Alejandro Sosnik

New old challenges in tuberculosis: potentially effective nanotechnologies in drug delivery.

Tuberculosis (TB) is the second most deadly infectious disease. Despite potentially curative pharmacotherapies being available for over 50 years, the length of the treatment and the pill burden can hamper patient lifestyle. Thus, low compliance and adherence to administration schedules remain the main reasons for therapeutic failure and contribute to the development of multi-drug-resistant (MDR) strains. Pediatric patients constitute a high risk population. Most of the first-line drugs are not commercially available in pediatric form. The design of novel antibiotics attempts to overcome drug resistance, to shorten the treatment course and to reduce drug interactions with antiretroviral therapies. On the other hand, the existing anti-TB drugs are still effective. Overcoming technological drawbacks of these therapeutic agents as well as improving the effectiveness of the drug by targeting the infection reservoirs remains the central aims of Pharmaceutical Technology. In this framework, nanotechnologies appear as one of the most promising approaches for the development of more effective and compliant medicines. The present review thoroughly overviews the state-of-the-art in the development of nano-based drug delivery systems for encapsulation and release of anti-TB drugs and discusses the challenges that are faced in the development of a more effective, compliant and also affordable TB pharmacotherapy.

Improved reverse thermo-responsive polymeric systems

Novel reverse thermo-responsive (RTG) polymeric systems displaying superior rheological properties were generated by polymerization of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) segments. Two basic synthetic pathways were followed: (1) The bulk polymerization of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock (Pluronic(RTM) F127) (MW=12,600, 70wt% PEO) with hexamethylene diisocyanate (HDI) and (2) The covalent binding of poly(ethylene glycol) and poly(propylene glycol) chains, using phosgene as the connecting molecule. While in the former, the basic amphiphilic F127 repeating unit is known for its own RTG behavior, the latter polymers consist of segments unable of exhibiting reverse thermal gelation of their own. These new materials achieved viscosities at least 15 times higher than F127, at 37 degrees C. Dynamic light scattering measurements revealed that the microstructures formed by these novel polymers were markedly larger than those generated by PEO-PPO-PEO triblocks. While the size of Pluronic F127 micelles ranged from 15 to 20nm, the higher molecular weight amphiphiles generated much larger nanostructures (20-400nm). Finally, the ability of reverse thermo-sensitive gels to perform as drug delivery systems was exemplified by releasing an anti-restenosis model drug (RG-13577). A 30% P[F127](4) gel delivered the drug over 40 days, whereas a F127 gel having the same concentration released the drug over a 7 days period.

Efavirenz-loaded polymeric micelles for pediatric anti-HIV pharmacotherapy with significantly higher oral bioavailability

UNLABELLED Children constitute the most challenging population in anti-HIV/AIDS pharmacotherapy. Efavirenz (EFV; aqueous solubility 4 microg/ml, bioavailability 40-45%) is a first-line agent in the pediatric therapeutic cocktail. The liquid formulation of EFV is not available worldwide, preventing appropriate dose adjustment and more convenient administration. The bioavailability of liquid EFV is lower than that of the solid formulation. Improving the bioavailability of the drug would reduce the cost of treatment and enable less affluent patients to access this drug. AIM To encapsulate EFV in polymeric micelles to improve the aqueous solubility and the the oral bioavailability of the drug. METHODS EFV was incorporated into the core of linear and branched poly(ethylene oxide)-poly(propylene oxide) block copolymer micelles. The size and size distribution of the drug-loaded aggregates were characterized by dynamic light scattering and the morphology by transmission electron microscopy. The bioavailability of the EFV-loaded micellar system (20 mg/ml) was assessed in male Wistar rats (40 mg/kg) and compared to that of a suspension prepared with the content of EFV capsules in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in a medium-chain triglyceride (Miglyol 812). RESULTS This work demonstrates that the encapsulation of EFV, which is poorly water soluble, into polymeric micelles of different poly(ethylene oxide)-poly(propylene oxide) block copolymers significantly improves the oral bioavailability of the drug, and reduces the interindividual variability. CONCLUSION This strategy appears a very promising one towards the development of a liquid aqueous EFV formulation for the improved pediatric HIV pharmacotherapy.

Drug delivery systems in HIV pharmacotherapy: what has been done and the challenges standing ahead.

Worldwide, over 40 million people are infected with the Human Immunodeficiency Virus (HIV). The High Activity Antiretroviral Therapy (HAART) combines at least three antiretroviral (ARV) drugs and, for over a decade, has been used to extend the lifespan of the HIV-infected patients. Chronic intake of HAART is mandatory to control HIV infection. The frequent administration of several drugs in relatively high doses is a main cause of patient incompliance and a hurdle toward the fulfillment of the pharmacotherapy. High adherence to HAART does not lead to complete HIV virus elimination from the host. Intracellular and anatomical viral reservoirs are responsible for the perpetuation of the infection. Active transport mechanisms involving proteins of the ATP-binding cassette superfamily prevent the penetration of ARV drugs into the brain and may account for the limited bioavailability after oral administration. A new research that addresses from simple organoleptic or technological problems to more complex issues involving the targeting of specific tissues and organs has emerged. With the aim to reduce dosing frequency, to improve the compliance of the existing pharmacotherapy and to target viral reservoirs, the design of drug delivery systems (DDS) is becoming complementary to new drug discovery. Based on the common molecular features that characterize the different families of ARV drugs, the present review describes state-of-the-art ARV DDS and thoroughly discusses the challenges in the development of medicines with enhanced biopharmaceutical properties. In addition, a number of specific issues such as pediatric HAART, preventive pharmacotherapy and specific HIV-associated ethical issues are addressed in an integrative manner. Finally, the impact of such novel drug development on the Pharmaceutical Technology field is discussed.

Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers.

Spray-drying is a rapid, continuous, cost-effective, reproducible and scalable process for the production of dry powders from a fluid material by atomization through an atomizer into a hot drying gas medium, usually air. Often spray-drying is considered only a dehydration process, though it also can be used for the encapsulation of hydrophilic and hydrophobic active compounds within different carriers without substantial thermal degradation, even of heat-sensitive substances due to fast drying (seconds or milliseconds) and relatively short exposure time to heat. The solid particles obtained present relatively narrow size distribution at the submicron-to-micron scale. Generally, the yield% of spray-drying at laboratory scale with conventional spray-dryers is not optimal (20-70%) due to the loss of product in the walls of the drying chamber and the low capacity of the cyclone to separate fine particles (<2 μm). Aiming to overcome this crucial drawback in early development stages, new devices that enable the production of submicron particles with high yield, even for small sample amounts, have been introduced into the market. This review describes the most outstanding advantages and challenges of the spray-drying method for the production of pure drug particles and drug-loaded polymeric particles and discusses the potential of this technique and the more advanced equipment to pave the way toward reproducible and scalable processes that are critical to the bench-to-bedside translation of innovative pharmaceutical products.

Self-Associative Behavior and Drug-Solubilizing Ability of Poloxamine (Tetronic) Block Copolymers

The incidence of the structural features on the self-assembly of different poloxamines (the conventional sequential Tetronic 304, 901, 904, 908, 1107, 1301, and 1307; a reverse-sequential counterpart Tetronic 150R1; and a chemically modified derivative, N-methylated Tetronic 1107) was thoroughly studied in 10 mM HCl by means of pi-A isotherm, surface tension, and pyrene fluorescence measurements. The size and size distribution of the aggregates were investigated by dynamic and static light scattering, and the morphology was probed by transmission electron microscopy. The abilities of the different derivatives to solubilize the drug simvastatin were also evaluated. Poloxamines with both higher PO/EO ratio and molecular weight (T1301 and T150R1) led to micelles with larger and more hydrophobic cores, particularly adequate for hosting hydrophobic molecules and protecting the labile lactone form of simvastatin from hydrolysis. On the other hand, the hydroxy acid form of simvastatin interacted with the central ethylenediamine group under alkaline pH (T304) or when a permanent positive charge due to methylation was present. Micelles of long poloxamine molecules containing large PPO blocks (with 23-29 units, namely, T1301, T1307, and T150R1), particularly the one that also has long PEO blocks, were the most physically stable toward dilution.

Nanotechnology and pulmonary delivery to overcome resistance in infectious diseases

Abstract Used since ancient times especially for the local treatment of pulmonary diseases, lungs and airways are a versatile target route for the administration of both local and systemic drugs. Despite the existence of different platforms and devices for the pulmonary administration of drugs, only a few formulations are marketed, partly due to physiological and technological limitations. Respiratory infections represent a significant burden to health systems worldwide mainly due to intrahospital infections that more easily affect immune-compromised patients. Moreover, tuberculosis (TB) is an endemic infectious disease in many developing nations and it has resurged in the developed world associated with the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic. Currently, medicine faces the specter of antibiotic resistance. Besides the development of new anti-infectious drugs, the development of innovative and more efficient delivery systems for drugs that went off patent appears as a promising strategy pursued by the pharmaceutical industry to improve the therapeutic outcomes and to prolong the utilities of their intellectual property portfolio. In this context, nanotechnology-based drug delivery systems (nano-DDS) emerged as a promising approach to circumvent the limitations of conventional formulations and to treat drug resistance, opening the hypothesis for new developments in this area.

PEO-PPO Block Copolymers for Passive Micellar Targeting and Overcoming Multidrug Resistance in Cancer Therapy

Drug carriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles are attracting much attention owing to their unique beneficial features: i) core-shell structure capable to host hydrophobic drugs, raising the apparent solubility in aqueous medium; ii) size adequate for a preferential accumulation (passive targeting) within the tumor, exhibiting enhanced permeability and retention (EPR effect), and iii) unimers that modulate the activity of efflux pumps involved in multidrug resistance (MDR). This review focuses on amphiphilic poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers, namely the linear poloxamers (Pluronic® or Lutrol®) and the X-shaped poloxamines (Tetronic®), as components of polymeric micelles able to play these three roles. Specific facets of poloxamers have been highlighted some years ago, but recently their wide range of possibilities is beginning to be fully elucidated and understood. Poloxamines are new excipients in the cancer arena and the comparison of their performance with that of poloxamers may enable to identify aspects of their architecture relevant for the optimization of micellar carriers. Clinical trials in progress indicate that drug-loaded polymeric micelles are beneficial regarding efficiency, safety, and compliance of the treatment and quality of life of the patients. The fact that some copolymers are already approved for internal use and several chemotherapy agents will be off patent soon may help to bring the clinical use of poloxamer- or poloxamine-based micelles into a reality in the coming years.

Crosslinkable PEO-PPO-PEO-based reverse thermo-responsive gels as potentially injectable materials

This paper describes the functionalization and crosslinking of PluronicRTM derivatives in aqueous solution at 37° C. Pluronic dimethacrylate was obtained by reacting native PEO-PPO-PEO triblocks with methacryloyl chloride and then crosslinking them by free radical polymerization at 37° C, using a redox system. The resulting gel and its rheological behavior were characterized by different techniques. The swelling study of the crosslinked polymer was indicative of its reverse thermo-responsive behavior, as illustrated by the almost 800% water uptake of the polymer at 37° C, as opposed to the 1600% attained by the polymer at 25° C. As expected, while the Pluronic dimethacrylate gel displayed an E c value of 142.5 ± 29.7 kPa at 37° C, the crosslinked system attained a Youngs modulus three times higher: 415.2 ± 45.7 kPa. Finally, the environmental SEM analysis revealed the porous microstructure of the crosslinked gels.

N-alkylation of poloxamines modulates micellar assembly and encapsulation and release of the antiretroviral efavirenz

Poloxamines (X-shaped poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) diblocks connected to a central ethylenediamine group) were N-methylated and N-allylated with the aim of widening their versatility as drug nanocarriers. The self-aggregation properties of various derivatives, covering a wide range of molecular weights and EO/PO ratios, were thoroughly investigated. The cytocompatibility of different modified poloxamines was compared to that of the pristine counterparts by MTT and LDH assays. The most hydrophilic varieties were highly cytocompatible even at concentrations of 5%. Toward the optimization of the oral pharmacotherapy of the Human Immunodeficiency Virus (HIV) infection in pediatric patients, the encapsulation and in vitro delivery of efavirenz (EFV), a lipophilic first-line antiretroviral drug, were evaluated. Pristine and N-alkylated poloxamines behaved as highly efficient EFV solubilizers enhancing the aqueous solubility of the drug between 166 and 7426-times. EFV promotes self-micellization of poloxamines; their tiny structural modification (i.e., just one methyl- or allyl-group) being able to regulate drug/micellar core interaction. Despite the physical stability of the micelles against dilution in physiological mimicking fluids, the N-alkylated derivatives were slightly more prone to disassembly promoting EFV release from the micellar reservoir. For all the derivatives evaluated, the in vitro release fitted zero-order kinetics and was sustained for at least 24 h. These findings point out N-alkylated poloxamines as promising nanocarriers for oral or parenteral drug delivery.