Current Pharmaceutical Design - Volume 19, Issue 41, 2013

In the area of drug delivery, novel tools and technological approaches have captured the attention of researchers in order to improve the performance of conventional therapeutics and patient compliance to pharmacological therapy. Stimuli-responsive drug delivery systems (DDS) appear as a promising approach to control and target drug delivery. When these DDS are administered, the drug release is activated and then modulated through some action or external input and facilitated by the energy supplied externally. The stimuli responsible to activate the drug release can be classified into three types according to their nature or the type of energy applied: physical (e.g. magnetic field, electric field, ultrasound, temperature and osmotic pressure); chemical (e.g. pH, ionic strength and glucose); and biological (enzymes and endogenous receptors). The present review gives an overview of the most significant physical and chemical stimuliresponsive DDS and elucidates about their current and relevant applications in controlled and targeted drug delivery attending different routes of administration.

Currently Alzheimer's disease and schizophrenia are both well-established neuropsychiatric diseases. Nonetheless, the treatment of these disorders is not unanimous and fully effective. As a consequence, several approaches have been studied to improve patient’s conditions. In this context, the development of new drug nanodelivery systems to increase drug bioavailability and reduce adverse effects has been claimed as a good option. Among these systems we focus on the ones that seem to be most promising, such as lipidbased systems (e.g. liposomes, nanoemulsions and lipid nanoparticles), drug nanocrystals, polymeric nanoparticles and micelles. Moreover, the application of these systems by means of alternative administration routes is also discussed. Regardless of the satisfactory results and the associated progresses that have been done in the last years, more studies are required to quickly licence the application of drug nanodelivery systems in human medicines.

A methotrexate (MTX)-loaded layered double hydroxide (LDH) nanoparticle system was synthesized by intercalating MTX into the interlayer spaces of LDH. In vivo pharmacokinetic study demonstrated that the MTX-LDH hybrid had similar kinetic behaviors as free MTX, showing a rapid decline in the plasma MTX level, with characteristics of a biexponential function. However, the hybrid system remarkably suppressed tumor growth in human osteosarcoma-bearing mice compared to an equivalent amount of free MTX. Using MTX-LDH nanoparticles, a significantly high amount of MTX was delivered to target tumor tissue, whereas a low level was found in normal tissues. Moreover, LDH nanocarriers did not accumulate in any specific tissue nor cause acute toxicity up to the applied dose for the hybrid system. These results suggest that the MTX-LDH nanohybrid system has great potential as an anti-cancer drug with enhanced in vivo anti-tumor activity and bioavailability in target tumor tissue along with reduced side effects.

Nanogels are nanosized hydrogel particles formed by physical or chemical cross-linked polymer networks. The advantageous properties of nanogels related to the ability of retaining considerable amount of water, the biocompatibility of the polymers used, the ability to encapsulate and protect a large quantity of payload drugs within the nanogel matrix, the high stability in aqueous media, their stimuli responsively behavior potential, and the versatility in release drugs in a controlled manner make them very attractive for use in the area of drug delivery. The materials used for the preparation of nanogels ranged from natural polymers like ovalbumin, pullulan, hyaluronic acid, methacrylated chondroitin sulfate and chitosan, to synthetic polymers like poly (N-isopropylacrylamide), poly (Nisopropylacrylamide- co-acrylic acid) and poly (ethylene glycol)-b-poly (methacrylic acid). The porous nanogels have been finding application as anti-cancer drug and imaging agent reservoirs. Smart nanogels responding to external stimuli such as temperature, pH etc can be designed for diverse therapeutic and diagnostic applications. The nanogels have also been surface functionalized with specific ligands aiding in targeted drug delivery. This review focus on stimuli-sensitive, multi-responsive, magnetic and targeted nanogels providing a brief insight on the application of nanogels in cancer drug delivery and imaging in detail.

Pharmaceutical technology has introduced a promising pathway in the future of medicine in particular nanotechnological innovations have provided the opportunity to design and develop efficient drug delivery systems able to target and treat several diseases, including those mediated by inflammation. The engineering of drug delivery systems can be used to target tissues involved in the pathology under treatment, to avoid early drug biological environmental degradation and to modulate drug pharmacokinetics. Glucocorticoids and non-steroidal anti-inflammatory drugs are the most commonly prescribed drug categories worldwide for the treatment of disorders associated with inflammation. Although glucocorticoids can be highly effective in treating inflammation, their systemic application is limited due to the high incidence of serious adverse effects, mainly in long-term treatment. Non-steroidal anti-inflammatory drugs are a heterogeneous group of compounds and most of them have unfavorable pharmacokinetics and pharmacodynamics, leading to adverse effects, such as gastrointestinal disorders. Therefore, the need for drug delivery systems for long term administration of anti-inflammatory drugs with a well-controlled release profile is evident. The aim of this review is to assess innovative colloidal drugs carriers, in particular liposomes and nanoparticles, with special focus on site-specific delivery for particularly problematic tissues such as the gastrointestinal tract, joints and eyes.

Complications related to infectious diseases have significantly reduced, specially in the developed countries, due to the availability and use of a wide variety of antibiotics and antimicrobial agents, however, anti-infective therapy is still not considered to be optimal. Excessive use of antibiotics and antimicrobial agents increased the number of drug resistant pathogens, leading to urgent need for advanced therapeutic strategies. Nanotechnology and nanomedicine provide platform for advanced therapeutic strategies of various infectious diseases, as nanomedicine, due to small size and targeted designed nano sized particles, permit passage through many previously impermeable biological membranes, often resulting in targeted delivery of antimicrobials. In particular, specific properties of nanomaterials and nanodelivery systems enable their closer and more efficient interactions with pathogen membranes and cell walls. The focus of this review is on the strategies and benefits related to using nanotechnology and nanomedicine in the topical therapy of skin infectious diseases. Current status and future prospects of most promising nanodelivery systems for antibiotics and antimicrobials delivery are discussed, and issues related to potential toxicity of such systems are addressed.

Arguably one of the greatest medical advancements in the 20th Century was the discovery of insulin. Physiologically, insulin is a potent hypoglycaemic agent, which is vital in order for plasma glucose levels to be maintained within the normal range of 4- 7mmol/L. Various attempts have been made in the production, purification, formulation and methods of delivery of insulin. Despite alternative routes being investigated, these routes have met with limited success. Although the pulmonary route offers potential for the delivery of polypeptide drugs due to its large surface area for insulin absorption, it has low bioavailability. Microencapsulation and nanoencapsulation exhibit potential progress in insulin delivery although delivery is at an early stage. In this Review, we discuss the structure of insulin and the physiological importance in addition to the injectable and non-injectable methods used. The currently available insulin therapies are presented and the clinical importance of such therapies.

Polymeric microparticles containing the calcium channel blocker nimodipine were successfully obtained through simple emulsion/ organic solvent evaporating method. The extended release formulations, composed by the polymers poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV) and polycaprolactone (PCL), were submitted to characterization through X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), Fourier transform infrared analysis (FT-IR) and determination of the mean particle diameter. All formulations obtained revealed an amorphous characteristic, proven through XRPD and DSC results. Besides, no chemical interaction was observed between drug and polymer in polymeric microparticles. PHBV-NMP formulation showed a higher drug entrapment, a larger particle size, a thermal degradation behavior similar to that observed for nimodipine and a longer drug release time, being selected for in vivo evaluation. The PHBV-NMP polymeric microparticles were able to keep the pharmacological antihypertensive effect for a longer period of time, becoming a good alternative to control nimodipine release in hypertension treatment.

Chronic pain is usually treated with pharmacological measures using opioids alone or in combination with adjuvant analgesics that play an important role in the treatment of pain not fully responsive to opioids administered alone, especially in neuropathic, bone and visceral colicky pain. The important part of the chronic pain treatment is the appropriate use of non-pharmacological measures along with psychosocial and spiritual support. Opioids may be administered by different routes; the most common and most convenient for majority of treated patients are oral and transdermal. However, in certain circumstances such as inability to swallow, lack of analgesic efficacy and intractable opioid-induced adverse effects parenteral routes (subcutaneous, intravenous) might be more useful. When these routes fail, in some patients intrathecal administration of opioids is required. Recently, more patients have been treated with short-acting opioids for breakthrough pain with sublingual, buccal and intranasal routes of opioid administration that may provide efficacy superior to oral and comparable to intravenous routes. Alternative routes comprise rectal, inhaled and topical administration of opioids. This article discusses various routes of opioid administration.

In nanomedicine, different nanomaterials and nanoparticles have been proposed as therapeutic agents or adjuvants, as well as diagnosis devices. Considering that the principal cause of the ulcerations is the imbalance among the gastric juice secretion and the protection provided by the mucosal barrier and the neutralization of the gastric acid, as well as that nanoparticles are able to accumulate in the gastro-intestinal tissues, we proposed a 2² factorial design to evaluate the influence of the chemical composition and the volume fraction of the dispersed phase on the gastric protective effect against ulceration induced by ethanol. Cocoa-theospheres (CT) and lipid-core nanocapsules (LNC) (two different kinds of surfaces: lipid and polymeric, respectively) prepared at two different concentrations of soft materials: 4% and 12% (w/v) were produced by high pressure homogenization and solvent displacement methods, respectively. Laser diffraction showed volume-weighted mean diameters ranging from 133 to 207 nm, number median diameters lower than 100 nm and specific surfaces between 41.2 and 51.2 m² g^-1. The formulations had pH ranging from 4.7 to 6.3; and zeta potential close to -9 mV due to their coating with polysorbate 80. The ulcer indexes were 0.40 (LNC⁴) and 0.48 (CT⁴) for the lower total administered areas (3.3 and 4.1 m² g^-1, respectively), and 0.09 (LNC¹² and CT¹²) for the higher administered areas (10.0 and 12.0 m² g^-1, respectively). LNC⁴, LNC¹² and CT¹² showed lower levels in the lipid peroxidation assay when compared either to the negative control (saline) or to CT⁴. LNC¹² and CT¹² showed similar TBARS levels, as well as CT⁴ was similar to the negative control. SEM analysis of the stomach mucosa showed coatings more homogenous and cohesive when LNC formulations were administered compared to the correspondent CT formulations. The higher total area of administered nanoparticles showed film formation. Moreover, LNC¹² provided a more thick and cohesive film, completely covering the mucosal surface. In conclusion, both kinds of formulations are able to prevent ulceration induced by ethanol in rats. The 2² factorial design showed that the chemical composition had a strong influence when the lower areas of nanoparticles are administered, while when the higher areas are used this is the more influencing parameter on the gastroprotection.

Topical administration is attractive and non-invasive gene delivery approach. It is simple and allows repeated administration. In addition, the skin is active immune surveillance site. Topical gene therapy, although promising for treatment of cancer, dermatological disorders, vaccination and autoimmune disease, has not progressed yet to clinical trials. The inability of nucleic acids to survive the extraand intracellular environment and to permeate through the outermost layer of the skin, the stratum corneum, compromise the therapeutic outcomes of nucleic acids-based therapies. Nanostructured vehicles (e.g. transfersomes, niosomes, nanoemulsions, gemini-lipid nanoparticles and biphasic vesicles) have the ability to partially disrupt and perturb lipids that are found in the skin layers and deliver their nucleic acid cargos to their targeted subcellular compartments. However, the efficiency of these carriers is still inferior to other invasive methods (e.g. epidermal and intradermal injections). The goal of this review is to examine the critical parameters required to enhance the efficiency of the currently available nanostructured vehicles, for example, by combining them with minimally invasive techniques, such as, electroporation, iontophoresis, microneedles, ultrasound, gene gun and femtosecond laser. The recent advances in engineering these nanovectors will be discussed with a focus on their future prospects.

Neglected diseases are prevalent in less developed countries and are associated with high levels of mortality and/or morbidity. The drugs used in clinical practice are toxic, reducing patient compliance, and generally do not result in a cure, and there has also been a surge in drug resistance. Additionally, a major challenge in drug treatment lies in reaching the intracellular sites infected by parasites. The development of nanotechnology-based drug delivery systems for drugs intended to treat neglected diseases is a promising avenue because the use of nanocarriers presents the ability to target drugs to the infected cells, and the prolonged drug release profile possible with these systems permits longer contact between the drug and the parasite. This review describes the roles of colloidal drug carriers, such as liposomes, polymeric nanoparticles and solid lipid nanoparticles, in research on optimizing the delivery of antileishmanial, antitrypanosomal, antichagasic and antimalarial agents.