micelles were extensively applied as drug vehicles due to the ability of solubilization and transdermal absorption enhancement.Conclusion: Polymeric micelles can be used as promising vehicles in transdermal delivery systems, which show a good application prospect.