Foam-in-vein: A review of rheological properties and characterization methods for optimization of sclerosing foams.

Varicose veins are chronic venous defects that affect >20% of the population in developed countries. Among potential treatments, sclerotherapy is one of the most commonly used. It involves endovenous injection of a surfactant solution (or foam) in varicose veins, inducing damage to the endothelial layer and subsequent vessel sclerosis. Treatments have proven to be effective in the short-term, however recurrence is reported at rates of up to 64% 5-year post-treatment. Thus, once diagnosed with varicosities there is a high probability of a permanently reduced quality of life. Recently, foam sclerotherapy has become increasingly popular over its liquid counterpart, since foams can treat larger and longer varicosities more effectively, they can be imaged using ultrasound, and require lower amounts of sclerosing agent. In order to minimize recurrence rates however, an investigation of current treatment methods should lead to more effective and long-lasting effects. The literature is populated with studies aimed at characterizing the fundamental physics of aqueous foams; nevertheless, there is a significant need for appropriate product development platforms. Despite successfully capturing the microstructural evolution of aqueous foams, the complexity of current models renders them inadequate for pharmaceutical development. This review article will focus on the physics of foams and the attempts at optimizing them for sclerotherapy. This takes the form of a discussion of the most recent numerical and experimental models, as well as an overview of clinically relevant parameters. This holistic approach could contribute to better foam characterization methods that patients may eventually derive long term benefit from.

A Modiied 3-Way Tap to Enhance the Stability and Uniformity of Sclerosant Foam.

BACKGROUND: The Tessari method, mixing air with the sclerosant through a 3-way tap and 2 syringes, is the most widely used method to prepare foam in foam sclerotherapy. Uniform foam with smaller bubbles has great clinical significance for venous insufficiency. We aim to modify the traditional 3-way tap to produce more uniform and stable foam with smaller bubbles. METHODS: The traditional 3-way tap was modified by inserting a porous film within its channel. EXPERIMENT DESIGN: the foam was prepared with 2 mL polidocanol plus 8 mL air plus 0.05 mL hyaluronic acid; group 1, foam prepared with 20 quick passes through a traditional 3-way tap; and groups 2-7, foam prepared using the modified 3-way tap, with 10, 12, 14, 16, 18, and 20 quick passes, respectively. The uniformity of the foam was observed under optical microscopy, and the size of bubbles quantified using the Nano measurement software. The stability of the foam was evaluated using the foam half-life time. RESULTS: The foam half-life times of groups 1-7 were 306.4, 257.4, 285.6, 304.4, 318.6, 330.2, 331.3 sec, respectively. The modified tap also produced a more uniform distribution of smaller bubbles (group 7) compared with traditional tap (group 1). CONCLUSIONS: Modified 3-way tap enhanced the stability of the sclerosant foam, with a more uniform distribution of smaller bubbles.

Comparison of the Safety and Efficacy of Foam Sclerotherapy With 1: 2 Polidocanol to Air Ratio Versus 1: 4 Ratio for the Treatment of Reticular Veins of the Lower Extremities.

BACKGROUND: Foam sclerotherapy is a common treatment of lower extremity reticular veins. The effect of different liquid-gas ratios on foam stability and efficacy has been controversial. OBJECTIVE: To evaluate the use of 2 different polidocanol (POL) to air ratios for the treatment of reticular veins of the lower extremities. METHODS AND MATERIALS: Patients with lower extremity reticular veins were randomized to foam sclerotherapy with POL mixed with 4 mL of room air for one lower extremity or 2 mL for the other lower extremity. All telangiectasias were treated with glycerin immediately after treatment of the reticular veins. Adverse events (AEs) and efficacy were evaluated by both subject and blinded investigator. RESULTS: Thirty subjects completed the study. No statistically significant difference was seen in AEs between the 2 different POL to air ratios by subject questionnaire and blinded investigator scores at all time points. Subjects and blinded investigator reported a mean improvement between 0% and 50% at Day 21 and 26% to 75% at Day 90, which was not significantly different between groups. CONCLUSION: Two different POL to air ratios, 1:2 versus 1:4, were similarly safe and efficacious for the treatment reticular veins of the lower extremities.

A Novel Compound Sclerosant: Polidocanol-Bleomycin Foam.

BACKGROUND: Foam sclerotherapy is an effective treatment strategy for venous malformations. Both polidocanol (POL) and bleomycin are effective sclerosants; however, no studies have reported POL-bleomycin foam. OBJECTIVE: To introduce a method for producing POL-bleomycin foam and evaluate the stability of POL-bleomycin foam with bleomycin concentrations. MATERIALS AND METHODS: Group A: 2 mL of 1% POL + 8 mL of air; Group B: 2 mL of 1% POL + 3 U bleomycin + 8 mL of air; Group C: 2 mL of 1% POL + 6 U bleomycin + 8 mL of air; Group D: 2 mL of 1% POL + 12 U bleomycin + 8 mL of air. Tessari method was used for foam generation. The foam half-life time (FHT) was used to evaluate foam stability. Five recordings were made for each group. RESULTS: The FHT was 148.6 ± 2.9 seconds in Group A, 148.8 ± 4.0 seconds in Group B, 148.4 ± 2.6 seconds in Group C, and 148.8 ± 1.6 seconds in Group D. The FHT in different groups showed no significant differences. CONCLUSION: The POL-bleomycin foam was prepared successfully and its FHT was as long as the POL foam.

Bleomycin Polidocanol Foam (BPF) Stability - In Vitro Evidence for the Effectiveness of a Novel Sclerosant for Venous Malformations.

OBJECTIVE: This study investigated the in vitro stability of a novel sclerosant, bleomycin polidocanol foam (BPF), for venous malformation (VM) sclerotherapy. METHODS: The study was designed with control groups treated with polidocanol (0.5%, 1%, and 3%) only. The experimental groups included 21 BPFs, which was made by dissolving bleomycin at seven different concentrations (0.1%-1.5%) in polidocanol (0.5%, 1%, and 3%). The Tessari method was used to prepare sclerosant foam with a liquid:gas ratio of 1:4 at room temperature in vitro. The foam stability was measured for each group. The decay process, one component of foam stability, was recorded with a camera. Foam decay process experiments were performed 10 times per group. The stability indices included drainage rate, drainage time, half life, and microscopic measurement of the foams (mean bubble diameter, minimum and maximum bubble diameters, wall thickness, and bubble diameter distribution). RESULTS: Compared with the control groups, the half lives of BPFs mainly increased significantly with the addition of bleomycin (p < .001). BPF with 3% polidocanol and 0.1% bleomycin recorded the highest half life (246 ± 1.6 sec), and this group also achieved the smallest bubble diameter and wall thickness (69.9 µm and 5.80 µm) among the experimental groups. For the same polidocanol concentration, the bubble diameter and wall thickness increased when bleomycin was added. CONCLUSION: Bleomycin concentrations account for different BPF stability. BPF stability mainly increased significantly with the addition of a small amount of bleomycin but this advantage was no longer apparent with increasing bleomycin dose.

A Review of Sclerosing Foam Stability in the Treatment of Varicose Veins.

BACKGROUND: Varicose veins are common clinical entities. Foam sclerotherapy is a minimally invasive and simple procedure; however, the side effects, efficacy, and stability of sclerosing foam are not ideal. OBJECTIVE: To summarize the current studies on sclerosing foam stability and promote foam sclerotherapy development. MATERIALS AND METHODS: We reviewed the literature before June 2018 and included only representatives studies on sclerosing foam stability. We summarized the foam half-life time (FHT) of polidocanol (POL) under 17 preparation conditions and the FHT of sodium tetradecyl sulfate under 21 preparation conditions. The preparation conditions included various combinations of temperature, liquid-gas ratio, preparation method, etc. RESULTS: The FHT of POL varied between 40 and 4,000 seconds under different conditions. The FHT of sodium tetradecyl sulfate varied from 25.7 to 390 seconds. The higher the drug concentration, the lower the temperature required to increase foam stability. The addition of surfactant greatly increased foam stability. For different gas compositions, the FHT sequence was as follows: CO2 < CO2 + O2 < O2 < air. CONCLUSION: Foam stability can be improved by changing the preparation conditions; therefore, the role of surfactants and predictive methods for FHT are worth investigating further.

Improper Potency and Impurities in Compounded Polidocanol

Polidocanol is an FDA-approved sclerosant indicated for treating uncomplicated spider veins and reticular veins in the lower extremities. Despite restrictions against compounding drugs that are essentially copies of FDA-approved or commercially available products, polidocanol is also available from compounding pharmacies and outsourcing facilites. Compounded drug products are not FDA-approved and have not undergone premarket FDA review for safety, effectiveness, and quality. Seven samples of polidocanol were obtained from three compounding pharmacies and analyzed using high pressure liquid chromatography. None of the samples contained the labeled concentration of polidocanol and five contained excessive levels of impurities. Since the potency and purity of compounded polidocanol injection cannot be assured, physicians who use these products should consider FDA-approved products to ensure optimal safety and efficacy. J Drugs Dermatol. 2019;18(11):1124-1127.

Ex situ soil washing of highly contaminated silt loam soil using core-crosslinked amphiphilic polymer nanoparticles.

Non-ionic surfactants (Triton X-100 and Brij 30) and core-crosslinked amphiphilic polymer (CCAP) nanoparticles were used as extractants in the ex situ soil washing of silt loam soil contaminated with large quantities of petroleum oil, and their soil-washing performances were compared. Following washing with the surfactants, highly turbid aqueous solutions containing large numbers of soil and petroleum oil particles were produced. In contrast, the CCAP nanoparticles successfully extracted the petroleum oils from the soil samples without the formation of such a turbid aqueous solution. In addition, the CCAP nanoparticles extracted 96% of the petroleum oils, which is a significantly larger quantity than that by Brij 30 and Triton X-100 under equivalent conditions. Indeed, owing to their crosslinked micelle-like structure, the CCAP nanoparticles maintained their nanostructure even upon contact with a highly contaminated silt loam soil matrix, thereby resulting in the extraction of only the hydrophobic oily contaminants from the soil matrix and avoiding the formation of dispersions of soil particles and hydrophobic contaminants. As such, CCAP nanoparticles could be considered as suitable washing materials for highly contaminated silt loam soils.

Improved In vivo Effect of Chrysin as an Absorption Enhancer Via the Preparation of Ternary Solid Dispersion with Brij®L4 and Aminoclay.

BACKGROUND: Chrysin is a strong inhibitor of breast cancer resistance protein (BCRP) but it is practically insoluble in water. Effective solubilization of chrysin is critical for its pharmaceutical application as an absorption enhancer via inhibition of BCRP-mediated drug efflux. OBJECTIVE: This study aimed to develop an effective oral formulation of chrysin to improve its in vivo effect as an absorption enhancer. METHOD: Solid dispersions (SDs) of chrysin were prepared with hydrophilic carriers having surface acting properties and a pH modulator. In vitro and in vivo characterizations were performed to select the optimal SDs of chrysin. RESULTS: SDs with Brij®L4 and aminoclay was most effective in increasing the solubility of chrysin by 13-53 fold at varying drug-carrier ratios. Furthermore, SDs significantly improved the dissolution rate and extent of drug release. SDs (chrysin: Brij®L4: aminoclay=1:3:5) achieved approximately 60% and 83% drug release within 1 h and 8 h, respectively, in aqueous medium, while the dissolution of the untreated chrysin was less than 13%. XRD patterns indicated the amorphous state of chrysin in SDs. The SD formulation was effective in improving the bioavailability of topotecan, a BCRP substrate in rats. Following oral administration of topotecan with the SDs of chrysin, the Cmax and AUC of topotecan was enhanced by approximately 2.6- and 2-fold, respectively, while the untreated chrysin had no effect. CONCLUSION: The SD formulation of chrysin with Brij®L4 and aminoclay appeared to be promising in improving the dissolution of chrysin and enhancing its in vivo effect as an absorption enhancer.

Polydocanol foam stabilized by liposomes: Supramolecular nanoconstructs for sclerotherapy.

Vascular pathology of the lower limbs is a widespread disease affecting the quality of life for more than 30% of the adult world population. Polydocanol foam is presently the main therapeutic option for treating varicosities, inflammation, and chronic disease which affect the vascular endothelium and blood vessels. Unfortunately, the commercial product contains detergents and surfactants which can provoke several side effects and decrease the efficacy of therapy. In an attempt to overcome these drawbacks, polydocanol foam was mixed with different liposomes before use. The resulting mixture was stable and generated supramolecular nanoconstructs, which may prevent the interaction of the components of the commercial polydocanol foam with the vascular endothelium. This effect depends on the presence of liposomes, which can induce polydocanol foam to change its structure from micelles to complex nanostructures, thus improving its stability. In this attempt, the physicochemical features of the resulting nanoconstructs were tested through dynamic- and multiple light scattering analyses, rheological studies and gel permeation chromatography, while the stability was tested in biological fluids. Our preliminary results showed that the nanoconstructs have some potential as therapeutic agents in sclerotherapy.