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Nanoparticles (NPs) have shown potential in cancer therapy, while a single administration conferring a satisfactory outcome is still unavailable. To address this issue, the dissolving microneedles (DMNs) were developed to locally deliver functionalized NPs with combined chemotherapy and photothermal therapy (PTT). α-Tocopheryl polyethylene glycol succinate (TPGS)/hyaluronic acid (HA) dual-functionalized PLGA NPs (HD10 NPs) were fabricated to co-load paclitaxel and indocyanine green. HD10 NPs significantly enhanced the cytotoxicity of low-dose paclitaxel because of active and mitochondrial targeting by HA and TPGS, respectively. PTT could further sensitize tumor cells toward chemotherapy by promoting apoptosis into the advanced period, highly activating caspase 3 enzyme, and significantly reducing the expression of survivin and MMP-9 proteins. Further, the anti-tumor effects of HD10 NPs delivered through different administration routes were conducted on the 4T1 tumor-bearing mice. After a single administration, HD10 NPs delivered with DMNs showed the best anti-tumor effect when giving chemotherapy alone. As expected, the anti-tumor effect was profoundly enhanced after combined therapy, and complete tumor ablation was achieved in the mice treated with DMNs and intra-tumor injection. Moreover, DMNs showed better safety due to moderate hyperthermia. Therefore, the DMNs along with combined chemo-photothermal therapy provide a viable treatment option for superficial tumors., Graphical abstract Dissolving microneedles encapsulating TPGS/HA functionalized PLGA nanoparticles provide a highly efficient local treatment for superficial tumor by integrating chemotherapy and photothermal therapy (PTT). The functionalized nanoparticles significantly enhanced the cytotoxicity, and sensitized tumor cells toward chemotherapy through multiple pathways.Image 1

Purpose. To evaluate whether clinical measures of postoperative binocular functions could predict the long-term stability of postoperative ocular alignment in children with intermittent exotropia.Methods. A retrospective study was performed in thirty-nine children (median: 7 years) who have been surgically treated from intermittent exotropia without overcorrection (less than 10 prism diopters [pd] of exodeviation at 1 month postoperatively). Angles of deviation and binocular functions were measured preoperatively and at 1 month, 6 months, and the final follow-up visit (≥24 months) postoperatively. We examined the relationships between postoperative drift (change of ocular alignment) and binocular functions (sensory fusion, fusional convergence amplitude, and stereoacuity).Results. The surgical success rate (esophoria/tropia ≤5 pd to exophoria/tropia ≤10 pd) dropped to 76.9% at 6 months after surgery and to 53.8% at individuals’ last visit (mean: 37 months). The mean exodrift was 7.7 ± 9.2 pd from the postoperative month 1 to the final visit (p<0.001) on distance fixation. Distance stereoacuity, central fusion, and fusional convergence amplitude significantly improved following surgery (p<0.05). However, no significant correlation was found between their binocular functions measured at the beginning of each follow-up period and the postoperative drift (allp>0.13).Conclusion. Our findings suggest that the clinical measures of sensory fusion, fusional convergence amplitude, and stereoacuity cannot serve as a robust predictor for the long-term stability of postoperative ocular alignment in patients who underwent successful surgery without overcorrection at 1 month postoperatively.

PurposeTo study the longitudinal rehabilitation of binocular visual function in adolescent intermittent exotropia (IXT) after successful surgery and compare the results with those of a normal population. The role of binocular function in ocular alignment stability was also evaluated postoperatively.MethodsIn this prospective study, 30 adolescents with IXT successfully corrected after 1 month were followed for 12 months, and 30 children with normal vision were enrolled as controls. Stereopsis, the fusional vergence amplitude, sensory fusion, and accommodative flexibility were measured to assess binocular function at baseline and 6 and 12 months postoperatively. The controls were tested once when they were enrolled in the study.ResultsThe deviation was −32.00 ± 8.60 prism diopters (PD) at distance fixation and −36.0 ± 9.10 PD at near fixation preoperatively with an average correction of 28.53 ± 3.79 PD and 30.67 ± 1.34 PD at 1 month postoperatively. Distance stereoacuity and near stereoacuity improved from 1 to 12 months postoperatively (p = 0.025 and p = 0.041, respectively). Compared with the controls, the fusional convergence reserve at distance (p = 0.025) and near (p = 0.033) fixations and fusion reserve ratio at distance (p = 0.000) and near (p = 0.000) fixations remained subnormal, whereas sensory fusion (p = 0.237), distance stereopsis (p = 0.120), and the fusional divergence amplitude at a distance (p = 0.168) were normal. However, no significant correlations were found between binocular functions at 1 month postoperatively and the postoperative drift.ConclusionBinocular function significantly improved from before to after successful corrective surgery and continued to improve from 1 to 12 months postoperatively in adolescents with IXT. No significant correlations were found between binocular functions at 1 month postoperatively and ocular alignment stability.

The ultra-fine particle processing system (UPPS) previously developed by our lab has been used to prepare various microparticulate formulations. Microspheres prepared by UPPS can achieve sustained release with a reduced initial burst compared to the microspheres prepared by the conventional water-in-oil-in-water (W/O/W) double emulsion technique. However, the in vitro drug release mechanism of the microspheres prepared by UPPS is still uninvestigated. This study aimed to investigate the mechanisms of bovine serum albumin (BSA) released from poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres prepared by UPPS in comparison with microspheres prepared by the W/O/W double emulsion technique. The morphology, in vitro drug release, water uptake, and structural evolution of microspheres prepared by both techniques were evaluated. UPPS microspheres showed solid and compact internal structures without any pores or channels thereby exhibiting a reduced rate of water permeation in the release medium. In addition, the release of BSA in UPPS microspheres was mainly controlled by the erosion of the polymer matrix during the entire process, while BSA was released from W/O/W microspheres by both drug diffusion and matrix erosion. Moreover, the observed surface and internal structural evolution also confirmed their different release mechanisms. This work elaborates the release mechanism of PLGA microspheres prepared by UPPS and facilitates the design of microparticulate formulations. Graphical abstract.

Introduction: DBS is a widely used therapy for PD. There is now a choice between fixed-life implantable pulse generators (IPGs) and rechargeable IPGs, each having advantages and disadvantages. This study aimed to evaluate the preference and satisfaction of Chinese patients with Parkinson's disease (PD) who were treated with deep brain stimulation (DBS).Materials and Methods: Two hundred and twenty PD patients were treated with DBS and completed a self-reported questionnaire to assess their long-term satisfaction and experience with the type of battery they had chosen and the key factors affecting these choices. The survey was performed online and double-checked for completeness and accuracy.Results: The median value of the postoperative duration was 18 months. The most popular way for patients to learn about DBS surgery was through media (79/220, 35.9%) including the Internet and television programs. In total, 87.3% of the DBS used rechargeable IPGs (r-IPG). The choice between rechargeable and non-rechargeable IPGs was significantly associated with affordability (χ(1)2 = 19.13, p < 0.001). Interestingly, the feature of remote programming significantly affected patients' choices between domestic and imported brands (χ(1)2 = 16.81, p < 0.001). 87.7% of the patients were satisfied with the stimulating effects as well as the implanted device itself. 40.6% of the patients with r-IPGs felt confident handling devices within 1 week after discharge. More than half of the patients checked their batteries every week. The mean interval for battery recharge was 4.3 days. 57.8% of the patients spent around 1 h recharging, and 71.4% of them recharged the battery independently.Conclusions: Most patients were satisfied with their choice of IPGs. The patients' economic status and the remote programming function of the device were the two most critical factors in their decision. The skill of recharging the IPG was easy to master for most patients.

Amorphous solid dispersions (ASDs) are inherently unstable because of high internal energy. Evaluating physical and chemical stability during the process and storage is essential. Numerous researches have demonstrated how polymers influence the drug precipitation and physical stability of ASDs, while the influence of polymers on the chemical stability of ASDs is often overlooked. Therefore, this study aimed to investigate the effect of polymers on the physical and chemical stability of spray-dried ASDs using dipyridamole (DP) as a model drug. Proper polymers were selected by assessing their abilities to inhibit drug recrystallization in supersaturated solutions. HPMC E5, Soluplus®, HPMCP-55, and HPMCAS-LP were shown to be effective stabilizers. The optimized formulations were further stored at a high temperature (60 °C) and high humidity (40 °C, 75% RH) for 2 months, and their physical and chemical stability was evaluated using polarizing optical microscopy, FTIR, HPLC, and mass spectrometry (MS). In general, crystallization was observed in all samples, which indicated the physical instability under stressed storage conditions. Also, it was noted that the polymers in ASDs rather than physical mixtures, induced a dramatic drug degradation after being exposed to a high temperature (HPMCP-55 > 80% and HPMCAS-LP > 50%) and high humidity (HPMCP-55 > 40% and HPMCAS-LP > 10%). The MS analysis further confirmed the degradation products, which might be generated from the reaction between dipyridamole and phthalic anhydride decomposed from HPMCP-55 and HPMCAS-LP. Overall, the exposure of ASDs to stressed conditions resulted in recrystallization and even the chemical degradation induced by polymers.

Background Daytime napping has been postulated as both a protective and a risk factor for depression in previous studies. In addition to these conflicting results, research gaps also exist with regard to controlling confounding bias between daytime napping and depression and examining the potential association within the Chinese population. To facilitate the prevention and diagnosis of depression, this study aims to provide insight into the association of daytime napping and depression in 0.5 million Chinese adults by fully controlling confounders, and further examine the modifying effects of socio-economic status (SES) and age. Methods Data were drawn from the baseline of a Chinese cohort study of 0.5 million adults. Depressive status was measured by the Composite International Diagnostic Inventory (CIDI). Logistic regression models were used to examine the association between depression and daytime napping adjusted for SES, sleep-related factors, lifestyle factors and related diseases. Further stratified analyses were conducted to identify the modifying effects of socio-economic status and age. Results The odds ratio of depression by daytime napping was 1.15 (95% CI: 1.01–1.31) in females and 1.42 (95% CI: 1.18–1.71) in males. Factors including living in a rural area (OR = 1.31, 95% CI: 1.13–1.52), receiving less education (OR = 1.42, 95% CI: 1.22–1.66), getting married (OR = 1.24, 95% CI: 1.10–1.40) and being 45–65 years old (OR = 1.29, 95% CI: 1.12–1.49) had a modifying effect on daytime napping and depression that could strengthen the association. Conclusions A significantly positive association was found between depression and daytime napping, as well as daytime dysfunction, snoring and both shorter and longer sleep duration. Lower SES and age could possibly modify the association. Further clinical or epidemiological studies are needed to investigate the mechanism and facilitate the prevention of depression.

Dissolving microneedles (DMN) have been studied as a drug delivery system to enhance the transport of drug molecules across the skin with almost no pain. However, the poor dissolving ability of microneedles in the skin and low drug loading have limited their potential application. The aim of this study was to develop a novel dissolving microneedle system with improved dissolving ability for the delivery of poorly water soluble contraception drug, levonorgestrel (LNG). Chitosan and beta-sodium glycerophosphate (β-GP) were incorporated in the formulation of microneedles. It was found that 69.32±4.23% of the microneedles penetrated through the skin and dissolved within the first 2h, which was almost 2-fold higher than that of the conventional microneedles. In addition, drug loading was significantly increased by packaging LNG into the molecules of hydroxypropyl beta cyclodextrin (HP-β-CD) to form LNG-HP-β-CD inclusion compounds. The use of chitosan and β-GP together with HP-β-CD inclusion compounds was shown to enhance the bioavailability of LNG transdermally. This novel DMN system resulted in a similar pharmacokinetic profile as that following oral administration. In addition to similar Cmax and AUC values, drug concentrations in the blood were more consistent following the DMN in comparison to oral administration.

Dry powder for inhalation (DPI) is an attractive approach for the treatment of local lung diseases. However, the application of drugs with poor water solubility is often limited due to the dissolution obstacles in the fluid layer of the lung lining. In this study, fine solid-crystal suspension (FSCS) was proposed as a solvent-free method to improve the solubility of a drug with poor solubility (itraconazole) and achieve high deposition efficiency simultaneously. The FSCS, in which the crystalline drug particle was highly dispersed in the crystalline excipient, was initially prepared as drug-excipient extrudate by hot melt extrusion, followed by jet milling into fine particles. Unlike the amorphous solid dispersion in the high-energy state, which is liable to recrystallize and aggregate, the FSCS was expected not only to improve the solubility of itraconazole, but also to maintain excellent physical stability. As evidenced in the solubility and stability studies, the solubility of itraconazole in the FSCS was approximately 145-fold greater than that of the raw material, and the crystalline form of itraconazole in the FSCS was also unchanged after storage in the accelerated condition for 6 months (40 °C and 75% relative humidity [RH]). The improved solubility might be ascribed to the reduced crystal size and increased wettability, as confirmed by the particle size and contact angle test. The FSCS also showed an encouragingly high fine-particle fraction of 50.59 ± 0.67%, which might have benefited from the appropriate particle size. Therefore, the FSCS was suggested as a promising DPI for delivery of drugs with poor water solubility.

Glaucoma is an ocular disease featuring increased intraocular pressure (IOP) and its primary treatment strategy is to lower IOP by medication. Current ocular drug delivery in treating glaucoma is confronting a variety of challenges, such as low corneal permeability and bioavailability due to the unique anatomical structure of the human eye. To tackle these challenges, a cubosome drug delivery system for glaucoma treatment was constructed for timolol maleate (TM) in this study. The TM cubosomes (liquid crystalline nanoparticles) were prepared using glycerol monooleate and poloxamer 407 via high-pressure homogenization. These constructed nanoparticles appeared spherical using transmission electron microscopy and had an average particle size of 142 nm, zeta potential of -6.27 mV, and over 85% encapsulation efficiency. Moreover, using polarized light microscopy and small-angle X-ray scattering (SAXS), it was shown that the TM cubosomes have cubic liquid crystalline D-type (Pn3m) structure, which provides good physicochemical stability and high encapsulation efficiency. Ex vivo corneal permeability experiments showed that the total amount of TM cubosomes penetrated was higher than the commercially available eye drops. In addition, in vivo studies revealed that TM cubosomes reduced the IOP in rabbits from 27.8∼39.7 to 21.4∼32.6 mmHg after 1-week administration and had a longer retention time and better lower-IOP effect than the commercial TM eye drops. Furthermore, neither cytotoxicity nor histological impairment in the rabbit corneas was observed. This study suggests that cubosomes are capable of increasing the corneal permeability and bioavailability of TM and have great potential for ocular disease treatment.

Excessive maternal inflammatory response is involved in the pathogenesis of preeclampsia. Few epidemiologic studies have investigated the associations between genetic variations in the inflammatory mediator genes and preeclampsia risk, and these studies have reached inconsistent results. We examined 31 single-nucleotide polymorphisms in IL-1A, IL-1B, IL-1R1, IL-2RA, IL-5RA, IL-6, IL-6R, TNFSF11, TNFRSF11A, IL-28RA, IRAK4, and KIT genes and the risk of preeclampsia and its clinical subtypes in a nested case-control study including 203 preeclampsia cases and 233 controls. We found that IL-1R1, IL-5RA, IL-6R, and TNFSF11 were associated with the risk of preeclampsia. Although the significant associations observed for preeclampsia overall were mainly seen for late-onset preeclampsia and severe preeclampsia, IL-6R (rs2229238) and TNFSF11 (rs9525643) polymorphisms were associated with the risk of early-onset preeclampsia. TNFSF11 (rs2200287 and rs2148072) polymorphisms were associated with risk of mild preeclampsia. Our study provided the first evidence that genetic variations in inflammatory mediator genes IL-1R1, IL-6R, TNFSF11, and IL-5RA were associated with preeclampsia risk, and the risk varied by preeclampsia subtypes.

Spherical poly (D, L-lactic-co-glycolic acid) microparticles (PLGA-MPs) have long been investigated in order to achieve sustained delivery of proteins/peptides. However, the formation mechanism and release characteristics of the specific shape MPs were still unknown. This study aimed to develop a novel-dimpled exenatide-loaded PLGA-MPs (Exe-PLGA-MPs) using an ultra-fine particle processing system (UPPS) and investigate the formation mechanism and release characteristics. Exe-PLGA-MPs were prepared by UPPS and optimized based on their initial burst within the first 24 h and drug release profiles. Physicochemical properties of Exe-PLGA-MPs, including morphology, particle size, and structural integrity of Exe extracted from Exe-PLGA-MPs, were evaluated. Furthermore, pharmacokinetic studies of the optimal formulation were conducted in Sprague-Dawley (SD) rats to establish in vitro-in vivo correlations (IVIVC) of drug release. Exe-PLGA-MPs with dimpled shapes and uniform particle sizes achieved a high encapsulation efficiency (EE%, 91.50 ± 2.65%) and sustained drug release for 2 months in vitro with reduced initial burst (20.42 ± 1.64%). Moreover, the pharmacokinetic studies revealed that effective drug concentration could be maintained for 3 weeks following a single injection of dimpled Exe-PLGA-MPs with high IVIVC. Dimpled PLGA-MPs prepared using the UPPS technique could thus have great potential for sustained delivery of macromolecular proteins/peptides.

Dry powder inhalers (DPIs) offer distinct advantages as a means of pulmonary drug delivery and have attracted much attention in the field of pharmaceutical science. DPIs commonly contain micronized drug particles which, because of their cohesiveness and strong propensity to aggregate, have poor aerosolization performance. Thus carriers with a larger particle size are added to address this problem. However, the performance of DPIs is profoundly influenced by the physical properties of the carrier, particularly their particle size, morphology/shape and surface roughness. Because these factors are interdependent, it is difficult to completely understand how they individually influence DPI performance. The purpose of this review is to summarize and illuminate how these factors affect drug–carrier interaction and influence the performance of DPIs., Graphical abstract The physical properties of carrier particles used in dry powder inhalers (DPIs) particularly their size, morphology/shape, and surface roughness play a significant role in determining DPI performance by influencing the adhesion and detachment of drug–carrier adhesive mixtures. However, it is difficult to completely understand how they influence DPI performance as they are interdependent. fx1

To improve the solubility and bioavailability of oridonin (ORI), glycerol monooleate lipid (GMO)- or phytantriol (PYT)-Poloxamer 407-propylene glycol-water systems were firstly used to develop cubosomes containing ORI for oral delivery. These cubosomes prepared through the fragmentation of bulk gels under homogenization conditions of 1200 bar and nine cycles had a mean particle size of around 200 nm with narrow size distribution, and ORI encapsulation efficiency over 85%. Powder X-ray diffraction and differential scanning calorimetry indicated that ORI was in an amorphous or molecular form in the cubosomes. The internal structures of GMO- and PYT-based cubosomes were revealed by small-angle X-ray scattering as a bi-continuous cubic liquid crystalline phase with Im3m and Pn3m geometry, respectively. About 80% of ORI was released in vitro from GMO- and PYT-based cubosomes at 24 h, showing a sustained release kinetics fitted with Higuchi's equation. The pharmacokinetic study in rats showed that the PYT-based cubosomes significantly enhanced the adsorption of ORI as compared to the GMO-based cubosomes and ORI suspension, with evidence of longer half-life and greater relative bioavailability (p 0.01). Therefore, the PYT-based cubosomes containing ORI might be proposed as a promising candidate carrier for the efficient delivery of drug with therapeutic treatment.

Ethyl cellulose (EC) based microparticles (MPs) could provide sustained release for Huperzine A. The drug release mechanism of MPs was exploited to achieve an ideal drug release profile. We previously found that the wettability of MPs greatly contributed to facilitating drug release, which was detailed in a research article entitled “Huperzine A loaded multiparticulate disintegrating tablet: Drug release mechanism of ethyl cellulose microparticles and pharmacokinetic study” (Peng et al., 2019) [1]. In this article, the influence of different polymers and drugs on the drug release behavior was investigated to broaden or compensate this finding. Besides, powder characterization of MPs was used to evaluate the further application of MPs for tablets. Keywords: Microparticles, Drug release profile, Powder characteristic

Drug administration failure has been often witnessed in pediatric due to children’s resistance to take medicines with bitter taste. Taste-masking is the key requirement among the scanty drugs available for children. Solid taste-masking systems, such as tablets and capsules, are difficult to swallow for children. Therefore, a liquid taste-masking system based on lyotropic liquid crystalline nanoparticles (LLCNs) was developed in this study. Cefpodoxime proxetil (CFP), a typically bitter drug used as antibiotic in pediatric, was selected as the model drug, and the encapsulation of CFP into the LLCNs was envisaged to improve their taste. Pluronic F127 was added to improve the colloidal stability of CFP-LLCNs. The optimized CFP-LLCNs showed the particle size of 187.29 ± 4.12 nm and the encapsulation efficiency of 85.80%. The mesophase analysis by polarized light microscopy and small angle X-ray scattering confirmed the cubic phase of CFP-LLCNs. It showed a sustained-release profile well fitted to Higuchi model, indicating that diffusion and erosion were both responsible for the CFP release. The taste-masking ability of CFP-LLCNs was confirmed by electronic tongue, compared to CFP and commercial product. The colloidal stability was verified after 3 months storage in room condition (25 ± 2 °C, 70 ± 2%RH). To sum up, the taste-masking and colloidal-stable CFP-LLCNs showed great potential for pediatric oral delivery.

The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer–surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0–24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer–surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug.

Gestational diabetes mellitus is a growing public health concern due to its large disease burden; however, the underlying pathophysiology remains unclear. Therefore, we examined the relationship between 107 single-nucleotide polymorphisms in insulin signalling pathway genes and gestational diabetes mellitus risk using a nested case-control study. The SOS1 rs7598922 GA and AA genotype were statistically significantly associated with reduced gestational diabetes mellitus risk ( ptrend = 0.0006) compared with GG genotype. At the gene level, SOS1 was statistically significantly associated with gestational diabetes mellitus risk after adjusting for multiple comparisons. Moreover, AGGA and GGGG haplotypes in SOS1 gene were associated with reduced risk of gestational diabetes mellitus. Our study provides evidence for an association between the SOS1 gene and risk of gestational diabetes mellitus; however, its role in the pathogenesis of gestational diabetes mellitus will need to be verified by further studies.

Thymopentin (TP5) is commonly used in the treatment for autoimmune diseases, with a short plasma half-life (30s) and a long treatment period (7 days to 6 months). It is usually administrated by syringe injection, resulting in compromised patient compliance. Dissolving microneedle array (DMNA) offers a superior approach for transdermal delivery of biological macromolecules, as it allows painless penetration through the stratum corneum and generates minimal biohazardous waste after dissolving in the skin. Despite recent advances in DMNA as a novel approach for transdermal drug delivery, problem of insufficient mechanical strength remains to be solved. In this study, TP5-loaded DMNA (TP5-DMNA) was uniquely developed using a modified two-step molding technology. The higher mechanical strength was furnished by employing bovine serum albumin (BSA) as a co-material to fabricate the needles. The obtained TP5-DMNA containing BSA displayed better skin penetration and higher drug loading efficiency than that without BSA. The in vivo pharmacodynamics study demonstrated that TP5-DMNA had comparative effect on immunomodulation to intravenous injection of TP5, in terms of ameliorating the CD4+/CD8+ ratio, SOD activity and MDA value to the basal level. Only mild irritation was observed at the site of administration. These results suggest that the novel TP5-DMNA utilizing BSA provides an alternative approach for convenient and safe transdermal delivery of TP5, which is a promising administration strategy for future clinical application.