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There has been little understanding of acidification functionality in wound healing, highlighting the need to study the efficacy of wound acidification on wound closure and cellular activity in non-infected wounds. This study is focused on establishing the healing potential of wound acidification in non-infected wounds. Acidic buffers, constituting either phosphoric or citric acid, were employed to modify the physiological pH of non-infected full-thickness excisional murine wounds. Acidification of the wound by acidic buffers was found to be an effective strategy to improve wound healing. A significant improvement in wound healing parameters was observed as early as 2 days post-treatment with acidic buffers compared to controls, with faster rate of epithelialization, wound closure and higher levels of collagen at day 7. pH is shown to play a role in mediating the rate of wound healing, with acidic buffers formulated at pH 4 observed to stimulate faster recovery of wounded tissues than pH 6 buffers. Our study shows the importance of maintaining an acidic wound microenvironment at pH 4, which could be a potential therapeutic strategy for wound management., Competing Interests: The authors declare no conflicts of interest.

The efficient energy transfer in La 3 GaGe 5 O 16 :Cr 3+ , Yb 3+ /Nd 3+ and La 3 GaGe 5 O 16 :Cr 3+ , Yb 3+ , Nd 3+ was investigated in detail. In this phosphor, Cr 3+ acts as the energy absorber (250-700 nm) to sensitize Yb 3+ /Nd 3+ in La 3 GaGe 5 O 16 . Under excitation at 418 nm, La 3 GaGe 5 O 16 :Cr 3+ , Yb 3+ phosphors exhibited a broad emission band in the near-infrared (NIR) region located at 976 nm (La 3 GaGe 5 O 16 :Cr 3+ , Nd 3+ at 1056 nm), which was attributed to the 2 F 5/2 - 2 F 7/2 transition of the Yb 3+ ions ( 2 F 3/2 → 4 I 11/2 transition of Nd 3+ ). Moreover, a Nd 3+ ion was introduced into La 3 GaGe 5 O 16 :Cr 3+ , Yb 3+ . The analysis of excitation spectra and decay time proves that Nd 3+ acts as a bridging ion in the system. This can be used as a new strategy to enhance the energy transfer in Cr 3+ , Yb 3+ co-doped phosphors, and these phosphors have potential applications in NIR spectroscopy regulation.

Strategies that alter the pH of wounds to improve healing outcomes are an emerging area of interest. Currently, there is limited understanding of the effect of hydrogen (H + ) on the functionality of skin cells during proliferation and migration, highlighting the need for research to determine the effect of pH during wound healing. This study aimed to determine the effect of acidification on the metabolic activity and migration of human immortalized keratinocytes (HaCaT) and human foreskin fibroblasts (HFF). In vitro models were used with phosphoric and citric acid buffers at a pH range between 3 and 7. Our results showed that cells were more viable in buffers with low rather than high ionic strength. A time-dependent effect of the acidification treatment was also observed with cell metabolic activity varying with treatment duration and frequency. Our results showed that a 24 h treatment and subsequent resting phase significantly improved cell proliferation and migration. This in vitro study is the first to establish a correlation between the role of acidic pH, molarity and treatment regimen in cellular activity. Our data demonstrated a positive effect of acidic pH on cell metabolic activity and migration rate, suggesting a clinical potential in indications such as wound healing.

The inflammatory pain and stress some crated sows experience during farrowing has attendant risks of piglet-directed aggression, reduced teat exposure and hindered post-partum recovery. To counter this, the steroidal anti-inflammatory compound, dexamethasone, can be administered. To measure the potential for mucosal absorption as an alternative to injection, the permeability of porcine vaginal mucosa to dexamethasone was demonstrated using Franz cell diffusion. These studies found dexamethasone treatment diffused through vaginal mucosa at a constant rate, with 52.37 ± 5.54% permeation in 6 h. To examine in vivo effects on farrowing outcomes, dexamethasone was administered to gilts and parity one sows on the day of expected farrowing. We hypothesized that it would provide relief from farrowing discomfort and reduce behaviours threatening piglet survival. Sows were randomly assigned to receive dexamethasone as an intramuscular injection (n = 23); dexamethasone applied topically into the vagina (n = 20), or to receive no dexamethasone (n = 23). Sows (n = 66) and piglets (n = 593) were monitored for performance indicators during farrowing and early lactation. A subset of sows (n = 24) was also video monitored continuously over 24 h for behaviours associated with pain, postural changes and piglet interactions. No differences were observed between treatment for farrowing performance, piglet survival or behavioural changes for sows experiencing their first or second farrowing (p > 0.05), rejecting the hypothesis that corticosteroid administration will improve sow farrowing performance. This investigation did, however, show that dexamethasone can permeate through porcine vaginal mucosa and so can be administered as a non-injectable treatment.

The age-related loss of circulating estrogen that occurs during the menopausal transition manifests itself through a variety of symptoms including vasomotor (hot flushes and night sweats), genito-urinary syndrome (vaginal dryness and urinary symptoms), sexual dysfunction, mood, and sleep disturbance that often last longer than a decade. Furthermore, reductions in estrogen level increase the risks of chronic complications such as osteoporosis, cardiovascular disease, and cognitive decline among others, thereby affecting the quality of life of women. Although oral estrogens are the most widely used therapy for menopausal symptoms, they suffer from poor bioavailability, and there are concerns over their safety, creating a significant concern to consumers. Mucoadhesive buccal films are an innovative dosage form that offers several advantages including avoidance of the first-pass metabolism, fast onset of action, and importantly, improved patient acceptance. In the current work, we developed mucoadhesive estradiol film for hormonal replacement therapy using film-forming polymers. Two approaches, namely, co-solvency and nano-emulsion were evaluated to increase solubility and hence incorporate estradiol, a poorly water-soluble drug, into a formulation made from the hydrophilic polymer/s. The films were characterised for their mechanical and physicochemical properties. In-vitro release study showed that about 80% of the drug was released within 6 min from films prepared by the nano-emulsion approach, whereas it took about 10.5 min to get similar drug release from films prepared by the co-solvency approach. The ex-vivo permeation result indicates that about 15% of the drug permeated across the porcine buccal mucosa in the first 10 h from films prepared by the nano-emulsion approach, while permeation across porcine buccal mucosa was only observed at around 24 h from films prepared by the co-solvency method. The nano-emulsion films were evaluated for in vivo performance using a convolution technique using R software. The predicted Cmax and Tmax were found to be 740.74 ng mL -1 and 7 min, respectively, which were higher than previously reported in vivo concentration from oral tablets. The results demonstrated that mucoadhesive film of estradiol based on the nano-emulsion approach could be a promising platform for the delivery of estradiol through the buccal mucosa for the treatment of menopausal symptoms.

The swine industry has evolved significantly in the recent decades, but this has come at considerable expense to piglet survival. Breeding sows for greater prolificacy has been accompanied by a greater proportion of piglets being born underweight, of lower vigor, and higher susceptibility to early mortality. Inducing sows to farrow during working hours has the potential to increase piglet survivability, but non-therapeutic injectable products are often discouraged on farms. We aimed to design and develop a novel vaginal drug delivery system (NVDDS) that could reliably trigger luteolysis and induce parturition. To achieve this, two vaginal tablets containing the luteolytic agent cloprostenol were formulated to be inserted together: one would release constituents immediately on insertion (immediate release; IR) and the other would release cloprostenol in a controlled manner (controlled release; CR). The two formulations (IR and CR) were evaluated for drug release, swelling and bio-adhesion in conditions simulating the sow vaginal environment. The IR tablet released the drug completely for 5 min whereas the CR tablet took 5 h to release 50% of the drug. Furthermore, the release kinetics were evaluated by fitting the dissolution profiles into different mathematical models. Both IR and CR tablets were best fitted by the Makoid-Banakar model which assumes release by summation of different mechanisms. The performance of the optimized formulations was studied in vivo with 161 Large White x Landrace sows of varying parity (0-5). The sows were assigned to five groups. Group 1 (SI) received a single vulval injection of cloprostenol at 0700 h ( n = 32), group 2 (SDI) received the same dose split in two parts, at 0700h and 1300h ( n = 33). Group 3 (IRT) animals were administered an IR tablet at 0700h ( n = 32), while group 4 (IRCRT) received both IR and CR tablets at 0700 h ( n = 33). Group 5 was untreated and served as a control ( n = 32). The interval to farrowing was longer ( p < 0.001) for controls than for treated sows, but there were no differences among cloprostenol treatments for timing of farrowing. The finding confirms the efficacy of the NVDDS for induction of farrowing in sows.

Topical patches containing 5-fluorouracil (5-FU) are a feasible alternative to overcome the shortcomings of commercial cream for the treatment of non-melanoma skin cancer (NMSC). Plasticizers are a critical component of drug-in-adhesive (DIA) patches as they can significantly affect the mechanical, adhesive and drug release characteristics of the patches. Eudragit® E (EuE) is a methacrylate-based cationic copolymer capable of producing flexible and adhesive films for topical application. In this study, the effect of plasticizers on the mechanical, adhesive and 5-FU release characteristics of EuE-based patches was comprehensively evaluated. While the elongation at break (%) and adhesion of the films were significantly increased with increasing triacetin, dibutyl sebacate (DBS) and triethyl citrate (TEC) concentrations, the tensile strength showed an inverse relationship. EuE plasticized with 40% triacetin, 30% DBS or 40% w/w TEC produced elastic and adhesive films most suitable for topical application. In vitro release studies of the 5-FU-loaded patches demonstrated an initial burst release pattern during the first 10 min followed by a slow release over 120 min. In summary, this study provides important information on effect of plasticizers for preparation of EuE-based patches with desired mechanical, adhesive and release characteristics of 5-FU towards their potential application in the treatment of NMSC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Three-dimensional (3D) printing is among the rapidly evolving technologies with applications in many sectors. The pharmaceutical industry is no exception, and the approval of the first 3D-printed tablet (Spiratam ® ) marked a revolution in the field. Several studies reported the fabrication of different dosage forms using a range of 3D printing techniques. Thermosensitive drugs compose a considerable segment of available medications in the market requiring strict temperature control during processing to ensure their efficacy and safety. Heating involved in some of the 3D printing technologies raises concerns regarding the feasibility of the techniques for printing thermolabile drugs. Studies reported that semi-solid extrusion (SSE) is the commonly used printing technique to fabricate thermosensitive drugs. Digital light processing (DLP), binder jetting (BJ), and stereolithography (SLA) can also be used for the fabrication of thermosensitive drugs as they do not involve heating elements. Nonetheless, degradation of some drugs by light source used in the techniques was reported. Interestingly, fused deposition modelling (FDM) coupled with filling techniques offered protection against thermal degradation. Concepts such as selection of low melting point polymers, adjustment of printing parameters, and coupling of more than one printing technique were exploited in printing thermosensitive drugs. This systematic review presents challenges, 3DP procedures, and future directions of 3D printing of thermo-sensitive formulations.

Inulin's unique and flexible structure, stabilization/protective effects, and organ targeting ability make it an excellent drug delivery carrier compared to other biodegradable polysaccharides. The three hydroxyl groups attached to each fructose unit serve as an anchor for chemical modification. This, in turn, helps in increasing bioavailability, improving cellular uptake, and achieving targeted, sustained, and controlled release of drugs and biomolecules. This review focuses on the various types of inulin drug delivery systems such as hydrogel, conjugates, nanoparticles, microparticles, micelles, liposomes, complexes, prodrugs, and solid dispersion. The preparation and applications of the different inulin drug delivery systems are further discussed. This work highlights the fact that modification of inulin allows the use of this polymer as multifunctional scaffolds for different drug delivery systems.

As a variety of novel technologies, 3D printing has been considerably applied in the field of health care, including cancer treatment. With its fast prototyping nature, 3D printing could transform basic oncology discoveries to clinical use quickly, speed up and even revolutionise the whole drug discovery and development process. This literature review provides insight into the up-to-date applications of 3D printing on cancer research and treatment, from fundamental research and drug discovery to drug development and clinical applications. These include 3D printing of anticancer pharmaceutics, 3D-bioprinted cancer cell models and customised nonbiological medical devices. Finally, the challenges of 3D printing for cancer applications are elaborated, and the future of 3D-printed medical applications is envisioned.

Theranostic nanoplatforms integrating simultaneously photodynamic therapy (PDT) and photothermal therapy (PTT) exhibit intrinsic advantages in tumor therapy due to distinct mechanisms of action. However, it is challenging to achieve PDT and PTT under single near-infrared (NIR) laser irradiation with a nanoplatform utilizing conventional organic photodynamic agent and inorganic photothermal agent owing to the difference in inherent excitation wavelengths. Particularly, the single NIR light (660 nm)-triggered PTT and PDT nanoplatform, constructed from chlorin e6 (Ce6) and copper sulfide (CuS) nanoparticles (NPs), has never been reported. Herein, we, for the first time, designed and established a dual-modal phototherapeutic nanoplatform that achieved both PTT and PDT under single NIR laser (660 nm) irradiation for Ce6 and CuS NPs with the strategy of core-shell structured CuS@Carbon integrated with Ce6. Introducing of carbon shell not only endows small CuS NPs with excellent tumor accumulation, but also significantly strengthens the photothermal performance of CuS NPs, realizing efficient photothermal performance under 660 nm laser irradiation. Moreover, Ce6 in carbon shell endowed the nanoplatform with photodynamic effect under 660 nm laser irradiation. The as-prepared Ce6/CuS@Carbon nanoplatform thus achieved dual-modal phototherapy under single NIR laser irradiation, significantly inhibiting tumor growth with minimal adverse effects and superior biosafety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Drug-eluting gastrointestinal (GI) stents are emerging as promising platforms for the treatment of GI cancers and provide the combined advantages of mechanical support to prevent lumen occlusion and as a reservoir for localized drug delivery to tumors. Therefore, in this work we present a detailed quality assurance study of 5-fluorouracil (5FU) drug-eluting stents (DESs) as potential candidates for the treatment of obstructive GI cancers., Methods: The 5FU DESs were fabricated via a simple two-step sequential dip-coating process of commercial GI self-expanding nitinol stents with a 5FU-loaded polyurethane basecoat and a drug-free protective poly(ethylene-co-vinyl acetate) topcoat. The drug loading, content uniformity and drug stability were determined using a validated high-performance liquid chromatography (HPLC) method, which is also recommended in the United States Pharmacopeia. In vitro drug release studies were performed in phosphate buffered saline to determine the drug releasing properties of the two 5FU-loaded stents. Gas chromatography (GC) and HPLC were employed to determine total residual tetrahydrofuran and N,N -dimethylformamide in the stents remaining from the manufacturing process. Sterilization of the stents was performed using gamma radiation and stability testing was carried out for 3 months., Results: The drug loading analysis revealed excellent uniformity in the distribution of 5FU between and within individual stents. Determination of drug stability in the biorelevant release media confirmed that 5FU remains stable over 100 d. In vitro drug release studies from the stents revealed sustained release of 5FU across two different time scales (161 and 30 d), and mathematical modeling of drug release profiles revealed a diffusion-controlled mechanism for the sustained 5FU release. GC and HPLC analysis revealed that the daily residual solvent leached from the stents was below the United States (US) Food and Drug Administration (FDA) guidelines, and therefore, unlikely to cause localized/systemic toxicities. Sterilization of the stents with gamma radiation and accelerated stability tests over a period of 3 months revealed no significant effect on the stability or in vitro release of 5FU., Conclusion: Our results demonstrate that the 5FU DESs meet relevant quality standards and display favourable drug release characteristics for the potential treatment of GI cancers and related obstructions., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Arafat et al.)

For several decades, self-expanding metal stents (SEMSs) have shown significant clinical success in the palliation of obstructive metastatic oesophageal cancer. However, these conventional oesophageal stents can suffer from stent blockage caused by malignant tumour cell growth. To overcome this challenge, there is growing interest in drug-releasing stents that, in addition to palliation, provide a sustained and localized release of anticancer drugs to minimise tumour growth. Therefore, in this study we prepared and evaluated an oesophageal stent-based drug delivery platform to provide the sustained release of docetaxel (DTX) for the treatment of oesophageal cancer-related obstructions. The DTX-loaded oesophageal stents were fabricated via dip-coating of bare nitinol stents with DTX-polyurethane (PU) solutions to provide PU coated stents with DTX loadings of 1.92 and 2.79% w / w . Mechanical testing of the DTX-PU coated stents revealed that an increase in the drug loading resulted in a reduction in the ultimate tensile strength, toughness and Young's modulus. In vitro release studies showed a sustained release of DTX, with ~80-90% released over a period of 33 days. While the DTX-loaded stents exhibited good stability to gamma radiation sterilisation, UV sterilisation or accelerated storage at elevated temperatures (40 °C) resulted in significant DTX degradation. Cell proliferation, apoptosis and Western blotting assays revealed that the DTX released from the stents had comparable anticancer activity to pure DTX against oesophageal cancer cells (KYSE-30). This research demonstrates that the dip-coating technique can be considered as a promising approach for the fabrication of drug-eluting stents (DESs) for oesophageal cancer treatment.

A novel drug delivery system preventing Glioblastoma multiforme (GBM) recurrence after resection surgery is imperatively required to overcome the mechanical limitation of the current local drug delivery system and to offer personalised treatment options for GBM patients. In this study, 3D printed biodegradable flexible porous scaffolds were developed via Fused Deposition Modelling (FDM) three-dimensional (3D) printing technology for the local delivery of curcumin. The flexible porous scaffolds were 3D printed with various geometries containing 1, 3, 5, and 7% ( w / w ) of curcumin, respectively, using curcumin-loaded polycaprolactone (PCL) filaments. The scaffolds were characterised by a series of characterisation studies and in vitro studies were also performed including drug release study, scaffold degradation study, and cytotoxicity study. The curcumin-loaded PCL scaffolds displayed versatile spatiotemporal characteristics. The polymeric scaffolds obtained great mechanical flexibility with a low tensile modulus of less than 2 MPa, and 4 to 7-fold ultimate tensile strain, which can avoid the mechanical mismatch problem of commercially available GLIADEL wafer with a further improvement in surgical margin coverage. In vitro release profiles have demonstrated the sustained release patterns of curcumin with adjustable release amounts and durations up to 77 h. MTT study has demonstrated the great cytotoxic effect of curcumin-loaded scaffolds against the U87 human GBM cell line. Therefore, 3D printed curcumin-loaded scaffold has great promise to provide better GBM treatment options with its mechanical flexibility and customisability to match individual needs, preventing post-surgery GBM recurrence and eventually prolonging the life expectancy of GBM patients.

Conventional chemotherapies used for breast cancer (BC) treatment are non-selective, attacking both healthy and cancerous cells. Therefore, new technologies that enhance drug efficacy and ameliorate the off-target toxic effects exhibited by currently used anticancer drugs are urgently needed. Here we report the design and synthesis of novel mesoporous silica nanoparticles (MSNs) equipped with the hormonal drug tamoxifen (TAM) to facilitate guidance towards estrogen receptors (ERs) which are upregulated in breast tumours. TAM is linked to the MSNs using a poly-ʟ-histidine (PLH) polymer as a pH-sensitive gatekeeper, to ensure efficient delivery of encapsulated materials within the pores. XRD, HR-TEM, DLS, SEM, FT-IR and BET techniques were used to confirm the successful fabrication of MSNs. The MSNs have a high surface area (>1000 m 2 /g); and a mean particle size of 150 nm, which is an appropriate size to allow the penetration of premature blood vessels surrounding breast tumours. Successful surface functionalization was supported by FT-IR, XPS and TGA techniques, with a grafting ratio of approximately 29%. The outcomes of this preliminary work could be used as practical building blocks towards future formulations.

Self-expanding metal stents (SEMSs) are currently the gold standard for the localised management of malignant gastrointestinal (GI) stenosis and/or obstructions. Despite encouraging clinical success, in-stent restenosis caused by tumour growth is a significant challenge. Incorporating chemotherapeutic drugs into GI stents is an emerging strategy to provide localised and sustained release of drugs to intestinal malignant tissues to prevent tumour growth. Therefore, the aim of this work was to develop and evaluate a local GI stent-based delivery system that provides a controlled release of 5-fluorouracil (5FU) over a course of several weeks to months, for the treatment of colorectal cancer and cancer-related stenosis/obstructions. The 5FU-loaded GI stents were fabricated via sequential dip-coating of commercial GI stents with a drug-loaded polyurethane (PU) basecoat and a drug-free poly(ethylene- co -vinyl acetate) (PEVA) topcoat. For comparison, two types of commercial stents were investigated, including bare and silicone (Si) membrane-covered stents. The physicochemical properties of the 5FU-loaded stents were evaluated using photoacoustic Fourier-transform infrared (PA-FTIR) spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and thermal analysis. In vitro release studies in biological medium revealed that the 5FU-loaded stents provided a sustained release of drug over the period studied (18 d), and cell viability, cell cycle distribution and apoptosis assays showed that the released 5FU had comparable anticancer activity against human colon cancer cells (HCT-116) to pure 5FU. This study demonstrates that dip-coating is a facile and reliable approach for fabricating drug-eluting stents (DESs) that are promising candidates for the treatment of GI obstructions and/or restenosis.

Oesophageal stents have been widely used to prevent occlusion or stenosis in the treatment of oesophageal cancers. However, stent restenosis caused by tumour ingrowth occurs frequently after stent placement. Incorporating anti-cancer drugs into endoluminal stents is a promising strategy to provide a sustained release of drugs to oesophageal malignant tissues while prolonging the retention of the stent and relieving dysphagia. Recognizing the potential of 3D printing to produce personalised stents with patient specific geometries, we herein report the development of a drug-loaded 3D printed stent for the sustained local delivery of 5-fluorouracil (5-FU) to treat oesophageal cancer. The 3D printed drug-eluting stents (DESs) were fabricated via fused deposition modelling using 5-FU-loaded polyurethane filament. Determination of the 5-FU in the filament and stent (>97%) confirmed that minimal degradation of the drug occurred during the thermal extrusion and 3D printing processes. The physicochemical properties of the stents were investigated using photoacoustic Fourier-transform infrared (PA-FTIR) spectrophotometry, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and mechanical testing. In vitro release studies revealed that the drug-loaded stents provided a sustained release of 5-FU over a period of 110 days and allowed the constant diffusion of 5-FU when in contact with oesophageal mucosa. Furthermore, the 3D printed stents exhibited good stability following sterilization with gamma or UV irradiation, and during accelerated storage. This study demonstrates that 3D printing is a powerful tool for manufacturing DESs which could easily be customized to provide personalized, patient specific geometries and drug doses.

Despite the promising properties of tea tree oil (TTO) as potential therapeutics for several superficial skin conditions, certain limitations such as physical instability and skin irritation have restricted its widespread use. This study focuses on developing a rationally designed lipid-based nanoformulation (TTO-LNF) in accordance with the US Food and Drug Administration standard using a well-recognized quality-by-design (QbD) approach. Using a mixture experimental design, TTO-LNF has been optimized with 5% TTO, 10% surfactant, 5% co-surfactant, and 80% water, which showed a 14.4 ± 4.4 nm droplet size and 0.03 ± 0.01 polydispersity index (PDI). To ease the topical administration, the TTO-LNF gel formulation was further developed using xanthan gum to achieve the desired viscosity and form a gel. The in vitro antibacterial tests of TTO-LNF showed promising inhibitory effects toward both Gram-negative and Gram-positive bacteria. In fact, a complete growth inhibition of S. epidermidis was observed when exposed to TTO-LNF and TTO-LNF gel for 24 h, showing better activity than antibiotic kanamycin (25 µg/mL). Additionally, the in vitro release study showed a sustained release profile with a 50% release in 24 h, which could be beneficial to reduce the toxicity and thereby improve the therapeutic efficacy for long-acting applications. Furthermore, the formulations were remarkably stable at 40 °C/75% Relative humidity (RH) for at least 4 weeks. Therefore, this study presents a promising strategy to develop a biocompatible and stable formulation that can be used for the topical treatment of skin infections.

Following the huge clinical success of drug-eluting vascular stents, there is a significant interest in the development of drug-eluting stents for other applications, such as the treatment of gastrointestinal (GI) cancers. Central to this process is understanding how particular drugs are released from stent coatings, which to a large extent is controlled by drug-polymer interactions. Therefore, in this study we investigated the release of docetaxel (DTX) from a selection of non-degradable polymer films. DTX-polymer films were prepared at various loadings (1, 5 and 10% w / w ) using three commercially available polymers including poly(dimethylsiloxane) (PSi), poly (ethylene- co -vinyl acetate) (PEVA) and Chronosil polyurethane (PU). The formulations were characterised using different techniques such as photoacoustic Fourier-transform infrared (PA-FTIR) spectrophotometry, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The effect of DTX on the mechanical properties of the films, in-vitro release, and degradation tests were also assessed. For all polymers and DTX loadings, the drug was found to disperse homogenously without crystallisation within the polymer matrix. While no specific interactions were observed between DTX and PSi or PEVA, hydrogen-bonding appeared to be present between DTX and PU, which resulted in a concentration-dependent decrease in the Young's moduli of the films due to disruption of inter-polymeric molecular interactions. In addition, the DTX-PU interactions were found to modulate drug release, providing near-linear release over 30 days, which was accompanied by a significant reduction in degradation products. The results indicate that DTX-loaded PU films are excellent candidates for drug-eluting stents for the treatment of oesophageal cancer.

This paper reports the oxidation of inulin using varying ratios of sodium periodate and the characterization of the inulin polyaldehyde. The physicochemical properties of the inulin polyaldehyde (oxidized inulin) were characterized using different techniques including 1D NMR spectroscopy, 13 C Nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), differential scanning calorimetric (DSC), ultraviolet-visible spectroscopy (UV), and scanning electron microscopy (SEM). The aldehyde peak was not very visible in the FTIR, because the aldehyde functional group exists in a masked form (hemiacetal). The thermal stability of the oxidized inulin decreased with the increasing oxidation degree. The smooth spherical shape of raw inulin was destructed due to the oxidation, as confirmed by the SEM result. The 1 HNMR results show some new peaks from 4.8 to 5.0 as well as around 5.63 ppm. However, no aldehyde peak was found around 9.7 ppm. This can be attributed to the hemiacetal. The reaction of oxidized inulin with tert-butyl carbazate produced a carbazone conjugate. There was clear evidence of decreased peak intensity for the proton belonging to the hemiacetal group. This clearly shows that not all of the hemiacetal group can be reverted by carbazate. In conclusion, this work provides vital information as regards changes in the physicochemical properties of the oxidized inulin, which has direct implications when considering the further utilization of this biomaterial.

Breast cancer (BC) is one of the leading causes of death from cancer in women; second only to lung cancer. Tamoxifen (TAM) is a hydrophobic anticancer agent and a selective estrogen modulator (SERM), approved by the FDA for hormone therapy of BC. Despite having striking efficacy in BC therapy, concerns regarding the dose-dependent carcinogenicity of TAM still persist, restricting its therapeutic applications. Nanotechnology has emerged as one of the most important strategies to solve the issue of TAM toxicity, owing to the ability of nano-enabled-formulations to deliver smaller concentrations of TAM to cancer cells, over a longer period of time. Various TAM-containing-nanosystems have been successfully fabricated to selectively deliver TAM to specific molecular targets found on tumour membranes, reducing unwanted toxic effects. This review begins with an outline of breast cancer, the current treatment options and a history of how TAM has been used as a combatant of BC. A detailed discussion of various nanoformulation strategies used to deliver lower doses of TAM selectively to breast tumours will then follow. Finally, a commentary on future perspectives of TAM being employed as a targeting vector, to guide the delivery of other therapeutic and diagnostic agents selectively to breast tumours will be presented., Competing Interests: The authors declare no conflict of interest.

Objective: This study aimed to quantify the amount of perindopril and its active metabolite perindoprilat present in breast milk and corresponding maternal and infant plasma concentrations., Design: Prospective, longitudinal, observational., Setting: Tertiary specialist paediatric and obstetric hospital in Adelaide, South Australia., Population: Breastfeeding women actively treated with perindopril for hypertensive disorders postpartum., Methods: Eight breast milk samples and a single plasma sample were collected from each participant over a 24 hrs period, and plasma samples were taken from eligible breastfed infants. Breast milk and plasma concentrations of perindopril and perindoprilat were analysed using a validated Liquid Chromatography tandem-Mass Spectrometry (LC-MS/MS) method., Main Outcome Measures: Mean breast milk concentrations of perindopril and perindoprilat, Relative Infant Dose (RID) <10%, and Theoretical Infant Dose (TID)., Results: Ten women and three infants participated in the study. The mean concentration of perindopril in breast milk for each participant ranged from 0.003 to 1.2 ng/mL and perindoprilat 0.2-36 ng/mL. RID for perindopril was 0.0005-0.2% and perindoprilat 0.03-4.6%. TID for perindopril was 0.00045-0.18 µg/kg/day and perindoprilat 0.032-5.4 µg/kg/day. Infant plasma levels for perindopril ranged from 0.44 to 1.12 ng/mL and perindoprilat undetectable - 10.14 ng/mL. Maternal reports described normal infant growth and development., Conclusion: Infant exposure to perindopril and perindoprilat through breast milk is low. However, some infants were found to have plasma perindoprilat concentrations consistent with pharmacodynamic effects. Perindopril may be used in mothers of healthy term infants, provided the infant is carefully monitored., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Leggett et al.)

Delta inulin, also known as microparticulate inulin (MPI), was modified by covalently attaching doxorubicin to its nanostructured surface for use as a targeted drug delivery vehicle. MPI is readily endocytosed by monocytes, macrophages, and dendritic cells and in this study, we sought to utilize this property to develop a system to target anti-cancer drugs to lymphoid organs. We investigated, therefore, whether MPI could be used as a vehicle to deliver doxorubicin selectively, thereby reducing the toxicity of this antibiotic anthracycline drug. Doxorubicin was covalently attached to the surface of MPI using an acid-labile linkage to enable pH-controlled release. The MPI-doxorubicin conjugate was characterized using FTIR and SEM, confirming covalent attachment and indicating doxorubicin coupling had no obvious impact on the physical nanostructure, integrity, and cellular uptake of the MPI particles. To simulate the stability of the MPI-doxorubicin in vivo, it was stored in artificial lysosomal fluid (ALF, pH 4.5). Although the MPI-doxorubicin particles were still visible after 165 days in ALF, 53% of glycosidic bonds in the inulin particles were hydrolyzed within 12 days in ALF, reflected by the release of free glucose into solution. By contrast, the fructosidic bonds were much more stable. Drug release studies of the MPI-doxorubicin in vitro, demonstrated a successful pH-dependent controlled release effect. Confocal laser scanning microscopy studies and flow cytometric analysis confirmed that when incubated with live cells, MPI-doxorubicin was efficiently internalized by immune cells. An assay of cell metabolic activity demonstrated that the MPI carrier alone had no toxic effects on RAW 264.7 murine monocyte/macrophage-like cells, but exhibited anti-cancer effects against HCT116 human colon cancer cells. MPI-doxorubicin had a greater anti-cancer cell effect than free doxorubicin, particularly when at lower concentrations, suggesting a drug-sparing effect. This study establishes that MPI can be successfully modified with doxorubicin for chemotherapeutic drug delivery.

The use of particles for monocyte-mediated delivery could be a more efficient strategy and approach to achieve intracellular targeting and delivery of antitubercular drugs to host macrophages. In this study, the potential of inulin microparticles to serve as a drug vehicle in the treatment of chronic tuberculosis using a monocytes-mediated drug targeting approach was evaluated. Isoniazid (INH) was conjugated to inulin via hydrazone linkage in order to obtain a pH-sensitive inulin-INH conjugate. The conjugate was then characterized using proton nuclear magnetic resonance ( 1 HNMR), Fourier transform infrared spectroscopy (FTIR) as well as in vitro, cellular uptake and intracellular Mycobacterium tuberculosis (Mtb) antibacterial efficacy. The acid-labile hydrazone linkage conferred pH sensitivity to the inulin-INH conjugate with ~95, 77 and 65% of the drug released after 5 h at pH 4.5, 5.2, and 6.0 respectively. Cellular uptake studies confirm that RAW 264.7 monocytic cells efficiently internalized the inulin conjugates into endocytic compartments through endocytosis. The intracellular efficacy studies demonstrate that the inulin conjugates possess a dose-dependent targeting effect against Mtb-infected monocytes. This was through efficient internalization and cleavage of the hydrazone bond by the acidic environment of the lysosome, which subsequently released the isoniazid intracellularly to the Mtb reservoir. These results clearly suggest that inulin conjugates can serve as a pH-sensitive intracellular drug delivery system for TB treatment.

Stents are currently the primary choice for the treatment of both vascular and non-vascular occlusions and/or stenosis. Despite the proven history of clinical safety and efficacy, the benefit of traditional vascular or non-vascular stenting is often limited by in-stent restenosis, resulting in failure of existing stent or reintervention by use of another stent. Coronary drug-eluting stents (DESs) significantly reduce restenosis of vascular stents and have revolutionised the percutaneous coronary intervention (PCI) treatment in coronary stenting patients. Following the similar concept of coronary DESs, non-vascular DESs are being investigated to reduce non-vascular restenosis caused by tumour growth, enhance stenting functions, and increase their effectiveness in the treatment of obstructive gastrointestinal (GI) cancers. This article summarises and updates the outcomes of preclinical and clinical studies on non-vascular DESs for localised management of malignant GI obstructions with emphasis on fabrication techniques and regulatory requirements relevant to development and marketing approval., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Inulin-based hydrogels are useful carriers for the delivery of drugs in the colon-targeted system and in other biomedical applications. In this project, inulin hydrogels were fabricated by crosslinking oxidized inulin with adipic acid dihydrazide (AAD) without the use of a catalyst or initiator. The physicochemical properties of the obtained hydrogels were further characterized using different techniques, such as swelling experiments, in vitro drug release, degradation, and biocompatibility tests. The crosslinking was confirmed with Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC). In vitro releases of 5-fluorouracil (5FU) from the various inulin hydrogels was enhanced in acidic conditions (pH 5) compared with physiological pH (pH 7.4). In addition, blank gels did not show any appreciable cytotoxicity, whereas 5FU-loaded hydrogels demonstrated efficacy against HCT116 colon cancer cells, which further confirms the potential use of these delivery platforms for direct targeting of 5-FU to the colon.

The propensity of monocytes to migrate into sites of mycobacterium tuberculosis (TB) infection and then become infected themselves makes them potential targets for delivery of drugs intracellularly to the tubercle bacilli reservoir. Conventional TB drugs are less effective because of poor intracellular delivery to this bacterial sanctuary. This study highlights the potential of using semicrystalline delta inulin particles that are readily internalised by monocytes for a monocyte-based drug delivery system. Pyrazinoic acid was successfully attached covalently to the delta inulin particles via a labile linker. The formation of new conjugate and amide bond was confirmed using zeta potential, Proton Nuclear Magnetic Resonance ( 1 HNMR) and Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) confirmed that no significant change in size after conjugation which is an important parameter for monocyte targeting. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to establish the change in thermal properties. The analysis of in-vitro release demonstrated pH-triggered drug cleavage off the delta inulin particles that followed a first-order kinetic process. The efficient targeting ability of the conjugate for RAW 264.7 monocytic cells was supported by cellular uptake studies. Overall, our finding confirmed that semicrystalline delta inulin particles (MPI) can be modified covalently with drugs and such conjugates allow intracellular drug delivery and uptake into monocytes, making this system potentially useful for the treatment of TB.

Faulty bony repair causes dysrepair of injured growth plate cartilage and bone growth defects in children; however, the underlying mechanisms are unclear. Recently, we observed the prominent induction of neurotrophin‑3 (NT-3) and its important roles as an osteogenic and angiogenic factor promoting the bony repair. The current study investigated its roles in regulating injury site remodelling. In a rat tibial growth plate drill-hole injury repair model, NT-3 was expressed prominently in osteoblasts at the injury site. Recombinant NT-3 (rhNT-3) systemic treatment enhanced, but NT-3 immunoneutralization attenuated, expression of cartilage-removal proteases (MMP-9 and MMP-13), presence of bone-resorbing osteoclasts and expression of osteoclast protease cathepsin K, and remodelling at the injury site. NT-3 was also highly induced in cultured mineralizing rat bone marrow stromal cells, and the conditioned medium augmented osteoclast formation and resorptive activity, an ability that was blocked by presence of anti-NT-3 antibody. Moreover, NT-3 and receptor TrkC were induced during osteoclastogenesis, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts although rhNT-3 alone did not affect activation of osteoclastogenic transcription factors NF-κB or NFAT in RAW 264.7 osteoclast precursor cells. Furthermore, rhNT-3 treatment increased, but NT-3 neutralization reduced, expression of osteoclastogenic cytokines (RANKL, TNF-α, and IL-1) in mineralizing osteoblasts and in growth plate injury site, and rhNT-3 augmented the induction of these cytokines caused by RANKL treatment in RAW 264.7 cells. Thus, injury site osteoblast-derived NT-3 is important in promoting growth plate injury site remodelling, as it induces cartilage proteases for cartilage removal and augments osteoclastogenesis and resorption both directly (involving activing Erk1/2 and substantiating RANKL-induced increased expression of osteoclastogenic signals in differentiating osteoclasts) and indirectly (inducing osteoclastogenic signals in osteoblasts)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Curcumin (CUR) is considered as one of the most bioactive molecules ever discovered from nature due to its proven anti-inflammatory and antioxidant in both preclinical and clinical studies. Despite its proven safety and efficacy, the clinical translation of CUR into a useful therapeutic agent is still limited due to its poor oral bioavailability. To overcome its limitation and enhance oral bioavailability by improving its aqueous solubility, stability, and intestinal permeability, a novel CUR formulation (NCF) was developed using the self-nanomicellizing solid dispersion strategy. From the initial screening of polymers for their potential to improve the solubility and stability, Soluplus (SOL) was selected. The optimized NCF demonstrated over 20,000-fold improvement in aqueous solubility as a result of amorphization, hydrogen bonding interaction, and micellization determined using differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance, dynamic light scattering, and transmission electron microscopy. Moreover, the greater stabilizing effect in alkaline pH and light was observed. Furthermore, significant enhancement of dissolution and permeability of CUR across everted sacs of rat small intestine were noticed. Pharmacokinetic studies demonstrated that the oral bioavailability of CUR was increased 117 and 17-fold in case of NCF and physical mixture of CUR and SOL compared to CUR suspension. These results suggest NCF identified as a promising new approach for repositioning of CUR for pharmaceutical application by enhancing the oral bioavailability of CUR. The findings herein stimulate further in vivo evaluations and clinical tests of NCF.

Purpose: Results of a study to determine the stability of an extemporaneously compounded minoxidil oral suspension under various temperature and stress conditions are reported., Methods: Commercially available minoxidil tablets (10 mg) were crushed to a fine powder, and predetermined amounts of 2 suspending vehicles were added to produce a 1-mg/mL suspension, which was stored in glass bottles at room temperature (25 ± 2 °C) or in a refrigerator (4 ± 2 °C). To simulate daily patient use, 5 days weekly 1 bottle of the suspension was removed from refrigerated storage and shaken and 0.5 mL of the contents discarded. At each specified time point, samples were analyzed in duplicate ( n = 6 for each test condition) using a validated high-performance liquid chromatography method. Samples were visually observed and their pH measured at each time point. Microbiological studies were performed on day 0 and at week 24., Results: The mean percentage of initial minoxidil concentration remaining in all refrigerated samples exceeded 90% throughout the 24-week study, with no change in appearance, pH, microbial activity, odor, or redispersibility. During storage at room temperature, the suspension exhibited a color change at week 4, with slight sedimentation after 6 weeks, although minoxidil recovery exceeded 90% for 10 weeks., Conclusion: An extemporaneously compounded minoxidil oral suspension was stable for 24 weeks when stored in a refrigerator. This suspension can be used for up to 3 weeks when stored at room temperature., (Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

The transdermal delivery of 2 fluorescent probes with similar molecular weight but different lipophilicity, into and through the skin from 2 commercially available transdermal bases, pluronic lecithin organogel, and Lipoderm ® has been evaluated. First, in vitro penetration of fluorescein sodium and fluorescein (free acid) through porcine skin was evaluated. Retention and depth distribution profiles in skin were obtained by tape stripping and then followed by optical sectioning using multiphoton microscopy. The results showed that Lipoderm ® led to an enhanced penetration of the hydrophilic compound, fluorescein sodium. For the lipophilic compound fluorescein (free acid), Lipoderm ® performed similar to pluronic lecithin organogel base, where minimal drug was detected in either receptor phase. The skin retention and depth distribution results also showed that the hydrophilic fluorescein sodium had high skin retention with Lipoderm ® , whereas fluorescein (free acid) had very low penetration and retention with increasing skin depth. Moreover, optical sectioning by multiphoton microscopy revealed an uneven distribution of probes across the skin in the x-y plane for both transdermal bases. This work showed that a hydrophilic compound has significantly increased skin penetration and retention when formulated with Lipoderm ® , and the skin retention of the probe was the main determinant of its skin flux., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

A first of its kind, simple, rapid, and sensitive liquid chromatography mass spectrometry (LC-MS/MS) method was developed and validated for quantification of perindopril and perindoprilat in both human plasma and breast milk. The analytes and internal standards (phenazone and acetyl salicylic acid) were extracted from biological matrices by protein precipitation. A Phenomenex® C-18 column was used to provide an appropriate chromatographic separation of the analytes, followed by detection with tandem mass spectrometry. Gradient chromatographic and mass spectrometric detection conditions with mobile phases (A: 5% methanol + 0.1% formic acid in water v/v, and B: 95% methanol + 0.1% formic acid in water v/v) were developed to achieve a LOQ of 0.5 ng/mL in both human plasma and milk. The method was suitable of evaluating clinical samples. The mass transition was followed as m/z 369.10/172.00 for perindopril, m/z 339.00/168.10 for perindoprilat, m/z 188.90/55.95 for phenazone, and m/z 179.04/137.02 for acetyl salicylic acid. The developed method was optimized and validated with a linear range of 0.1-200 ng/mL (r 2  = better than 0.99 for both perindopril and perindoprilat). The precision and accuracy values were within 15% CV. The overall recovery of the analytes was 80-110%. The method has good specificity and repeatability. Stability studies were conducted in both human plasma and bovine milk for up to 3 months, at the storage conditions of 25, 4, and -80 °C.

Insoluble, nanostructured delta inulin particles enhance the immunogenicity of co-administered protein antigens and consequently are used as a vaccine adjuvant (Advax™). To better understand their immunomodulatory properties, the in vitro hydrolysis and in vivo distribution of delta inulin particles were investigated. Delta inulin particle hydrolysis under bio-relevant acidic conditions resulted in no observable change to the bulk morphology using SEM, and HPLC results showed that only 6.1% of the inulin was hydrolysed over 21days. However, 65% of the terminal glucose groups were released, showing that acid hydrolysis relatively rapidly releases surface bound chemistries. This was used to explain in vivo biodistribution results in which delta inulin particles surface-labelled with fluorescein-5-thiosemicabizide were administered to mice using intramuscular (I.M.) or subcutaneous (S.C.) routes. Comparison analysis of the fluorescence of soluble inulin in the supernatants of homogenised tissues maintained at room temperature or heated to 100°C to solubilise particulate inulin was used to distinguish between fluorescent probe on soluble inulin and probe bound to inulin within particles. Following both I.M. and S.C. injection delta inulin exhibited a depot behaviour with local injection site residence for several weeks. Over this time, as injection site inulin reduced, there was measurable transport of intact delta inulin particles by macrophages to secondary lymphoid organs and the liver. Ultimately, the injected delta inulin became solubilised resulting in its detection in the plasma and in the urine. Thus injected delta inulin particles are initially taken up by macrophages at the site of injection, trafficked to secondary lymphoid tissue and the liver, and hydrolysed resulting in their becoming soluble and diffusing into the blood stream, from whence they are glomerularly filtered and excreted into the urine. These results provide important insights into the biodistribution of I.M. or S.C. injected delta inulin particles when used as vaccine adjuvants and their method of excretion., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Targeting drug carrier systems based on graphene oxide (GO) are of great interest, since it can selectively deliver anticancer drugs to tumor cells, and enhance therapeutic activities with minimized side effects. However, direct grafting target molecules on GO usually results in aggregation of physiological fluid, limiting its biomedical applications. Here, we propose a new strategy to construct targeting GO drug carrier using folic acid grafted bovine serum albumin (FA-BSA) as both the stabilizer and targeting agent. FA-BSA decorated graphene oxide-based nanocomposite (FA-BSA/GO) was fabricated by the physical adsorption of FA-BSA on GO, which was developed as a targeting drug delivery carrier. FA-BSA/GO as the drug carrier was associated with anticancer drug doxorubicin (DOX) through π-π and hydrogen-bond interactions, resulting in high drug loading (up to 437.43μgDOX/mgFA-BSA/GO). FA-BSA/GO/DOX systems demonstrated pH responsive and sustained drug release. The hemolysis ratio of FA-BSA/GO was less than 5%, demonstrating its safety as drug carrier for intravenous injection. Moreover, in vitro cell cytotoxicity and cellular uptake analysis suggested that the constructed FA-BSA/GO/DOX nanohybrids could significantly enhance the anticancer activity. The present work has confirmed the potential for fabrication of highly stable and dispersible GO-based targeting delivery systems for efficient cancer therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Esophageal cancer (EC) mostly affects the elderly population and is frequently diagnosed at an advanced stage. Self-expanding metal stents (SEMS) are the most popular mode of palliation, but they are associated with reocclusion caused by tumor growth. To overcome this problem, docetaxel (DTX)-loaded polyurethane formulations were prepared for stent application. The films were evaluated against the cancer cell lines, OE-19 and OE-21, and normal esophageal cell line Het-1A. The DTX and the formulations were evaluated in vitro for the cytotoxicity and in vivo in nude mice. It was found that DTX and the formulations have a weak activity against the EC cell lines and an even weaker activity against Het-1A cell line. Preliminary in vivo studies showed skin toxicity in nude mice necessitating modification of the formulation. Reevaluation in a mouse xenograft model resulted in toxicity at high dose formulations while the low dose formulation exhibited modest advantage over commercial IV formulation; however, there was no significant difference between the commercial IV and blank formulation. DTX combination with an anti-cancer agent having complementary mode of action and non-overlapping toxicity could yield better outcome in future.

Drug combinations are widely employed in chemotherapy for colorectal cancer treatment. However, traditional cocktail combination in clinic causes the uncertainty of the treatment, owing to varying pharmacokinetics of different drugs. The aim of this study was to design co-loaded liposomes to achieve the synchronised delivery and release. Oxaliplatin and irinotecan hydrochloride, as one of recommended combination schemes for the treatment of colorectal cancer in clinic, were co-loaded into the liposomes. The particle sizes of the liposomes were <200nm with uniform size distribution. In vitro release study showed that both drugs could be synchronously released from the liposomes, which means the optimized synergistic ratio of two drugs could be achieved. In vitro cellular uptake revealed that co-loaded liposomes could efficiently deliver different drugs into the same cells, indicating their potential as carriers for enhancing the cancer therapy. CLSM images of cryo-sections for in vivo co-delivery study also revealed that co-loaded liposomes had superior ability to co-deliver both the cargoes into the same tumor cells. Besides, in vivo NIRF imaging indicated that the liposomes could increase the drug accumulation in tumor compared with free drug. In vitro cytotoxicity evaluation demonstrated that co-loaded liposomes exhibited higher cytotoxicity than the mixture of single loaded liposomes in both CT-26 and HCT-116 cells. Furthermore, co-loaded liposomes also presented superior anti-tumor activity in CT-26 bearing BALB/c mice. In vivo safety assessment demonstrated that liposomes had lower toxicities than their solution formulations. These results indicated that oxaliplatin and irinotecan hydrochloride co-loaded liposomes would be an efficient formulation for improving colorectal cancer therapy with potential clinical applications., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this paper, we successfully synthesized folate-modified pH-sensitive copolymer methoxy-poly(ethylene glycol)2K-poly(ε-caprolactone)4K-poly(glutamic acid)1K (mPEG2K-PCL4K-PGA1K-FA), which could form the polymeric assembly in an aqueous solution, for co-delivering hydrophilic drugs doxorubicin hydrochloride (DOX) and verapamil hydrochloride (VER) (FA-poly(DOX+VER)). Since VER was an effective P-glycoprotein inhibitor, the combination of DOX and VER could reverse the multidrug resistance efficiently and enhance the therapeutic effect. Therefore, the inhibition ratios of MCF-7/ADR resistant cancer cell treated by FA-poly (DOX+VER) were almost more than 30% higher than those of FA-polyDOX after 48h and 72h. Furthermore, the conjugation of FA could lead the co-delivery systems actively targeting into the FA receptor over-expressing cancer cells in addition to the passive accumulation of the assembly in tumor tissues. Importantly, the prepared mPEG2K-PCL4K-PGA1K-FA assembly showed high pH-sensitive property, which made the drugs mostly released in tumor tissue (acid environment) than in physiological environment (neutral environment). In summary, the as-prepared co-delivery system FA-poly(DOX+VER) demonstrated a high efficiency in reversing the multidrug resistance and targeting FA receptor to improve the anticancer effect of DOX in MCF-7/ADR resistant cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The present review discusses the pharmaceutical impact of the anatomy and physiology of the canine gastrointestinal tract to provide a comprehensive guide to the theories and challenges associated with the development of oral drug delivery systems for dogs. Novel pharmaceutical technologies applied to veterinary drugs are discussed indicating the advantages and benefits for animals. There are currently immense research and development efforts being funneled into novel canine health products. Such products are being used to overcome limitations of drugs that display site-dependent absorption or possess poor biopharmaceutical properties. Techniques that are employed to increase bioavailability of the Biopharmaceutics Classification System class II drugs are discussed in this article. Furthermore, an overview of palatable oral formulations for dog care is provided as an approach to easy administration. In vitro and in vivo evaluation and correlation of oral drug formulations in dogs are also addressed. This article assesses the outlook of canine oral drug development recognizing substantial growth forecasts of the dog care market., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Characterization of intestinal absorption of nanoparticles is critical in the design of noninvasive anticancer, protein-based, and gene nanoparticle-based therapeutics. Here we demonstrate a general approach for the characterization of the intestinal absorption of nanoparticles and for understanding the mechanisms active in their processing within healthy intestinal cells. It is generally accepted that the cellular processing represents a major drawback of current nanoparticle-based therapeutic systems. In particular, endolysosomal trafficking causes degradation of therapeutic molecules such as proteins, lipids, acid-sensitive anticancer drugs, and genes. To date, investigations into nanoparticle processing within intestinal cells have studied mass transport through Caco-2 cells or everted rat intestinal sac models. We developed an approach to visualize directly the mechanisms of nanoparticle processing within intestinal tissue. These results clearly identify a mechanism by which healthy intestinal cells process nanoparticles and point to the possible use of this approach in the design of noninvasive nanoparticle-based therapies., From the Clinical Editor: Advances in nanomedicine have resulted in the development of new therapies for various diseases. Intestinal route of administration remains the easiest and most natural. The authors here designed experiments to explore and characterize the process of nanoparticle transport across the intestinal tissue. In so doing, further insights were gained for future drug design., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Mastitis is a major disease of dairy cattle. Given the recent emergence of methicillin-resistant Staphylococcus aureus as a cause of bovine mastitis, new intramammary (IMA) treatments are urgently required. Lasalocid, a member of the polyether ionophore class of antimicrobial agents, has not been previously administered to cows by the IMA route and has favorable characteristics for development as a mastitis treatment. This study aimed to develop an IMA drug delivery system (IMDS) of lasalocid for the treatment of bovine mastitis., Methods: Minimum inhibitory concentrations (MICs) were determined applying the procedures recommended by the Clinical and Laboratory Standards Institute. Solid dispersions (SDs) of lasalocid were prepared and characterized using differential scanning calorimetry and Fourier transform infrared spectroscopy. IMDSs containing lasalocid of micronized, nano-sized, or as SD form were tested for their IMA safety in cows. Therapeutic efficacy of lasalocid IMDSs was tested in a bovine model involving experimental IMA challenge with the mastitis pathogen Streptococcus uberis., Results: Lasalocid demonstrated antimicrobial activity against the major Gram-positive mastitis pathogens including S. aureus (MIC range 0.5-8 μg/mL). The solubility test confirmed limited, ion-strength-dependent water solubility of lasalocid. A kinetic solubility study showed that SDs effectively enhanced water solubility of lasalocid (21-35-fold). Polyvinylpyrrolidone (PVP)-lasalocid SD caused minimum mammary irritation in treated cows and exhibited faster distribution in milk than either nano or microsized lasalocid. IMDSs with PVP-lasalocid SD provided effective treatment with a higher mastitis clinical and microbiological cure rate (66.7%) compared to cloxacillin (62.5%)., Conclusion: Lasalocid SD IMDS provided high cure rates and effectiveness in treating bovine mastitis with acceptable safety in treated cows.

Objectives: The aim of this study was to assess the potential of a novel delivery device for administering drugs that suffer from a high degree of first-pass metabolism., Methods: A tri-layered buccal mucoadhesive patch, comprising a medicated dry tablet adhered to a mucoadhesive film, was prepared and characterized by its physicochemical properties and mucoadhesive strength. Nicotine was used as a model drug for the characterization of drug release and drug permeation. The influence of different adsorbents on the release of nicotine base from the patches was evaluated in vitro. Different molecular forms of nicotine (base and complex salt) were evaluated for their effect on release performance and permeation in vitro., Key Findings: Results demonstrated acceptable physicochemical and mucoadhesive properties for the tri-layered patch. Rapid release of nicotine was observed when nicotine base was incorporated with calcium sulfate dihydrate as the adsorbent. Patches incorporating nicotine base showed distinct advantages over those containing nicotine polacrilex, in terms of drug release (complete drug release achieved at 30 vs 60 min) and transmucosal permeation (37.28 ± 4.25 vs 2.87 ± 0.26% of the dose permeating through mucosa within 120 min)., Conclusions: The novel tri-layered patch can effectively adhere to, and deliver an active ingredient through the buccal mucosa, confirming its potential for buccal mucoadhesive drug delivery., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

Background: A microemulsion is an effective formulation for improving the oral bioavailability of poorly soluble drugs. In this paper, a water-in-oil (w/o) microemulsion was investigated as a system for enhancing the oral bioavailability of Biopharmaceutic Classification System (BCS) III drugs., Methods: The microemulsion formulation was optimized using a pseudoternary phase diagram, comprising propylene glycol dicaprylocaprate (PG), Cremophor(®) RH40, and water (30/46/24 w/w)., Results: The microemulsion increased the oral bioavailability of hydroxysafflor yellow A which was highly water-soluble but very poorly permeable. The relative bioavailability of hydroxysafflor yellow A microemulsion was about 1937% compared with a control solution in bile duct-nonligated rats. However, the microemulsion showed lower enhanced absorption ability in bile duct-ligated rats, and the relative bioavailability was only 181%. In vitro experiments were further employed to study the mechanism of the enhanced effect of the microemulsion. In vitro lipolysis showed that the microemulsion was digested very quickly by pancreatic lipase. About 60% of the microemulsion was digested within 1 hour. Furthermore, the particle size of the microemulsion after digestion was very small (53.3 nm) and the digested microemulsion had high physical stability. An everted gut sac model demonstrated that cumulative transport of the digested microemulsion was significantly higher than that of the diluted microemulsion., Conclusion: These results suggested that digestion of the microemulsion by pancreatic lipase plays an important role in enhancing oral bioavailability of water-soluble drugs.

Poorly water-soluble drugs, such as phenylephrine, offer challenging problems for buccal drug delivery. In order to overcome these problems, particle size reduction (to the nanometer range) and cyclodextrin complexation were investigated for permeability enhancement. The apparent solubility in water and the buccal permeation of the original phenylephrine coarse powder, a phenylephrine-cyclodextrin complex and phenylephrine nanosuspensions were characterized. The particle size and particle surface properties of phenylephrine nanosuspensions were used to optimize the size reduction process. The optimized phenylephrine nanosuspension was then freeze dried and incorporated into a multi-layered buccal patch, consisting of a small tablet adhered to a mucoadhesive film, yielding a phenylephrine buccal product with good dosage accuracy and improved mucosal permeability. The design of the buccal patch allows for drug incorporation without the need to change the mucoadhesive component, and is potentially suited to a range of poorly water-soluble compounds.

The objective of this work was to evaluate the physical properties and in vivo circulation of chitosan (CH)-coated liposomes of mitoxantrone (MTO). Changes in particle size and zeta potential confirmed the existence of a coating layer on the surface of liposomes. The in vitro release of adsorbed CH from the liposomes was significantly slower than CH solution, indicating the stable interaction between CH and liposomes. The physical stability of the CH-coated liposomes was evaluated by measuring the change in particle size before and after freeze-drying and rehydration. The smallest change was observed when saturated adsorption of CH occurred (0.3%). The sustained release in vitro of MTO from CH-coated liposomes confirmed the increased stability of liposomes. Systemic circulation of CH-coated MTO liposomes was examined. The 0.3% CH-coated liposomes showed the longest circulation time. It could be concluded that the prolonged retention time of the liposomes was closely related with CH coating and its stability effect.

We report on a porous silica-lipid hybrid microcapsule (SLH) oral delivery system for indomethacin fabricated from Pickering emulsion templates, where the drug forms an electrostatic complex with cationic lipid present in the oil phase. Dry SLH microcapsules prepared either by spray drying (approximately 1-5 microm) or phase coacervation (20-50 microm) exhibit a specific internal porous matrix structure with pore diameters in the range of 20 to 100 nm. Dissolution studies under sink conditions and in the presence of electrolytes revealed a decreased extent of dissolution; this confirms the lipophilic nature the drug-lipid complex and its location in the oil phase. Orally dosed in-vivo studies in rats showed complete drug absorption and statistically higher fasted state bioavailability (F) (p<0.05) in comparison to aqueous suspensions and o/w submicron emulsions of indomethacin. It is postulated that the SLH microcapsules improve oral absorption via complete solubilisation of drug-lipid electrostatic complexes during enzymatic lipolysis in the GI track., (2010. Published by Elsevier B.V. All rights reserved.)

The aims of this study were to investigate the effect of ligusticum chuanxiong volatile oil (CVO) on the oral absorption of hydroxysafflor yellow A (HSYA). The effects were studied both IN VITRO and IN VIVO. The contents of CVO were measured by GC-MS. The Caco-2 cell model was used to evaluate HSYA permeation with or without the presence of CVO. Transepithelial electrical resistance (TEER) of the Caco-2 cell monolayers was monitored and the alteration in the subcellular localization of claudin-1, the tight junction protein, was observed by immunofluorescence. The irritation of CVO on rat intestine was studied by paraffin slice technology. Our results demonstrated that CVO mainly contained ligustilide (47.82 %). The Papp of HSYA was improved by 5.34-fold and 4.62-fold in the presence of 0.02 mg/mL and 0.01 mg/mL of CVO, respectively. After opening of the tight junctions of the Caco-2 cell monolayer, TEER decreased, the position of claudin-1 changed, and its expression increased. CVO at different concentrations (10, 25, 100 and 200 mg/kg) caused no significant irritation on rat intestine. The bioavailability of HSYA in rats was increased by 6.48-fold and 4.91-fold when 100 and 25 mg/kg of CVO were co-administrated, respectively. CVO was an effective absorption enhancer for oral delivery of BCS III drugs. It can cause redistribution of claudin-1 proteins and open the tight junctions., (Georg Thieme Verlag KG Stuttgart New York.)

Objective: To study the effect of combination components on pharmacokinetics of Shuxiong tablet to provide evidence for the new recipe., Method: Six groups of rats (6 for each group) were orally administered with co-extractum of chuanxiong and honghua (CHE), mixed solution of hydroxysafflor yellow A (HSYA) and ferulic acid (FA) (HFM). Panax notoginseng saponins solution (PNS), mixed solution of PNS and CHE (PCHE), mixed solution of PNS and HFM (PHFM) and mixed emulsion of Chuanxiong volatile oil (CVO) and PHFM (CVO-PHFM), respectively. The concentrations of HSYA, FA, ginsnenoside Rg1 and Rb1 in rat plasma were determined by HPLC. Pharmacokinetic parameters (Ka, Kel, Cmax, Tmax and AUC) were calculated by model simulation. The differences of HSYA, FA, Rg1 and Rb1 in pharmacokinetics parameters after administration of six preparations were demonstrated by statistical analysis., Result: After oral administration of six preparations to rats, the concentration-time curve of HSYA and Rg1 fitted to one-compartment model, and that of FA fitted to double-compartment model. After oral administration of CHE, Kel of FA reduced; Cmax decreased; but K12 increased, significantly, compared with oral administration of HFM. Other parameters were not significant differences. After co-administration of PNS and CHE (PCHE) or PNS and HFM (PHFM), Ka of HSYA increased; Tmax reduced, significantly. After oral administration of PNS and HFM (PHFM), Ka of Rg1 improved, Tmax decreased, significantly. However, the parameters of FA and Rb1 were not significantly changed. After co-administration of CVO and PHFM (CVO-PHFM), Cmax of Rb1 decreased, K12 improved, significantly. Meanwhile, the oral bioavailability of HSYA, FA and Rg1 was improved by 6.056, 2.854 and 2.055 folds, respectively., Conclusion: After oral administration of different combinations of Shuxiong tablet constituents, some pharmacokinetics parameters of active ingredients are significantly changed, but the bioavailability is improved only when CVO is co-administered.

We report on the fabrication and characterization of dry hybrid lipid-silica nanoparticle based microcapsules with an internal porous matrix structure for encapsulation of poorly soluble drugs, and their delivery properties (in vitro release and lipolysis and in vivo pharmacokinetics demonstrated for indomethacin as a model drug). Microcapsules were prepared by spray drying of Pickering o/w emulsions containing either negatively or positively charged lipophilic surfactant in the oil phase and hydrophilic silica nanoparticles in the aqueous phase. Effective microcapsule formation is critically dependent on the interfacial structure of the nanoparticle containing emulsions, which are in turn controlled by the surfactant charge and the nanoparticle to lipid ratio. Microcapsules (containing 50-85% oil) can be prepared with 10 times fewer silica nanoparticles when a droplet-nanoparticle charge neutralizing mechanism is operative. Cross-sectional SEM imaging has confirmed the internal porous matrix structure and identified pore sizes in the range 20-100 nm, which is in agreement with BET average pore diameters determined from gas adsorption experiments. Differential scanning calorimetry and X-ray diffraction analysis have confirmed that the model drug indomethacin remains in a noncrystalline form during storage under accelerated conditions (40 degrees C, 75% RH). Dissolution studies revealed a 2-5-fold increase in dissolution efficiency and significantly reduced the time taken to achieve 50% of drug dissolution values (> or =2- or 10-fold) for indomethacin formulated as microcapsules in comparison to o/w submicron emulsions and pure drug, respectively. Orally dosed in vivo studies in rats have confirmed superior pharmacokinetics for the microcapsules. Specifically, the fasted state absolute bioavailability (F) was statistically higher (93.07 +/- 5.09%) (p < 0.05) than for aqueous suspension (53.54 +/- 2.91%) and o/w submicron emulsion (64.57 +/- 2.11%). The microcapsules also showed the highest maximum plasma concentration (C(max)) among the investigated formulations (p < 0.05). In vitro lipolysis showed statistically higher (p < 0.05) fasted digestion (75.8% after 5 min) and drug solubilization (98% after 5 min) in digestive products for microcapsules than o/w emulsions. The hybrid lipid-silica microcapsules improve oral absorption by enhancing lipolysis and drug dissolution.

Aim: To compare pharmacokinetics of intravenous breviscapine liposomes in Beagle dogs, rabbits and rats., Methods: Six Beagle dogs, 6 rabbits and 12 rats were intravenously administrated with breviscapine liposomes and commercial injection (breviscapine solution) by the crossover design (two periods), respectively. Plasma concentration of scutellarin, the main active component in breviscapine, at different time intervals was determined by reverse phase-HPLC. The pharmacokinetic parameters including area under the curve (AUC), clearance (CL(s)) and volume of distribution (V(c)) were calculated., Results: The plasma concentration-time profiles were fitted to a two-compartment model. Breviscapine liposomes exhibited significant difference from injection in CL((s)) and AUC, examined by a one-way analysis of variance (ANOVA). With regard to both breviscapine liposomes and commercial injection (free breviscapine), the logarithm values of AUC, CL(s) and V(c) were all related to the logarithm of the body weight by the allometric equation: Y=axW(b)., Conclusion: The allometric equation might be applied to extroplate dosage for human from animal data and also for dosage adjustment of breviscapine liposomes in order to achieve same AUC as commercial injection. Compared with the breviscapine solution, breviscapine liposomes delivered more scutellarin into the plasma.

Due to its poor solubility in water and oil, silybin is hardly absorbed orally and cannot be dissolved directly for parenteral preparations. In this study, a silybin-phospholipid complex was prepared by single-factor design and orthogonal experimental design. Lipophilicity was improved to a large extent, which was determined by solubility experiments and oil/water partition studies. Various methods were used to confirm the formation and explore the properties of the silybin-phospholipid complex, such as UV, IR, ATR, CNMR, XRD,DSC, SEM and TEM. The structure of the phytosome when the complex was dispersed in aqueous solution is suggested.