Topical Delivery of Modified Da-Cheng-Qi Decoction () Using Low-Frequency Ultrasound Sonophoresis for Refractory Metastatic Malignant Bowel Obstruction: An Open-Label Single-Arm Clinical Trial / 中国结合医学杂志

OBJECTIVE@#To evaluate the efficacy and safety of topical delivery of modified Da-Cheng- Qi Decoction (, MDCQD) by low-frequency ultrasound sonophoresis (LFUS) in patients with refractory metastatic malignant bowel obstruction (MBO) using an objective performance criteria (OPC) design.@*METHODS@#Fifty patients with refractory metastatic MBO were enrolled in this open-label single-arm clinical trial. Alongside fasting, gastrointestinal decompression, glycerol enema, intravenous nutrition and antisecretory therapy, a 50 g dose of MDCQD (prepared as a hydrogel) was applied through topical delivery at the site of abodminal pain or Tianshu (S 25) using LFUS for 30 min, twice daily for 5 consecutive days. The overall outcome was the remission of intestinal obstruction, and improvement on abdominal pain, abdominal distention, nausea and vomiting scores. Indicators of safety evaluation included liver and renal function as well as blood coagulation indicators.@*RESULTS@#Among 50 patients, 5 patients (10%) showed complete remission of intestinal obstruction and 21 patients (42%) showed improvement of intestinal obstruction. The overall remission rate of bowel obstruction was 52%. The results of the symptom score, based on the severity and frequency of the episode, are as follows: 26 patients (52%) showed improvment on symptom scores, 20 patients (40%) did not respond to treatment, and 4 patients (8%) discontinued treatment due to intolerance. No serious adverse effects or abnormal changes on liver and renal function or blood coagulation were observed.@*CONCLUSION@#Topical delivery of MDCQD at 100 g/day using LFUS can improve the treatment response in patients with refractory metastatic MBO.

Novel gel-like microemulsion for topical delivery of Amphotericin B / Una nueva microemulsión tipo gel para la aplicación tópica de anfotericina B

The aim of the present work was to develop a ME for topical delivery of Amphotericin B (AmB). Microemulsions (MEs) are versatile systems to solubilize drugs due to the presence of both a hydrophobic and a hydrophilic region, as well as a distinctive interface composed of surfactant and cosurfactant. MEs have been reported for many advantages for topical application of drugs. Considering that AmB has very low water solubility a screening of surfactants and oils was performed. A gel-like ME system, that can be applied topically without the need for thickeners agents, was selected. AmB was incorporated up to 1 mg/g and remained stable for at least 90 days both at 4 °C and room temperature, so this formulation would be appropriate as a compounding medication. An in vitro skin penetration test was performed, the applied dose penetrated (10.16 +/- 0.01 µg/cm²/h as estimated flux) and remained completely within the skin during the assay; AmB was not detected in the receptor compartment. In vitro antifungal and antileishmanial activity was tested and drug showed proper activity. AmB is a second line drug for the treatment of cutaneous leishmaniasis, but topical dosage forms are still lacking. This system is potentially useful for the treatment of skin infections avoiding drug toxic systemic effects.

Se desarrolló una microemulsión (ME) para la aplicación tópica de anfotericina B (AmB). Las ME son sistemas versátiles que facilitan la solubilización de principios activos y, además, presentan muchas ventajas para aplicar fármacos en forma tópica. La AmB posee muy baja solubilidad en agua, por lo cual se realizó una evaluación de su solubilidad en distintos aceites y surfactantes. Se confeccionaron diagramas ternarios de fase y se seleccionó una ME-gel que puede ser aplicada tópicamente sin el agregado de agentes espesantes. Se solubilizó hasta 1 mg/g de AmB y el fármaco permaneció estable durante al menos 90 días a 4 °C y a temperatura ambiente, por lo cual esta formulación sería apropiada como un medicamento magistral. El estudio in vitro de permeación en piel mostró que la dosis aplicada penetró completamente (flujo estimado de difusión 10,16 +/- 0,01 µg/cm²/h) y permaneció retenida en la misma durante el tiempo de estudio sin detectarse AmB en el compartimento receptor. La actividad antifúngica y antileishmania in vitro fue adecuada. La AmB es una droga de segunda línea en el tratamiento de la leishmaniasis cutánea; sin embargo, no se dispone de preparados para uso tópico. Esta formulación sería útil para el tratamiento local de las infecciones de piel, evitando efectos adversos sistémicos.

Chitosan Nanoparticles for Topical Co-administration of the Antioxidants Glutathione and Idebenone: Characterization and In vitro Release.

Aims: The aim of this study was to explore the potential of novel nanoparticles (NPs) intended for topical administration of the hydrophilic antioxidant Glutathione and the lipophilic Idebenone. Glutathione was introduced into the NPs using two approaches: i) covalently bonded to Chitosan; ii) physically complexed with Idebenone and Sulfobutylether--cyclodextrin. Methodology: NPs were formulated using the ionic gelation technique, by dissolving the polysaccharide-forming matrix (Chitosan, Glycol chitosan, Glutathionyl Chitosan) in water or in slightly acidic solution. Idebenone was physically entrapped whereas glutathione was either physically entrapped or covalently bonded to chitosan. Physicochemical characterization of the resulting NPs included size, zeta potential measurements, antioxidant association efficiency, differential scanning calorimetry (DSC) and stability studies. Antioxidants in vitro release from the most stable NPs was assessed with Franz diffusion cells, and the in vitro antioxidant activity was evaluated by the 2,2- diphenyl-1-picrylhydrazyl (DPPH) radical test. NP cytotoxicity was assessed on immortalized human keratinocytes (HaCaT) cell line. Results: The NPs showed smaller particle size in acidic solution than in aqueous medium, whereas zeta potential values were always positive, irrespective of the medium. Stability studies led to the choice of the aqueous formulation where Glutathione was covalently bonded to Chitosan for this study. DSC highlighted amorphization of Idebenone in these NPs. In vitro release studies showed that only Idebenone was released from the NPs. The antioxidant activity test revealed a strong effect (close to 100%) of Idebenone loaded into NPs while its aqueous solution showed no activity. No cytotoxicity in human keratinocytes was observed for the investigated NPs. Conclusion: The results of this study suggest that Idebenone can be loaded into a hydrophilic delivery system without organic solvents, often used for its solubilization, possessing high antioxidant activity. Therefore, these nanocarriers represent a promising strategy for the design of formulations for topical treatments with antioxidants.

Formulation and evaluation of fluconazole pro-niosomal gel for topical administration.

The present investigation was aimed to explore the potential of proniosomal gel for the topical delivery of fluconazole. Fluconazole-loaded proniosomes were prepared by the coacervation method using different nonionic surfactants (spans and tweens) and evaluated for various parameters like size, shape, stability, entrapment efficiency, in-vitro release, ex-vivo skin permeation and retention study. Results showed that proniosomes composed of span 20 (F1), span 60 (F4), span 80 (F7) were more stable compared with tween 20 (F10) and tween 80 (F13) with smaller size, “i.e.” 4.08±0.18 μm, 2.61±0.15 μm, 2.01±0.12 μm, 8.56±0.20 μm, and 7.10±0.31 μm, respectively, along with higher entrapment efficiency (approx. >46%). Ex-vivo skin penetration and retention studies revealed that cutaneous deposition was affected by the nature of surfactant and vesicle size. Therefore the proniosomes containing span 60 having high amount of drug retained in skin, “i.e.” 25.97±1.28 which can help in localized delivery of drug especially in fungal mediated skin diseases, thereby increased efficacy for prolonged period can be achieved.

Design and Evaluation of Miconazole Nitrate loaded Nanostructured Lipid Carriers (NLC) for improving the Antifungal therapy.

The aim of this study was to prepare and evaluate gels incorporating nanostructured lipid carriers (NLC) of Miconazole nitrate (MN) for systemic delivery of the active after topical application. MN has been used as model drugs to be incorporated into nanostructured lipid carriers, once they are very well established as antimycotics for the treatment of topical fungal infections. NLC designed for topical administration of MN, were prepared by the hot high pressure homogenization technique. This MN-NLC was characterized for particle size, entrapment efficiency, and SEM. The lipid nanoparticles were incorporated in gels for convenient topical application and were evaluated forfor particle size, Rheological analysis Texture analysis , In vitro drug release studies and Ex Vitro skin permeation Studies. The preparation of aqueous NLC dispersions with a mean particle size lower than 300 nm has been obtained with uniform size distribution (PI < 0.350). The prepared semi-solid systems showed mean particle size remained lower than 250 nm and PI remained lower than 0.500 after 3 months of storage. An initial rapid release was observed in the case of Marketed gel, whereas MN- NLC Gel depicted a slow initial release with a lag time of 0.5 h and 1 h, respectively. High amount of MN release was facilitated through abdominal skin of rats from marketed gel than MN-NLC Gel. Research work could be concluded as successful development of MN-loaded NLC-bearing hydrogel to increase the encapsulation efficiency of colloidal lipid carriers with advantage of improved performance in terms of stability and provides a sustaining MN topical effect as well as faster relief from fungal infection.

Sorbitan ester niosomes for topical delivery of rofecoxib.

The aim of the present investigation is to encapsulate rofecoxib in niosomes and incorporate the prepared niosomes into dermal gel base for sustained therapeutic action. Niosomes were prepared by lipid film hydration technique and were analyzed for size, entrapment efficiency and drug retention capacity. Niosomal vesicles were then incorporated into blank carbopol gel to form niosomal gel. The in vitro permeation study across pig skin was performed using Keshary-Chien glass diffusion cell. The size and entrapment efficiency of the niosomal vesicles increased with gradual increase in HLB value of nonionic surfactants used. Maximum drug entrapment was observed with Span 20 with HLB value of 8.6 and drug leakage from vesicles was less at refrigerated condition than at the room temperature. Higher proportion of cholesterol made the niosomal formulation more stable with high drug retention properties. The niosomal gel showed a prolong drug release behavior compared to plain drug gel. Differential scanning calorimetric study of drug loaded gel and pig skin after permeation study confirmed inertness of carbopol gel base toward rofecoxib and absence of drug metabolism in the skin during permeation study, respectively. The niosomal formulations were successfully prepared by lipid film hydration technique using cholesterol and Span as nonionic surfactant. Presence of cholesterol made niosomes more stable with high drug entrapment efficiency and retention properties. The lower flux value of niosomal gel as compared to plain drug gel across pig skin assured the prolong drug release behavior with sustained action.