Challenges and advancements in membrane distillation crystallization for industrial applications.

Membrane distillation crystallization (MDC) is an emerging hybrid thermal membrane technology that synergizes membrane distillation (MD) and crystallization, which can achieve both freshwater and minerals recovery from high concentrated solutions. Due to the outstanding hydrophobic nature of the membranes, MDC has been widely used in numerous fields such as seawater desalination, valuable minerals recovery, industrial wastewater treatment and pharmaceutical applications, where the separation of dissolved solids is required. Despite the fact that MDC has shown great promise in producing both high-purity crystals and freshwater, most studies on MDC remain limited to laboratory scale, and industrializing MDC processes is currently impractical. This paper summarizes the current state of MDC research, focusing on the mechanisms of MDC, the controls for membrane distillation (MD), and the controls for crystallization. Additionally, this paper categorizes the obstacles hindering the industrialization of MDC into various aspects, including energy consumption, membrane wetting, flux reduction, crystal yield and purity, and crystallizer design. Furthermore, this study also indicates the direction for future development of the industrialization of MDC.

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model.

Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1% [n = 4], 0.5% [n = 6], and 1% [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 10(5) 50% tissue culture infectious doses). Rx mice were challenged at 4 h (0.1%), 24 h (0.5%), and 7 days (1%) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100% protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality.

Poloxamer 188 (P188), A Potential Polymeric Protective Agent for Central Nervous System Disorders: A Systematic Review.

Poloxamer 188 (P188) is an FDA-approved biocompatible block copolymer composed of repeating units of Poly(Ethylene Oxide) (PEO) and poly(propylene oxide) (PPO). Due to its amphiphilic nature and high Hydrophile-Lipophile Balance (HLB) value of 29, P188 is used as a stabilizer/emulsifier in many cosmetics and pharmaceutical preparations. While the applications of P188 as an excipient are widely explored, the data on the pharmacological activity of P188 are scarce. Notably, the neuroprotective potential of P188 has gained a lot of interest. Therefore, this systematic review is aimed at summarizing evidence of neuroprotective potential of P188 in CNS disorders. The PRISMA model was used, and five databases (Google Scholar, Scopus, Wiley Online Library, ScienceDirect, and PubMed) were searched with relevant keywords. The search resulted in 11 articles, which met the inclusion criteria. These articles described the protective effects of P188 on traumatic brain injury or mechanical injury in cells, neurotoxicity, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), and ischemia/ reperfusion injury from stroke. All the articles were original research in experimental or pre-clinical stages using animal models or in vitro systems. The reported activities demonstrated the potential of P188 as a neuroprotective agent in improving CNS conditions such as neurodegeneration.

In Vitro Release Testing of Acyclovir Topical Formulations Using Immersion Cells.

The objective of the study was to reinforce the applicability of the immersion cells for the in vitro release testing (IVRT) of topical formulations by using marketed acyclovir 5% cream formulation (Cream 1) as a model. The method employing the immersion cells was optimized by studying the effect of variables, such as membrane type, media temperature and volume, agitation speed, and cell size, on acyclovir release from the formulation. The in-house formulation similar to the qualitative and quantitative composition of Cream 1 and the other trial formulations with variable compositions were prepared and studied by using the immersion cells. Various other brands of acyclovir topical formulations available in the Indian market were also subjected to IVRT by using the optimized method. An increase in the media temperature from 32°C to 37°C and the stirring speed from 50 to 100 to 150 rpm led to an increase in the drug release. As the immersion cell size increased (0.5, 2 and 4 cm2 surface area), the release rate also increased. Nitrocellulose membrane showed the highest drug release and Fluoropore™the least. The optimized IVRT method could establish the differences in the drug release rates among the formulations with the altered compositions. The method could also prove its discriminatory potential for various marketed formulations. The immersion cell method could serve as a simpler, facile, and reliable aid during product development and also as a quality control tool in assessing stability, aging, and batch-to-batch uniformity of semisolid formulations.

Pharmaceutically Acceptable Carboxylic Acid-Terminated Polymers Show Activity and Selectivity against HSV-1 and HSV-2 and Synergy with Antiviral Drugs.

Polyanionic macromolecules including carboxylate-terminated polymers (polycarboxylates) are capable of inhibiting sexually transmitted viruses such as human immunodeficiency virus (HIV) and herpes simplex virus (HSV). Cellulose acetate phthalate (CAP), a pharmaceutically acceptable pH-sensitive polycarboxylate polymer, showed promising prophylactic activity against HIV and HSV, but the instability of CAP in an aqueous environment prevented its clinical development. Interestingly, several pharmaceutically acceptable polycarboxylates have features similar to CAP with an aqueous stability significantly higher than that of CAP. However, their activity against sexually transmitted viruses remains unexplored. Here, we evaluate the activity of various polycarboxylates such as polyvinyl acetate phthalate (PVAP), various grades of hydroxypropyl methylcellulose phthalate (HPMCP-50, HPMCP-55, and HPMCP-55S), and various grades of methacrylic acid copolymers (Eudragit L100-55, Eudragit L100, Eudragit S100, and Kollicoat MAE 100P) against HSV. We, for the first time, demonstrate that PVAP, HPMCP-55S, and Eudragit S100 have activity and selectivity against HSV-1 and HSV-2. Further, we report that polycarboxylates can be easily transformed into nanoparticles (NPs) and in the nanoparticulate form, they show similar or enhanced activity against HSV. Finally, using PVAP NPs, as a model, we demonstrate using in vitro HSV therapy studies that polycarboxylate NPs are capable of synergizing with antiviral drugs such as acyclovir (ACV), tenofovir, and tenofovir disoproxil fumarate. Thus, pharmaceutically acceptable carboxylic acid-terminated polymers and their NPs have the potential to be developed into topical formulations for the prevention and treatment of HSV infection.

Gelling hypotonic polymer solution for extended topical drug delivery to the eye.

Eye-drop formulations should hold as high a concentration of soluble drug in contact with ocular epithelium for as long as possible. However, eye tears and frequent blinking limit drug retention on the ocular surface, and gelling drops typically form clumps that blur vision. Here, we describe a gelling hypotonic solution containing a low concentration of a thermosensitive triblock copolymer for extended ocular drug delivery. On topical application, the hypotonic formulation forms a highly uniform and clear thin layer that conforms to the ocular surface and resists clearance from blinking, increasing the intraocular absorption of hydrophilic and hydrophobic drugs and extending the drug-ocular-epithelium contact time with respect to conventional thermosensitive gelling formulations and commercial eye drops. We also show that the conformal gel layer allows for therapeutically relevant drug delivery to the posterior segment of the eyeball in pigs. Our findings highlight the importance of formulations that conform to the ocular surface before viscosity enhancement for increased and prolonged ocular surface contact and drug absorption.

Development of a mucoinert progesterone nanosuspension for safer and more effective prevention of preterm birth.

Preterm birth (PTB) is a significant global problem, but few therapeutic options exist. Vaginal progesterone supplementation has been demonstrated to reduce PTB rates in women with a sonographic short cervix, yet there has been little investigation into the most effective dose or delivery form. Further, vaginal products like progesterone gel often contain excipients that cause local toxicity, irritation, and leakage. Here, we describe the development and characterization of a mucoinert vaginal progesterone nanosuspension formulation for improved drug delivery to the female reproductive tract. We compare the pharmacokinetics and pharmacodynamics to the clinical comparator progesterone gel in pregnant mice and demonstrate increased vaginal absorption and biodistribution via the uterine first-pass effect. Importantly, the unique plasma progesterone double peak observed in humans, reflecting recirculation from the uterus, was also observed in pregnant mice with vaginal dosing. We adapted a mouse model of progesterone withdrawal that was previously believed to be incompatible with testing the efficacy of exogenous progestins, and are first to demonstrate efficacy in preventing preterm birth with vaginal progesterone in this model. Further, improved vaginal progesterone delivery by the nanosuspension led to increased efficacy in PTB prevention. Additionally, we identified histological and transcriptional evidence of cervical and uterine toxicity with a single vaginal administration of the clinical gel that are absent after dosing with the mucoinert nanosuspension formulation. We demonstrate that a progesterone formulation that is designed for improved vaginal progesterone absorption and vaginal biocompatibility could be more effective for PTB prevention.

Potential of cyclodextrin complexation and liposomes in topical delivery of ketorolac: in vitro and in vivo evaluation.

The objective of this investigation was to evaluate the effect of delivery strategies such as cyclodextrin complexation and liposomes on the topical delivery of ketorolac acid (KTRA) and ketorolac tromethamine. Ketorolac acid-hydroxypropyl-beta-cyclodextrin solid dispersions (KTRA-CD) were prepared by kneading method. The liposomes containing ketorolac tromethamine (KTRM) and KTRA-CD were prepared. The in vitro permeation of KTRM solution, KTRA solution, KTRA-CD, and liposomes containing KTRM or KTRA-CD through guinea pig skin was evaluated. The anti-inflammatory activity of the topically applied KTRA-CD gel (containing 1% w/w KTRA) was compared to that of orally delivered KTRM solution. The KTRA-CD demonstrated significantly higher transdermal transport of ketorolac as compared to all other systems whereas liposomes significantly reduced the transport of ketorolac. The anti-inflammatory activity of the topically applied KTRA-CD gel was similar to that of the orally administered KTRM. Thus, cyclodextrin complexation enabled effective transdermal delivery of the ketorolac.

Mucus-penetrating budesonide nanosuspension enema for local treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder that affects more than 1 million individuals in the USA. Local therapy with enema formulations, such as micronized budesonide (Entocort®), is a common strategy for treating patients with distally active IBD. However, we hypothesize that micronized particulates are too large to effectively penetrate colorectal mucus, limiting the extent of drug delivery to affected tissues prior to clearance. Here, we describe the development of a budesonide nanosuspension (NS) with the appropriate surface coating and size to enhance penetration of colorectal mucus and ulcerated colorectal tissues. We demonstrate that model fluorescent polystyrene (PS) particles ∼200 nm in size with a muco-inert Pluronic F127 coating provide enhanced mucosal distribution and tissue penetration in mice with trinitrobenzenesulfonic acid (TNBS)-induced IBD compared to model 2 µm PS particles coated with polyvinylpyrollidone (PVP), the stabilizer used in the clinical micronized budesonide formulation. We then used a wet-milling process to develop a budesonide NS formulation with a muco-inert Pluronic F127 coating (particle size ∼230 nm), as well as a budesonide microsuspension (MS) stabilized with PVP (particle size ∼2 µm). Using an acute TNBS mouse model of IBD, we show that daily budesonide NS enema treatment resulted in a significant reduction in the macroscopic (decreased colon weight) and microscopic (histology score) symptoms of IBD compared to untreated controls or mice treated daily with the budesonide MS enema. Further, we show that the budesonide NS enema treated mice had a significantly reduced number of inflammatory macrophages and IL-ß producing CD11b + cells in colon tissue compared to untreated controls or mice treated with the budesonide MS enema. We conclude that the nano-size and muco-inert coating allowed for enhanced local delivery of budesonide, and thus, a more significant impact on local colorectal tissue inflammation.

Parasitic diseases: Liposomes and polymeric nanoparticles versus lipid nanoparticles.

Parasitic diseases such as malaria, leishmaniasis, and trypanosomiasis represent a significant global burden and pose a great challenge to drug discovery and delivery scientists due to their intracellular nature and disseminated locations. Moreover, poor rate of discovery in the anti-parasitic segment seen in last few decades has necessitated effective management of existing drugs by modulating their delivery. The review focuses on the biological and biopharmaceutical issues to be considered in the design of delivery strategy for treating parasitic infections such as malaria, leishmaniasis, and trypanosomiasis. Also, it describes the role of the colloidal carriers liposomes, polymeric nanoparticles, lipid nanoparticles including lipid drug conjugate (LDC) nanoparticles in optimizing the delivery of anti-malarial, anti-leishmanial and anti-trypanosomial agents. Furthermore, the review emphasizes especially the potential of solid lipid nanoparticles (SLN) in the treatment of parasitic infections with the help of recent reports and our own experience.

MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound.

Systemically administered chemotherapeutic drugs are often ineffective in the treatment of invasive brain tumors due to poor therapeutic index. Within gliomas, despite the presence of heterogeneously leaky microvessels, dense extracellular matrix and high interstitial pressure generate a "blood-tumor barrier" (BTB), which inhibits drug delivery and distribution. Meanwhile, beyond the contrast MRI-enhancing edge of the tumor, invasive cancer cells are protected by the intact blood-brain barrier (BBB). Here, we tested whether brain-penetrating nanoparticles (BPN) that possess dense surface coatings of polyethylene glycol (PEG) and are loaded with cisplatin (CDDP) could be delivered across both the blood-tumor and blood-brain barriers with MR image-guided focused ultrasound (MRgFUS), and whether this treatment could control glioma growth and invasiveness. To this end, we first established that MRgFUS is capable of significantly enhancing the delivery of ~60nm fluorescent tracer BPN across the blood-tumor barrier in both the 9L (6-fold improvement) gliosarcoma and invasive F98 (28-fold improvement) glioma models. Importantly, BPN delivery across the intact BBB, just beyond the tumor edge, was also markedly increased in both tumor models. We then showed that a CDDP loaded BPN formulation (CDDP-BPN), composed of a blend of polyaspartic acid (PAA) and heavily PEGylated polyaspartic acid (PAA-PEG), was highly stable, provided extended drug release, and was effective against F98 cells in vitro. These CDDP-BPN were delivered from the systemic circulation into orthotopic F98 gliomas using MRgFUS, where they elicited a significant reduction in tumor invasiveness and growth, as well as improved animal survival. We conclude that this therapy may offer a powerful new approach for the treatment invasive gliomas, particularly for preventing and controlling recurrence.

Preclinical Evaluation of Intravesical Cisplatin Nanoparticles for Non-Muscle-Invasive Bladder Cancer.

Purpose: Prior clinical trials evaluating cisplatin for non-muscle-invasive bladder cancer (NMIBC) were stopped due to local and systemic toxicity. Currently, there is still a need for improved intravesical therapies, and nanoparticle-based CDDP may be efficacious without the toxicity of free cisplatin observed in the past.Experimental Design: Cisplatin nanoparticles (CDDP NPs) were developed using biocompatible poly(l-aspartic acid sodium salt; PAA), both with and without low and high grafting density of methoxy-polyethylene glycol (PEG). In vitro cytotoxicity studies confirmed activity of CDDP NPs and CDDP solution against a papillary bladder cancer cell line. Local toxicity was assessed by three weekly intravesical administrations of CDDP formulations. CDDP NPs and CDDP solution were evaluated for bladder absorption in murine models 1 and 4 hours after intravesical administration. In vivo efficacy was evaluated in an immunocompetent carcinogen model of NMIBC.Results: CDDP NPs showed decreased local toxicity, as assessed by bladder weight, compared with CDDP solution. Furthermore, >2 µg/mL of platinum was observed in mouse serum after intravesical administration of CDDP solution, whereas serum platinum was below the limit of quantification after intravesical administration of CDDP NPs. CDDP NPs provided significantly increased (P < 0.05) drug levels in murine bladders compared with CDDP solution for at least 4 hours after intravesical administration. In vivo, CDDP NPs reduced cancer cell proliferation compared with untreated controls, and was the only treatment group without evidence of invasive carcinoma.Conclusions: Cisplatin-loaded PAA NPs have the potential to improve intravesical treatment of NMIBC while reducing local and systemic side effects. Clin Cancer Res; 23(21); 6592-601. ©2017 AACR.

Thermosensitive Gel Containing Cellulose Acetate Phthalate-Efavirenz Combination Nanoparticles for Prevention of HIV-1 Infection.

The objective of this investigation was to develop and evaluate a nano-microbicide containing a combination of cellulose acetate phthalate (HIV-1 entry inhibitor) and efavirenz (anti-HIV agent) for HIV prophylaxis. Cellulose acetate phthalate-efavirenz combination nanoparticles (CAP-EFV-NPs) were fabricated by the nanoprecipitation method and were characterized for particle size, zeta potential and encapsulation efficiency of efavirenz. CAP-EFV-NPs were incorporated into a thermosensitive gel (CAP-EFV-NP-Gel). CAP-EFV-NPs, CAP-EFV-NP-Gel and efavirenz solution were evaluated for cytotoxicity to HeLa cells and for in vitro short-term (1-day) and long-term (3-day) prophylaxis against HIV-1 infection in TZM-bl cells. CAP-EFV-NPs had size < 100 nm, negative surface charge and encapsulation efficiency of efavirenz was > 98%. CAP-EFV-NPs and CAP-EFV-NP-Gel were significantly less toxic (P < 0.01) to HeLa cells as compared to efavirenz solution. CAP-EFV-NPs showed significantly higher prophylactic activity (P < 0.01) against HIV-1 infection to TZM-bl cells as compared to efavirenz solution and blank CAP nanoparticles. CAP-EFV-NP-Gel can be a promising nano-microbicide for long-term HIV prophylaxis.

Polymeric nanoparticles containing combination antiretroviral drugs for HIV type 1 treatment.

The use of combination antiretroviral nanoparticles (cART NPs) was investigated as a novel treatment approach for the inhibition of HIV-1 replication. We developed nanoparticles of biodegradable polymer, poly-(dl-lactide-co-glycolic acid; PLGA) containing efavirenz (EFV) and boosted lopinavir (lopinavir/ritonavir; LPV/r) by a high-pressure homogenization method. The method resulted in >79% drug entrapment efficiency for each of the three drugs. The average size of cART NPs was 138.3±55.4 nm as measured by dynamic light scanning, confirmed by scanning electron microscopy (SEM) with an average surface charge of -13.7±4.5. Lissamine-rhodamine-labeled fluorescent PLGA NPs exhibited efficient uptake in nonimmune (HeLa cells) and immune (H9 T cells) cells as measured by confocal microscopy. Cells treated with cART NPs resulted in minimal loss of cell viability over 28 days. Subcellular fractionation studies demonstrated that HIV-1-infected H9 monocytic cells treated with cART NPs contained significantly (p<0.05) higher nuclear, cytoskeleton, and membrane antiretroviral drug levels compared to cells treated with drug solutions alone. Finally, cART NPs efficiently inhibited HIV-1 infection and transduction. The IC50 for each of the three drugs in the cART NPs was <31 nM. These experiments demonstrate the efficacy of a novel PLGA NPs formulation for the delivery of cART to inhibit HIV-1 replication.

Development and evaluation of a thermosensitive vaginal gel containing raltegravir+efavirenz loaded nanoparticles for HIV prophylaxis.

The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL+EFV-NPs) for pre-exposure prophylaxis of HIV. RAL+EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL+EFV-NP were 81.8±6.4 nm and -23.18±7.18 mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL+EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL+EFV-NPs in the gel did not result in nanoparticle aggregation and RAL+EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL+EFV-NPs was lower than raltegravir+efavirenz (RAL+EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL+EFV-NPs or blank gel were not cytotoxic for 14 days in vitro. The intracellular levels of efavirenz in RAL+EFV-NPs treated HeLa cells were above the EC(90) for 14 days whereas raltegravir intracellular concentrations were eliminated within 6 days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30 min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.

Eudragit EPO nanoparticles: application in improving therapeutic efficacy and reducing ulcerogenicity of meloxicam on oral administration.

The objective of this investigation was to evaluate the potential of Eudragit EPO nanoparticles (EPO NP) in improving therapeutic efficacy of meloxicam (MLX). MLX loaded EPO NP were prepared by nanoprecipitation method and were characterized for particle size, encapsulation efficiency and for morphology. The in vitro dissolution profile of MLX loaded EPO NP and MLX suspension was evaluated. MLX loaded EPO NP had particle size of approximately 100 nm and the encapsulation efficiency of MLX was approximately 90%. The EPO NP significantly improved anti-inflammatory activity of MLX (P < 0.01) as compared to that of MLX suspension. The enhanced anti-inflammatory effect was maintained for a longer duration (6 h) in case of MLX loaded EPO NP Oral administration of MLX loaded EPO NP also resulted in lesser ulcerogenicity as compared to that of MLX suspension indicating that nanoparticles can also decrease the adverse effects associated with MLX treatment.

Tween 80-sodium deoxycholate mixed micelles: structural characterization and application in doxorubicin delivery.

The objective of the present investigation is to develop and characterize anionic mixed micelles of two biocompatible surfactants, Tween 80 (T-80) and sodium deoxycholate (NaDC), and evaluate their potential in the delivery of doxorubicin hydrochloride (DOX), a cationic anticancer drug. The mixed micelles were characterized for their microstructure, intermicellar interactions, and doxorubicin binding ability by dynamic light scattering, small angle neutron scattering (SANS), viscosity, and optical absorption measurements. Salt-induced growth of the mixed micelles at different compositions suggests that both electrostatic interaction of the anionic bile salts and steric repulsion of the ethylene oxide groups in nonionic components are affected by the presence of electrolytes. Addition of bile salt molecules to T-80 micelles suppresses the salt-induced growth of nonionic T-80 micelles. SANS studies indicate that bile salt micelles are prolate ellipsoidal in shape, and the addition of T-80 transforms them toward a spherical shape. The anionic bile salt can successfully bind to the cationic drug doxorubicin. The in vitro cytotoxicity studies in various cancer cell lines revealed that DOX-loaded micelles have greater in vitro anticancer activity as compared to DOX solution, indicating their potential in pharmaceutical applications.