In Vitro Evaluation of a Foamable Microemulsion Towards an Improved Topical Delivery of Diclofenac Sodium.

Topical microemulsion (ME) might provide a novel and advanced transdermal delivery system due to the enhances of drug solubility and permeability across the stratum corneum. Foams are topical delivery systems that have excellent patient compliance, acceptability, and preference. Therefore, this study aimed to investigate a foamable microemulsion as an alternative topical and transdermal dosage form for diclofenac sodium (DS). The physicochemical properties (optical clarity, percentage transmittance, homogeneity, consistency of formulation, particle size, zeta potential, conductivity, viscosity, and morphology, etc.) of the DS-loaded ME were investigated. The foam stability of both drug-free ME and DS-loaded ME was measured. The foam quality was evaluated, and the chemical stability over 90 days was determined. Franz diffusion cells were employed to assess the in vitro drug release of a foamed DS-loaded ME and compared with a commercial topical product. A foamable and stable DS-loaded ME that maintained small particle sizes and constant zeta potential and was transparent and translucent in appearance after 90 days was successfully produced. The foam of the DS-loaded ME was physically more stable compared to the drug-free foam. The foam had an increased drug release rate compared to the commercial product. The foamable DS-loaded ME has a great potential to enhance the transdermal delivery of DS after topical administration. Foamed DS-loaded ME is a promising alternative to the current topical formulation of DS.

Traditional Chinese Medicine "Pill", an Ancient Dosage Form with Surprising Modern Pharmaceutical Characteristics.

Currently, the use of Traditional Chinese Medicine (TCM) for healthy living in daily practice is widely accepted across the world. However, not much attention has been paid to the particular characteristics of TCM "pills", one of the classic dosage forms in TCM. For a better understanding, this review was undertaken to provide a modern pharmaceutical overview of pills. Over many centuries, pills have been developed in different types (honeyed pill, water-honeyed pill, watered pill, pasted pill, waxed pill, concentrated pill, and dripping pill) to achieve varying intended TCM release patterns. It suggests that knowledge relating to the impact of binders and excipients on drug release from TCM pills can be traced back to before dissolution testing was invented. Therefore, although Pills may be considered as an ancient and outdated dosage form compared to current drug delivery systems, they have surprisingly modern pharmaceutical properties that is highlighted in this article. In addition, this review found that the quality control standards for TCM pill are globally substantially different. Hence, greater effort should be taken to establish an internationally harmonized and proper standard to safeguard the quality of this dosage form and to ensure the alignment with TCM use.

The Lymphatic System: A Sometimes-Forgotten Compartment in Pharmaceutical Sciences.

The uniqueness of structure and physiology of the lymphatic system make it challenging to delineate all its contributions in the maintenance of our health. However, in the past two decades, the understanding of the importance of the function of this system has evolved and more appreciation has been drawn to the distinctive role it plays in health and disease. The lymphatic system has been linked to the pathophysiology of numerous ailments including cancer, various metabolic diseases, inflammatory conditions, and infections. Moreover, it has also been revealed that lymphatic targeted formulations can enhance the delivery of drugs through the lymphatic system to the bloodstream, bypassing the hepatic first-pass metabolism if taken orally, thus increasing the bioavailability, and improving the pharmacokinetic and toxicological profiles in general. Engineering lymphotropic preparations requires the understanding of many factors, the most important one being that of the physiological environment which they will encounter. Therefore, in this review, we detail the basic structure of the lymphatic system, then highlight the therapeutic and the pharmacokinetic benefits of drug delivery into the lymphatic system. The criteria for drugs and formulations used for lymphotropic delivery are also detailed with a contemporary overview of various studies undertaken in this field.

Bortezomib-loaded lipidic-nano drug delivery systems; formulation, therapeutic efficacy, and pharmacokinetics.

AIM: Nano drug delivery systems can provide the opportunity to reduce side effects and improve the therapeutic aspect of a variety of drugs. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Severe side effects of BTZ are the major dose-limiting factor. Particulate drug delivery systems for BTZ are polymeric and lipidic drug delivery systems. This review focussed on lipidic-nano drug delivery systems (LNDDSs) for the delivery of BTZ. RESULTS: LNDDSs including liposomes, solid lipid nanoparticles, and self-nanoemulsifying drug delivery systems showed reduce systemic side effects, improved therapeutic efficacy, and increased intestinal absorption. Besides LNDDSs were used to target-delivery of BTZ to cancer. CONCLUSION: Overall, LNDDSs can be considered as a novel delivery system for BTZ to resolve the treatment-associated restrictions.

Raman Spectroscopy for Quantitative Analysis in the Pharmaceutical Industry.

Raman spectroscopy is a very promising technique increasingly used in the pharmaceutical industry. Due to its development and improved instrumental versatility achieved over recent decades and through the application of chemometric methods, this technique has become highly precise and sensitive for the quantification of drug substances. Thus, it has become fundamental in identifying critical variables and their clinical relevance in the development of new drugs. In process monitoring, it has been used to highlight in-line real-time analysis, and it has been used more commonly since 2004 when the Food and Drug Administration (FDA) launched Process Analytical Technology (PAT), integrated with the concepts of Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century. The present review presents advances in the application of this tool in the development of pharmaceutical products and processes in the last six years.

Enhancement of the intestinal absorption of bortezomib by self-nanoemulsifying drug delivery system.

Purpose: Intestinal drug absorption is one of the main factors that govern the fraction of oral dose absorbed (Fa) of drugs. It is reported that oral absorption of bortezomib (BTZ) can be restricted by its low intestinal permeability. In this study, we aimed to evaluate the impact of self-nanoemulsifying drug delivery systems (SNEDDS) on the intestinal absorption and Fa of BTZ.Methods: Intestinal permeability studies were conducted using in situ single-pass intestinal perfusion (SPIP) technique in rats. Human intestinal absorption (Peff (Human)) and Fa values of BTZ and BTZ-SNEDDS were predicted based on SPIP data.Results: Based on the obtained data, Peff (rat) values of (3.36 ± 0.5) × 10-5 and (8.9 ± 3) × 10-5 cm/s (mean ± SEM) were calculated for BTZ and BTZ-SNEDDS, respectively. Meanwhile, Peff (human) values of (7 × 10-5) and (68 × 10-5) cm/sec were predicted for BTZ and BTZ-SNEDDS, respectively. Besides, Fa (human) values of 72.5 and 97% were estimated for BTZ and BTZ-SNEDDS, respectively.Conclusions: According to the obtained data, it is concluded that SNEDDS can be considered as a promising drug delivery system to improve the intestinal absorption and Fa values of BTZ.

In silico Tools at Early Stage of Pharmaceutical Development: Data Needs and Software Capabilities.

In early drug development, the selection of a formulation platform and decisions on formulation strategies have to be made within a short timeframe and often with minimal use of the active pharmaceutical ingredient (API). The current work evaluated the various physicochemical parameters required to improve the prediction accuracy of simulation software for immediate release tablets in early drug development. DDDPlus™ was used in simulating dissolution test profiles of immediate release tablets of ritonavir and all simulations were compared with experimental results. The minimum data requirements to make useful predictions were assessed using the ADMET predictor (part of DDDPlus) and Chemicalize (an online resource). A surfactant model was developed to estimate the solubility enhancement in media containing surfactant and the software's transfer model based on the USP two-tiered dissolution test was assessed. One measured data point was shown to be sufficient to make predictive simulations in DDDPlus. At pH 2.0, the software overestimated drug release while at pH 1.0 and 6.8, simulations were close to the measured values. A surfactant solubility model established with measured data gave good dissolution predictions. The transfer model uses a single-vessel model and was unable to predict the two in vivo environments separately. For weak bases like ritonavir, a minimum of three solubility data points is recommended for in silico predictions in buffered media. A surfactant solubility model is useful when predicting dissolution behavior in surfactant media and in silico predictions need measured solubility data to be predictive.

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 1: Fasted State Conditions.

The goal of this project was to explore and to statistically evaluate the responsible gastrointestinal (GI) factors that are significant factors in explaining the systemic exposure of ibuprofen, between and within human subjects. In a previous study, we determined the solution and total concentrations of ibuprofen as a function of time in aspirated GI fluids, after oral administration of an 800 mg IR tablet (reference standard) of ibuprofen to 20 healthy volunteers in fasted state conditions. In addition, we determined luminal pH and motility pressure recordings that were simultaneously monitored along the GI tract. Blood samples were taken to determine ibuprofen plasma levels. In this work, an in-depth statistical and pharmacokinetic analysis was performed to explain which underlying GI variables are determining the systemic concentrations of ibuprofen between (inter-) and within (intra-) subjects. In addition, the obtained plasma profiles were deconvoluted to link the fraction absorbed with the fraction dissolved. Multiple linear regressions were performed to explain and quantitatively express the impact of underlying GI physiology on systemic exposure of the drug (in terms of plasma Cmax/AUC and plasma Tmax). The exploratory analysis of the correlation between plasma Cmax/AUC and the time to the first phase III contractions postdose (TMMC-III) explains ∼40% of the variability in plasma Cmax for all fasted state subjects. We have experimentally shown that the in vivo intestinal dissolution of ibuprofen is dependent upon physiological variables like, in this case, pH and postdose phase III contractions. For the first time, this work presents a thorough statistical analysis explaining how the GI behavior of an ionized drug can explain the systemic exposure of the drug based on the individual profiles of participating subjects. This creates a scientifically based and rational framework that emphasizes the importance of including pH and motility in a predictive in vivo dissolution methodology to forecast the in vivo performance of a drug product. Moreover, as no extensive first-pass metabolism is considered for ibuprofen, this study demonstrates how intraluminal drug behavior is reflecting the systemic exposure of a drug.

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State.

Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma Cmax variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions.

Additive Polyplexes to Undertake siRNA Therapy against CDC20 and Survivin in Breast Cancer Cells.

Small interfering RNA (siRNA) delivered to silence overexpressed genes associated with malignancies is a promising targeted therapy to decrease the uncontrolled growth of malignant cells. To create potent delivery agents for siRNA, here we formulated additive polyplexes of siRNA using linoleic acid-substituted polyethylenimine and additive polymers (hyaluronic acid, poly(acrylic acid), dextran sulfate, and methyl cellulose) and characterized their physicochemical properties and effectiveness. Incorporating polyanionic polymer along with anionic siRNA in polyplexes was found to decrease the ζ-potential of polyplexes but enhance the cellular delivery of siRNA. The CDC20 and survivin siRNAs delivered by additive polyplexes showed promising efficacy in breast cancer MDA-MB-231, SUM149PT, MDA-MB-436, and MCF7 cells. However, the side effects of the siRNA delivery were observed in nonmalignant cells, and a careful formulation of siRNA/polymer polyplexes was needed to minimize side effects on normal cells. Because the efficacy of siRNA delivery by additive polyplexes was independent of breast cancer phenotypes used in this study, these polyplexes could be further developed to treat a wide range of breast cancers.

Are Excipients Inert? Phenytoin Pharmaceutical Investigations with New Incompatibility Insights.

PURPOSE: The U.S. Pharmacopeia defines excipients as substances other than the active pharmaceutic ingredient (API) that are added in a drug delivery system in order to aid in the manufacturing process and enhance stability, bioavailability, safety, effectiveness and delivery of the drug. The 1968 phenytoin intoxication outbreak in Brisbane, Australia, is a classic example of an API-excipient interaction. When administered with CaSO4 the absorption of phenytoin was reduced due to an interaction between the API and the excipient. When CaSO4 was replaced by lactose, the amount of drug absorbed was much higher, resulting in the observed intoxication. It was hypothesized that phenytoin was converted to a calcium salt prior to ingestion. The purpose of this study was to mechanistically investigate the interactions between excipients and phenytoin to confirm the hypothesis of the previous reports. METHODS: Titration experiments with phenytoin and calcium salt were performed. Isothermal micro calorimetry was used to determine incompatibilities between excipients, phenytoin and milk. NMR was used to characterize the compounds. Dissolution tests containing CaSO4, lactose or sorbitol as excipients were also performed. Both Canadian and United States of America commercially available capsules were tested with milk and water. RESULTS: The calorimeter results indicate that phenytoin sodium interacts with CaSO4 in aqueous media and the dissolution profile of CaSO4 containing capsules showed a reduced dissolution rate. In addition, phenytoin sodium also interacts with lactose through a Maillard reaction that can occur at body temperature. Likewise, commercial Phenytoin sodium products interacted with milk and the products containing lactose showed browning in water. CONCLUSION: In Canada and the USA, the reference product contains lactose as an excipient in the formulation, whereas the Canadian generic formulations do not contain lactose. Any clinical relevance of these difference has not been determined. A new incompatibility between phenytoin and lactose has been discovered and an incompatibility with calcium was confirmed, which may have implications in regard to excipients and food effects. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Nano-sized Droplets of Self-Emulsifying System for Enhancing Oral Bioavailability of Chemotherapeutic Agent VP-16 in Rats: A Nano Lipid Carrier for BCS Class IV Drugs.

PURPOSE: The purpose of this study was to investigate the ability of a self-nano-emulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of a BCS class IV drug, etoposide (VP-16). METHOD: A series of SNEDDS formulations with VP-16 were prepared consisting of medium chain triglycerides, polysorbate 80, diethylene glycol monoethyl ether and propylene glycol monolaurate type-1.  Based on an obtained ternary phase diagram, an optimum formulation was selected and characterized in terms of size, zeta potential, loading, morphology and in vitro drug release. The pharmacokinetic parameters and oral bioavailability of VP-16 suspension and VP-16 in SNEDDS was assessed using 30 Male Sprague-Dawley rats and compared with the commercial product (VePesid®). RESULTS: Pharmacokinetic data showed that the mean values for AUC0-t of VP-16 in SNEDDS was 6.4 fold higher compared to a drug suspension and 2.4-folds higher than VePesid®. Similarly, the mean value for Cmax of VP-16 in SNEDDS (1.13± 0.07 µg/ml µg.h/mL) was higher than VePesid® (0.62± 0.09 µg/mL) and drug suspension (0.13± 0.07 µg/mL). CONCLUSION: The SNEDDS formulation was able to enhance the oral bioavailability of the BCS Class IV chemotherapeutic agent VP-16 by increasing the dissolution and absorption of the drug. A good in vitro in vivo correlation was found between the in vitro dissolution and in vivo absorption data of VP-16 SNEDDS preparation. Therefore, SNEDDS formulations might be a very promising approach for BCS Class IV drugs.

Application of in Silico Tools in Clinical Practice using Ketoconazole as a Model Drug.

Hypochlorhydria is a condition where the production of hydrochloric acid in the stomach is decreased. As a result, the intragastric pH is elevated. This condition can be due to a series of causes, such as disease (gastric mucosal infection caused by Helicobacter pylori and is prominent in AIDS patients), ethnicity, age and also the use of antisecretory agents. This may significantly impact the absorption of other drugs that have pH-dependent solubility, such as ketoconazole, a weak base. Within this context, the purpose of this study was to demonstrate how GastroPlusTM - a physiological based software program- can be used to predict clinical pharmacokinetics of ketoconazole in a normal physiological state vs. elevated gastric pH. A simple physiologically based pharmacokinetic model was built and validated to explore the impact that different physiologic conditions in the stomach (hypochlorhydria, drug administered with water and Coca Cola®) had on ketoconazole's bioavailability. The developed model was able to accurately predict the impact of increased pH and beverage co-administration on dissolution and absorption of the drug, and confirmed that complete gastric dissolution is essential. Particle size only mattered in hypochlorhydric conditions due to the incomplete gastric dissolution, as its absorption would depend on intestinal dissolution, which corroborates with previous studies. Therefore, in silico approaches are a potential tool to assess a pharmaceutical product's performance and efficacy under different physiological and pathophysiological states supporting the assessment of different dosing strategies in clinical practice.

Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies.

PURPOSE: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in vivo approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery. METHODS: In silico software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin. In vitro cardiotoxicity was assessed using human cardiomyocytes (RL-14) while effects on CYP3A4 metabolic enzyme and antioxidant activity were examined using commercial kits. A novel HPLC assay was developed to measure MyoNovin concentration in serum, and delineate initial pharmacokinetic and acute toxicity after intravenous administration (20 mg/kg) to male Sprague-Dawley rats. RESULTS: MyoNovin showed relatively high lipophilicity with a LogP value of 3.49, a 20-fold higher skin permeability (19.89 cm/s*107) compared to guaifenesin (0.66 cm/s*107), and ~10-fold higher effective jejunal permeability (2.24 cm/s*104) compared to guaifenesin (0.26 cm/s*104). In vitro, MyoNovinwas not cytotoxic to cardiomyocytes at concentrations below 8 µM and did not inhibit CYP3A4 or show antioxidant activity. In vivo, MyoNovin had a short half-life (t1/2) of 0.16 h, and a volume of distribution Vss of 0.62 L/kg. Biomarkers of MyoNovincardiac and renal toxicity did not differ significantly from baseline control levels. CONCLUSIONS: The predicted high lipophilicity and skin permeability of MyoNovin render it a potential candidate for transdermal administration while its favourable intestinal permeation suggests it may be suitable for oral administration. Pharmacokinetics following IV administration of MyoNovin were delineated for the first time in a rat model. Preliminary single 20 mg/kg dose assessment of MyoNovin suggest no influenceon cardiac troponin or ß-N-Acetylglucosaminidase. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug.

PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75- 30 mM) by rotary film evaporation followed by nano-size reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts.  Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nano-sized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Inflammation Caused by Nanosized Delivery Systems: Is There a Benefit?

Secondary macrophage cytotoxicity induced by nanoparticles was described before. The study aim was to investigate the role of secondary cytotoxic effect in a macrophage-lung cancer coculture model after nanoparticle treatment in the presence and absence of anti-inflammatory drugs. An in vitro coculture model composed of confluent alveolar macrophage MH-S and A-549 lung cancer cells separated by a 0.4 µm porous membrane was used in the study. Macrophages were treated with two sizes of gelatin nanoparticles and two sizes of poly(isobutyl cyanoacrylate) (PIBCA) nanoparticles, with and without doxorubicin as a chemotherapeutic drug. The treatment effect with and without the presence of anti-inflammatory drug was studied using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The model drugs were ibuprofen, celecoxib, prednisolone, dexamethasone, and methotrexate. Different nanoparticles in different sizes were synthesized with a range of physicochemical characteristics. Doxorubicin loaded nanoparticles were prepared with an entrapment efficiency of 82-83% for PIBCA and 39-42% for gelatin. Nanoparticle treatment of macrophages showed a secondary cytotoxic effect on A-549 cancer cells at 24 and 36 h, with a drop in cell viability of 40-62%. However, this effect was significantly reduced to 10-48% if the macrophages were exposed to anti-inflammatory drugs. When ibuprofen and celecoxib were used the cell viability rebounded between 24 and 36 h. For prednisolone, dexamethasone, and methotrexate the cell viability dropped further between 24 and 36 h. Macrophages exposed to nanoparticles show secondary cytotoxicity, which has a significant antitumor effect in the microclimate of the coculture model. The beneficial nanoparticle treatment effect was significantly reduced if nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, or methotrexate was given at the same time. The data suggest that anti-inflammatory treatments can decrease the carrier-induced macrophage cytotoxicity and its antitumor effectiveness with chemotherapy.

Fabrication and in vitro characterization of gadolinium-based nanoclusters for simultaneous drug delivery and radiation enhancement.

We report the synthesis of a gadolinium hydroxide (Gd(OH)3) nanorod based doxorubicin (Dox) delivery system that can enhance both magnetic resonance imaging contrast and radiation sensitivity. A simple and cost effective wet-chemical method was utilized in the presence of manganese (Mn) ions and Dox to produce the Gd(OH)3:Mn·Dox nanocluster structure. The Gd(OH)3:Mn·Dox nanocluster was composed of Mn-doped Gd(OH)3 nanorods arranged in parallel with Dox as a linker molecule between the adjacent nanorods. No other studies have utilized Dox as both the linker and therapeutic molecule in a nanostructure to date. The Gd(OH)3 nanorod is reported to have no significant cellular or in vivo toxicity, which makes it an ideal base material for this biomedical application. The Gd(OH)3:Mn·Dox nanocluster exhibited paramagnetic behavior and was stable in a colloidal solution. The nanocluster also enabled high Dox loading capacity and specifically released Dox in a sustained and pH-dependent manner. The positively charged Gd(OH)3:Mn·Dox nanoclusters were readily internalized into MDA-MB-231 breast cancer cells via endocytosis, which resulted in intracellular release of Dox. The released Dox in cells was effective in conferring cytotoxicity and inhibiting proliferation of cancer cells. Furthermore, a synergistic anticancer effect could be observed with radiation treatment. Overall, the Gd(OH)3:Mn·Dox nanocluster drug delivery system described herein may have potential utility in clinics as a multifunctional theranostic nanoparticle with combined benefits in both diagnosis and therapy in the management of cancer.

Physical-chemical properties of furosemide nanocrystals developed using rotation revolution mixer.

Recently, several approaches have been reported to improve the dissolution rate and bioavailability of furosemide, a class IV drug. However, to the best of our knowledge, none of them proposed nanocrystals. In the last decade, nanocrystals successfully addressed solubility issues by increasing surface area and saturation solubility, both leading to an increase in the dissolution rate of poor water soluble drugs. The preparation of furosemide nanocrystals was by a rotation revolution mixer method. Size distribution and morphology were performed using laser diffraction and scanning electron microscopy, respectively. In addition, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction (XRD) and low frequency shift-Raman spectroscopy allowed investigating the thermal properties and crystalline state. Solubility saturation and intrinsic dissolution rate (IDR) studies were conducted. The thermal analysis revealed lower melting range for the nanocrystals comparing to furosemide. Moreover, a slight crystalline structure change to the amorphous state was observed by XRD and confirmed by low frequency shift Raman. The particle size was reduced to 231 nm with a polydispersity index of 0.232, a 30-fold reduction from the original powder. Finally, the saturation solubility and IDR showed a significant increase. Furosemide nanocrystals showed potential for development of innovative formulations as an alternative to the commercial products.

Design Space Approach for Preservative System Optimization of an Anti-Aging Eye Fluid Emulsion.

The use of preservatives must be optimized in order to ensure the efficacy of an antimicrobial system as well as the product safety. Despite the wide variety of preservatives, the synergistic or antagonistic effects of their combinations are not well established and it is still an issue in the development of pharmaceutical and cosmetic products. The purpose of this paper was to establish a space design using a simplex-centroid approach to achieve the lowest effective concentration of 3 preservatives (methylparaben, propylparaben, and imidazolidinyl urea) and EDTA for an emulsion cosmetic product. Twenty-two formulae of emulsion differing only by imidazolidinyl urea (A: 0.00 to 0.30% w/w), methylparaben (B: 0.00 to 0.20% w/w), propylparaben (C: 0.00 to 0.10% w/w) and EDTA (D: 0.00 to 0.10% w/w) concentrations were prepared. They were tested alone and in binary, ternary and quaternary combinations. Aliquots of these formulae were inoculated with several microorganisms. An electrochemical method was used to determine microbial burden immediately after inoculation and after 2, 4, 8, 12, 24, 48, and 168 h. An optimization strategy was used to obtain the concentrations of preservatives and EDTA resulting in a most effective preservative system of all microorganisms simultaneously. The use of preservatives and EDTA in combination has the advantage of exhibiting a potential synergistic effect against a wider spectrum of microorganisms. Based on graphic and optimization strategies, we proposed a new formula containing a quaternary combination (A: 55%; B: 30%; C: 5% and D: 10% w/w), which complies with the specification of a conventional challenge test. A design space approach was successfully employed in the optimization of concentrations of preservatives and EDTA in an emulsion cosmetic product.

Physicochemical, in vitro and in vivo evaluation of flurbiprofen microemulsion.

Flurbiprofen, a potent nonsteroidal anti-inflammatory drug, is widely used for relief of pain in patients suffering from rheumatic diseases, migraine, sore throat and primary dysmenorrheal. However, this drug has many gastrointestinal side effects produced by its oral administration, such as gastric bleeding and peptic ulcer. These effects were responsible for non-compliance among patients, which ultimately results in treatment failure. The physicochemical properties of flurbiprofen, make it a suitable candidate for transdermal drug delivery, which can overcome the drawbacks of oral administration. In this sense, microemulsions have been proved to increase the cutaneous absorption of lipophilic drugs when compared to conventional drug delivery systems. The purpose of this study was to formulate and characterize gel based microemulsions, for topical delivery of flurbiprofen. Different gel bases, containing microemulsion and hydro-alcoholic solution of flurbiprofen, were developed and compared. In vitro study showed that gels containing microemulsion had a higher permeation rate than those containing hydro-alcoholic solutions. Additionally, formulation of Carbopol-I (microemulsion) showed higher percent of inhibition of inflammation than others bases. Further, skin irritation study demonstrated that Carbopol-I was none irritating. Flurbiprofen microemulsion incorporated on Carbopol-I showed physicochemical, in vitro and in vivo characteristics suitable for the development of alternative transdermal delivery formulation.