Current Drug Delivery - Volume 15, Issue 7, 2018

A great number of new drug candidates identified from the discovery pipeline are poorly water soluble, which is a drawback to bring such candidates into the pharmaceutical market. Formulating these compounds as self-emulsifying/microemulsifying/ nanoemulsifying drug delivery systems (SEDDS/SMEDDS/SNEDDS) within lipid based formulations is of growing interest. Some of the recent studies have resulted in commercial products that provided improved bioava ilability and dissolution due to the better dispersion properties of SEDDS/SMEDDS/SNEDDS. An ongoing challenge that the pharmaceutical industry is facing is identifying in vitro tests that are needed in order to predict the behavior of dosage forms in the GI tract. The goal of the current review is to present the various levels of in vitro-in vivo correlations (IVIVCs) and to provide tools on the utilization of the IVIVCs in product development and optimization of SEDDS/SMEDDS/SNEDDS.

Drug administration to the posterior segment of the eye has many challenges due to the natural barriers and consequent problems of low and unpredictable bioavailability. There is an increasing need for managing severe posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy, etc. Most of these diseases, if left untreated, lead to blindness. Traditional ocular formulations and topical administrations are almost inefficient and the drug delivery to the back of the eye requires direct administrations through intravitreal injections of innovative drug delivery systems. These systems must be easily injectable, able to release the drug for a prolonged period of time (to overcome the problem of repeated administrations) and made of biodegradable/biocompatible polymers. Among these delivery systems, microspheres still have an important role. This overview wants to highlight the use of microspheres as intravitreal systems to overcome the challenges of back of the eye diseases. Studies have shown that microspheres are able to enhance the intravitreal half-life and thus bioavailability of many drugs, protecting them from degradation. Furthermore, personalized therapies can be made by changing the amount of administered microspheres. This review focuses on the materials (polymers) used for the preparation of the microparticulate systems and comparative remarks are made with respect to the use of nanoparticles.

Despite extended, aggressive use of conventional antibiotics, drug treatment of bone infections frequently fails as a combined result of the widespread of drug-resistant bacteria, poor accessibility of many antimicrobials to the deeper portion of the bones, the ease of biofilm formation on the bone surface, and high risk of drug toxicity. Emerging therapeutic nanotechnology offers potential solutions to these issues. In recent years, a number of nanoantimicrobials, i.e. nanoscale devices with intrinsic antibacterial activities or capacity for delivering antibiotics, have been developed for the treatment and prevention of bone infections. These nanoantimicrobials can be designed to have controlled and sustained drug release kinetics, surface-modifications for bone or bacteria targeting, and increased affinity for biofilms. Given the potential value of nanoantimicrobials, clinical application of nanoantimicrobials for bone infection treatment remains scant when compared with the number of ongoing research. It is, therefore, a good time to carefully examine this promising yet relatively uncharted area. This review will extensively discuss the development and state of the art of different classes of nanoantimicrobials for bone infections with emphasis on the treatment aspect and identify the factors that prevent the clinical translation of nanoantimicrobial therapy from bench to bedside.

Antioxidants are among the most important cosmeceuticals, with proven ability of inhibiting cellular damage. The topical skin administration of antioxidants is essential for minimizing skin aging and achieving better skin protection against harmful free radicals. However, their unfavorable physiochemical properties such as chemical instability, excessive hydrophilicity or lipophilicity and others could be a great obstacle against their skin promising effects as well as their delivery to deeper skin layers. These problems could all be remedied through the use of delivery carriers. The present review discusses the various delivery carriers which were proven successful in improving the beneficial effects of antioxidants against skin aging, namely different vesicular systems, lipidic systems, polymeric systems and carbon nanotubes, and their applications in topical antioxidant delivery.

Background: For the narrow therapeutic index anti-epileptic drugs, monitoring of plasma concentration is a necessity for avoiding complications related to fluctuation of plasma level. Objective: The work was aimed at extracting gabapentin by transdermal reverse iontophoresis to investigate its feasibility for noninvasive therapeutic drug monitoring. Methods: Gabapentin was delivered in phosphate buffer (pH 7.4) at a therapeutic concentration range of 2-10 μg/ml. The same media was also used in receiver compartment. Extractions were carried out under an electric field of 5 V (current intensity range 0.3 -0.5 mA/cm2), provided by a custom-made power source for a period of 4 h. Samples were withdrawn at hourly intervals and drug content was analyzed by HPLC. Results: Results indicated that gabapentin extraction occurred at both anode and cathode with cathodal extractions showing higher value at all concentrations. Extraction rates at both the chambers were affected by time, the first hour extraction was notably higher than the later hours. Highest extraction rate was noted at pH 5. Surprisingly, anodal extraction was found to show greater positive correlation with current intensity compared to cathodal extraction. Conclusions: As gabapentin carried no net charge at pH 7.4, orientation mediated electromigration was suggested to be the cause.

Objective: Gadolinium diethylenetriaminepentaacetic di[5-(4'-amidophenyl)-10,15,20- tris(4'-sulfonatophenyl) porphyrin trisodium salt] (Gd-DTPA-2APTSPP) was synthesized by the reaction of diethylenetriaminepentaacetic dianhydride with 5-(4'-aminophenyl)-10,15,20-tris(4'-sulfonatophenyl) porphyrin and subsequently chelation with gadolium chloride. Methods: This gadolinium complex was characterized and its properties in vitro and in vivo were also evaluated. Compared with Gd-DTPA, Gd-DTPA-2APTSPP possessed high relaxivity r1, low cytotoxicity to HeLa cells and high enhanced signal intensities of the VX2 carcinoma in rabbits for a prolonged time. Conclusion: Moreover, Gd-DTPA-2APTSPP can distinguish the VX2 carcinoma from the reactive hyperplasia incited by inflammation and normal tissues in rabbits. Therefore, Gd-DTPA-2APTSPP can be taken up selectively by tumors and show the potential as a tumor-targeting MRI contrast agent.

Background: Topotecan (TPT) is a water-soluble derivate of camptothecin, which undergoes ring-opening hydrolysis in neutral solutions, leading to stability loss and poor cellular uptake. Lipid nanoencapsulation can improve TPT stability, and polymer-lipid hybrid nanoparticles (PLN) are interesting alternatives to improve TPT nanoencapsulation. Objective: This study seeks to prepare complexes between the cationic TPT and the negatively charged dextran sulfate (DS) with a view of improving drug loading, chemical stability and release control. Methods: The optimum ionic molar ratio in DS-TPT complexation was determined, and the selected complex was characterized by FTIR and solid-state 13C NMR. TPT solubility in the free and complexed forms was also assayed. TPT-PLN was then obtained via a microemulsion technique, and particle size, zeta potential, encapsulation efficiency, drug loading and drug recovery were determined. Additionally, the TPT stability and in vitro release were determined from PLN and compared with free TPT, TPT-DS complex and TPT encapsulated in nanostructured lipid carriers (NLC) of similar composition. Results: TPT-DS complexation was confirmed by FTIR and NMR. TPT solubility in the complex was drastically decreased when compared to free TPT. TPT-PLN had high encapsulation efficiency (97%) and drug loading capacity (5.5%). Additionally, TPT-PLN showed a mean diameter, polidispersivity index e zeta potential of 140 nm, 0.2 and -22 mV, respectively. The TPT chemical stability and release from PLN were observed to be superior when compared to NLC. Conclusion: PLN has shown to be a more effective nanosystem for TPT nanoencapsulation because TPT loading, stability and release were superior when compared to TPT-NLC.

Background: Biodegradable nanoparticles with diameters between 100 nm and 500 nm are of great interest in the contexts of targeted delivery. Objective: The present work provides a review concerning the effect of binary organic solvents together with emulsifier on particle size as well as the influence of particle size on the in vitro drug release and uptake behavior. Methods: The polymeric lipid nanoparticles (PLNs) with different particle sizes were prepared by using binary solvent dispersion method. Various formulation parameters such as binary organic solvent composition and emulsifier types were evaluated on the basis of their effects on particle size and size distribution. PLNs had a strong dependency on the surface tension, intrinsic viscosity and volatilization rate of binary organic solvents and the hydrophilicity/hydrophobicity of emulsifiers. Acetone-methanol system together with pluronic F68 as emulsifier was proved to obtain the smallest particle size. Then the PLNs with different particle sizes were used to investigate how particle size at nanoscale affects interacted with tumor cells. Results: As particle size got smaller, cellular uptake increased in tumor cells and PLNs with particle size of ~120 nm had the highest cellular uptake and fastest release rate. The paclitaxel (PTX)-loaded PLNs showed a size-dependent inhibition of tumor cell growth, which was commonly influenced by cellular uptake and PTX release. Conclusion: The PLNs would provide a useful means to further elucidate roles of particle size on delivery system of hydrophobic drugs.

Background: The aim of this paper is to evaluate a simple in vitro skin penetration experiment in which the drug is extracted from the whole skin piece as a test valid for formulation screening and optimization during development process, equivalence assessment during quality control or postapproval after changes to the product. Methods: Twelve clobetasol propionate (CP) formulations (six creams and six ointments, being five generics and one reference from each formulation type) from the local market were used as a model to challenge the evaluated methodology in comparison to in vitro skin penetration following tape-stripping for drug extraction. To support the results, physicochemical tests for pH, viscosity, density and assay, as well as in vitro release were performed. Results: Both protocols, extracting the drug from the skin using the tape-stripping technique or extracting from the full skin were capable of differentiating CP formulations. Only one formulation did not present statistical difference from the reference drug product in penetration tests and only other two oitments presented equivalent release to the reference. The protocol is straightforward and reproducible. Conclusion: Results suggest the bioinequavalence of tested CP formulations reinforcing the necessity of such evaluations.

Objective: The aim of this study was to develop a novel W/O microemulsion for a natural extract of Wen-Luo-Tong (WLT) containing mainly icariin, hydroxysafflor yellow A (HSYA) and gallic acid to be applied to skin as a potential treatment for peripheral neuropathy. Methods: The oil phase was selected on the basis of affinity with the surfactant and co-surfactant. Pseudo-ternary diagrams were constructed to optimize microemulsions and finally stability studies were performed on the selected formulations. Droplet sizes were analyzed by using a zetasizer and were found to be within the desired range. Selected microemulsions with acceptable viscosities, containing 5%, 8% and 10% of water extract solution, were used for in vitro skin penetration studies using Franz diffusion cells and excised rat skin. New LC-MS/MS and UPLC-Q-TOF/MS methods were employed for quantitative and qualitative analysis. Results: The optimized formulation (ME-4) consisting of 10% (w/w) water extract solution, 60% isopropyl myristate, 30%(w/w) Smix: Propylene glycol (5:2) significantly increased the cumulative permeated amounts of HSYA, icariin and gallic acid compared with the water extract solution controls. Conclusion: This novel formulation also increased the number of components penetrating rat skin. Ten components were detected in the Franz cell receptor solution using a UPLC-Q-TOF/MS system after the application of formulation ME-4 for 24h on the skin in vitro. However, only one component was detected after applying the control. Therefore, the microemulsion ME-4 was selected for future in vivo pharmacodynamic studies.

Background: Apocynin has become a drug of choice in NADPH oxidase induced pathological conditions. Hyperoxaluria is one such pathological condition where NADPH oxidase is involved in eliciting renal injury. Objective: Recently apocynin has shown to reverse the transcriptome profile of the NADPH oxidaseassociated genes and reduced oxidative burden in hyperoxaluric animals. The poor solubility of this drug creates certain apprehensions about its bioavailability. PLGA (Poly Lactic co-Glycolic Acid) encapsulation of drug nanoparticles have showed to induce sustain release and henceforth enhance the efficiency and bioavailability of drugs. Therefore, the present study is aimed to envisage a novel approach of synthesizing apocynin doped PLGA nanoparticles. Methods: The PLGA nanoparticles (both unloaded and loaded) were prepared using solvent extraction method and analyzed for size and stability by Dynamic Light Scattering (DLS), TEM (transmission electron microscopy) and zeta potential. Furthermore, the drug release and encapsulation efficiency of the drug was calculated in vitro. Results: The nanoencapsulation formed was stable with desired size (217-259 nm) and posses a controlled drug release of 20%. Further this nanoencapsulation was explored for its potential to reduce hyperoxaluric manifestations in rats given ethylene glycol with ammonium chloride for 9 days. Conclusion: In comparison to free apocynin, it was found that nanoparticles containing apocynin showed moderately better results in vivo by maintaining serum urea and createnine levels. These nanoparticles can be used in diseases where a sustained release of apocynin is required.

Background: Amphotericin B (AmB), a polyene antibiotic used for the treatment of fungal and leishmanial infections is virtually insoluble in water and exhibits severe toxicity. AmB has been conjugated to various soluble polymers for improving its solubility and reducing its toxicity. Conjugating AmB to a polysorbate surfactant such as polyoxyethylene sorbitan monolaurate (Tween 20), was examined to improve its solubility and reduce its toxicity. Methods: AmB was coupled to Tween 20 via carbamate linkage at 15 and 30 wt% concentrations in high yield by activating the hydroxyl groups of the surfactant using p- nitrophenyl chloroformate. The conjugates were characterized by using 1H NMR, IR, UV and HPLC analysis and were examined for their toxicity, and anti-fungal and anti-leishmanial activities in vitro. Results: Tween-AmB conjugates were soluble to the extent of 10 mg/mL in water, showed improved critical micelle concentration in comparison with AmB, exhibited negligible hemolytic potential even at a concentration of 1000 μM and were not toxic against human embryonic kidney cell line (HEK293T) at similar concentrations. The conjugates showed potent anti-fungal activity against Candida albicans, Candida parapsilosis and Cryptococcus neoformans and anti-leishmanial activity against intramacrophage amastigotes of Leishmania donovani. Conclusions: Tween 20 is a surfactant approved by the US FDA as an additive in food and pharmaceutical preparations. Synthesis of drug conjugates with surfactants such as Tween-20 could open up new opportunities to improve the solubility of many drugs, reduce their toxicity and could possibly target the brain as polysorbates known to facilitate nanoparticulate systems to cross the blood-brain barrier.

Objective: A major challenge in targeting orally administered drugs to colon is their passage through the long gastrointestinal path comprising highly variant conditions in terms of pH, viscosity, gut motility and microbial flora. Approaches to pH controlled release and microbially triggered release have proved to be successful in achieving colon targeting only to a partial extent. Methods: In an attempt to improve targeting, both these approaches have been combined together with the approach of liquisolid technology which, hitherto, remains unexplored for colon targeting. The combination of these three approaches is being reported for the first time to achieve colon targeting along with a burst release of a Biopharmaceutical Classification System (BCS) Class IV drug at the target site. pH controlled polymer, Eudragit® S-100 was used to prevent the release of sulfasalazine in the gastric region while microbially triggered polymers, pectin and guar gum were used to ferry the system through the intestinal region. Results: Liquisolid formulation was designed to provide a burst release of sulfasalazine in colon on the digestion of polysaccharide coating. Conclusion: The results support the premise that the combination of pH sensitive, microbially triggered polymers and liquisolid formulation technique appears to be a pragmatic approach for colonic delivery of orally administered drugs.

Objective: In this study, bovine serum albumin (BSA) nanoparticles coated with polysorbate- 80 (PS-80) and containing amphotericin B (AmB) were developed using a coacervation method. Methods: The nanoparticles were spherical, had a uniform size distribution (polydispersity < 0.25), a small mean size (185 ± 5 nm), a high zeta potential (-38.0 ± 0.7 mV), and a high AmB encapsulation efficiency (93 ± 1%). The AmB release profile was prolonged and diffusion-controlled, resulting in a low degree of AmB aggregation in solution. The physicochemical characteristics of these AmB containing nanoparticles were evaluated by X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, and derivative thermogravimetry and showed that the nanoencapsulation process lead to AmB amorphization while maintaining its chemical integrity. Results: In a hemolysis assay, AmB-loaded PS-80-coated BSA nanoparticles demonstrated an absence of cytotoxicity toward erythrocytes, whereas pure and commercial AmB were highly hemolytic. Conclusion: In an assay to assess antifungal activity against Cryptococcus neoformans, AmB-charged PS-80-coated BSA nanoparticles were effective, however, due to the prolonged AmB release from the nanoparticles, the MIC was higher than for pure or commercial AmB. PS-80-coated BSA nanoparticles are potential carriers for the delivery of AmB for the treatment of Cryptococcus sp infections.

Background: PnPP-19 is a 19-amino-acid synthetic peptide previously described as a novel drug for the treatment of erectile dysfunction. Objective: The aim of this work was to evaluate the physicochemical properties of cationic transfersomes containing PnPP-19 and the skin permeation of free PnPP-19 and PnPP-19-loaded transfersomes. Methods: Three different liposomal preparation methods were evaluated. Cationic transfersomes contained egg phosphatidyl choline: stearylamine (9:1 w/w) and Tween 20 (84.6:15.4 lipid:Tween, w/w). Lipid concentration varied from 20 to 40 mM. We evaluated the entrapment percentage, mean diameter, zeta potential and stability at 4 °C of the formulations. The skin permeation assays were performed with abdominal human skin using Franz diffusion cell with 3 cm2 diffusion area at 32 °C and a fluorescent derivative of the peptide, containing 5-TAMRA, bound to PnPP-19 C-terminal region, where an extra lysine was inserted. Results: Our results showed variable entrapment efficiencies, from 6% to 30%, depending on the preparation method and the lipid concentration used. The reverse phase evaporation method using a total lipid concentration equal to 40 mM led to the best entrapment percentage (30.2 + 4.5%). Free PnPP-19 was able to permeate skin at a rate of 10.8 ng/cm2/h. However, PnPP-19 was specifically hydrolyzed by skin proteases, generating a fragment of 15 amino acid residues. Encapsulated PnPP-19 permeated the skin at a rate of 19.8 ng/cm2/h. Conclusion: The encapsulation of PnPP-19 in cationic transfersomes protected the peptide from degradation, favoring its topical administration.

Objective: The aim of this study was to develop new Rosuvastatin calcium (RCa) self nanoemulsifying drug delivery system (SNEDDS) and to evaluate the bioavailability and pharmacodynamic effect of RCa-SNEDDS in Yorkshire pigs. Methods: Firstly, SNEDDS was developed and prepared then RCa was incorporated into SNEDDS which was evaluated regarding their characterization, stability properties, drug release profiles, permeation and cytotoxicity studies. Finally, in vivo performance of RCa-SNEDDS (F1-RCa-SNEDDS) was examined by pharmacokinetic and pharmacodynamics studies. The average droplet size of RCa- SNEDDS ranged between 200 and 250 nm. RCa-SNEDDS that contained 12.8% Oleic acid, 11 % Labrafil M, 3.3 % Labrasol and 4.4 % Transcutol HP were found to be stable and exhibited approximately 4-fold higher permeation than commercial tablet (Crestor® 20 mg tablet). Results: In pharmacokinetic studies, when F1-RCa-SNEDDS and commercial tablet were administered orally, F1-RCa-SNEDDS showed higher bioavailability of RCa than commercial tablet. Respectively, in pharmacodynamic studies, triglyceride and total cholesterol levels were significantly reduced with F1- RCa-SNEDDS formulation by 37% and 19% when compared to baseline values. Conclusion: However, these decreases with commercial formulation were only 6% and 2% respectively. According to these findings, development formulation could be potentially used to enhance the oral absorption of RCa.