Systemic Administration of Orexin a Loaded Liposomes Potentiates Nucleus Accumbens Shell Dopamine Release by Sucrose Feeding

Orexin neurons originate in the lateral and dorsomedial hypothalamus and perifornical area and produce two different neuropeptides: orexin A (OxA) and orexin B (OxB), which activate OxR1 and OxR2 receptors. In the lateral hypothalamus (LH) orexin neurons are involved in behavior motivated by natural rewards such as palatable food (sugar, high-fat food) and it has been demonstrated similarly that the orexin signaling in the ventral tegmental area (VTA) is implicated in the intake of high-fat food. The VTA is an important area involved in reward processing. Given the involvement of nucleus accumbens (NAc) shell dopamine (DA) in motivation for food, we intended to investigate the effect of OxA on the basal and feeding-activated DA transmission in the NAc shell. OxA is a large peptide and does not cross the blood–brain barrier and for this reason was loaded on two kinds of liposomes: anti-transferrin-monoclonal antibodies (OX26-mAb) and lactoferrin-modified stealth liposomes. The effect of IV administration of both OxA liposomes on NAc shell DA was studied by microdialysis in freely moving rats. OxA, administered using both kinds of liposomes, produced a delayed and transitory increase in dialysate DA in the NAc shell, strongly and lastingly potentiated the increase in dialysate DA elicited by sucrose pellet consumption and increased the number of eaten pellets. These effects of OxA on DA transmission and feeding were prevented by the OxR1 antagonist SB 334867. Hence, OxA acting on VTA OxR1 can facilitate sucrose-stimulated NAc shell DA transmission directly by increasing the basal activity of VTA DA neurons that send their projections to the NAc shell

Needle-Free Jet Injectors and Nanosuspensions: Exploring the Potential of an Unexpected Pair

Needle-free liquid jet injectors are medical devices used to administer pharmaceutical solutions through the skin. Jet injectors generate a high-speed stream of liquid medication that can puncture the skin and deliver the drug to the underlying tissues. In this work, we investigated the feasibility of using liquid jet injectors to administer nanosuspensions, assessing the impact of the jet injection on their pharmaceutical and physicochemical properties. For this purpose, the model drug diclofenac was used to prepare a set of nanosuspensions, stabilized by poloxamer 188, and equilibrated at different pHs. The hydrodynamic diameter and morphology of the nanocrystals were analyzed before and after the jet injection across porcine skin in vitro, together with the solubility and release kinetics of diclofenac in a simulated subcutaneous environment. The efficacy of the jet injection (i.e., the amount of drug delivered across the skin) was evaluated for the nanosuspension and for a solution, which was used as a control. Finally, the nanosuspension was administered to rats by jet injector, and the plasma profile of diclofenac was evaluated and compared to the one obtained by jet injecting a solution with an equal concentration. The nanosuspension features were maintained after the jet injection in vitro, suggesting that no structural changes occur upon high-speed impact with the skin. Accordingly, in vivo studies demonstrated the feasibility of jet injecting a nanosuspension, reaching relevant plasma concentration of the drug. Overall, needle-free jet injectors proved to be a suitable alternative to conventional syringes for the administration of nanosuspensions

Peptide-based nanosystems for Vascular Cell Adhesion Molecule-1 targeting: a real opportunity for therapeutic and diagnostic agents in inflammation associated disorders

Inflammation is a phenomenon strictly connected with serious human disorders such as cardiovascular, neurodegenerative, autoimmune diseases, and cancer. The incidence of these pathologies has increased over the past decades and consequently the inflammatory markers have gained more and more importance in the scientific world. Among them, Vascular Cell Adhesion Molecule-1 (VCAM-1) represents one of the most interesting, as it is easy accessible on the endothelium and is upregulated at the early stages of inflammatory processes. Different studies have shown the role of VCAM-1 in the development of atherosclerosis, cancer, Alzheimer's and Parkinson's diseases, paving the way to a growing interest in diagnostics and therapeutics targeting this protein. This review reports an up-to-date series of peptide-targeted nanosystems specific for VCAM-1, proposed for the diagnosis or therapeutic treatment of different inflammatory-based pathologies. The listed approaches are described underlying the chemical aspects, the detection techniques and the in vitro and in vivo models employed. Numerous strategies have been pursued with peptide-based methods, i.e. liposomes, micelles, nanoparticles, microbubbles, quantum dots and just radiolabeled peptides. On the basis of the shown evidences, so far mainly gathered on animal models, the potential utility of VCAM-1 comes powerfully to light, suggesting in a near future a broader application of these specific nanosystems in clinical trials

Nanocrystals as effective delivery systems of poorly water soluble natural molecules

Natural products are an important source of therapeutically effective compounds throughout the world. Since ancient times, a huge amount of both plant extracts and isolated compounds have been largely employed in treatment and prevention of human disorders and, currently, more than 60% of the world’s population trusts on plant medicaments as demonstrated by the increasing quantity of herbal therapeutics in the market. Unfortunately, several promising natural molecules for the treatment of the most diverse ailments are characterized by extremely unfavourable features, such as low water solubility and poor/irregular bioavailability, which hinder their clinical use. To overcome these limitations and to make herbal therapy more effective, different formulative approaches have been employed. Among the different strategies for increasing drug solubility, nanocrystals can be considered one of the most interesting and successful approaches. Drug nanocrystals are nanosized drug particles usually formulated as nanosuspensions, namely submicron dispersions in liquid media where surfactants, polymers, or a mixture of both act as stabilisers. In this review, we described the most significant results and progresses concerning drug nanocrystal formulations for the delivery of natural compounds with a significant pharmacological activity. The text is organized in nine sections, each focusing on a specific poorly water- soluble natural compound (apigenin, quercetin, rutin, curcumin, baicalin and baicalein, hesperetin and hesperidin, resveratrol, lutein, silybin). To foster the clinical translation of these natural nanomedicines, our opinion is that future research should pair the essential pharmacokinetic studies with carefully designed pre-clinical experiments, able to prove the formulation efficacy in relevant animal models in vivo

Dermatitis in community pharmacies: a survey on italian pharmacists’ management and implications on corticophobia

Community pharmacists represent an important resource for the promotion of a safer and more effective self-management of common skin diseases, as well as the provision of educational support on therapies prescribed by clinicians, ultimately improving patients’ adherence. In this study, a semi-structured survey was administered to 154 Italian community pharmacists, in order to acquire information on their counseling activity on dermatological disorders. Collected data provide an overview on the frequency and methodology of counseling offered in Italian community pharmacies, identifying knowledge gaps and misbeliefs. In particular, an overall negative opinion on topical corticosteroid therapy emerged among pharmacists, unveiling a phenomenon previously described as corticophobia. Starting from this observation, we discuss the risks for patients’ adherence, associated with corticophobia among pharmacists. Lastly, we briefly report on the main tools desired by pharmacists to improve their education on dermatology, envisioning their implementation with the aim of a more effective counseling

Drug-Excipients Compatibility Studies in Proniosomal Formulation: A Case Study with Resveratrol

: Proniosomal drug delivery system is one of the advancements in nanotechnology. Similarly to traditional dosage forms, chemical and physical compatibility of proniosomes components with the active ingredient(s) is a key step in the preformulation process of such systems. In this work, the compatibility of resveratrol with selected excipients in the development of proniosomal formulation was investigated by thermal and spectroscopic techniques. To evaluate the drug-excipient compatibility, different techniques such as differential scanning calorimetric study, attenuated total reflectance Fourier transform infrared spectroscopy study and powder X-ray diffraction were adopted. The results showed that the excipients used in the formulation were compatible with resveratrol

3-Hydroxycoumarin loaded vesicles for recombinant human tyrosinase inhibition in topical applications

Tyrosinase is one of the key enzymes in mammalian melanin biosynthesis. Decreasing tyrosinase activity has been targeted for the prevention of conditions related to the hyperpigmentation of the skin, such as melasma and age spots. This paper is devoted to the engineering of vesicle formulations loaded with 3-hydroxycoumarin for topical pharmaceutical applications. At first, it was demonstrated the strong inhibiting ability of 3-hydroxycoumarin against recombinant human tyrosinase. Then, such a drug was effectively encapsulated within liquid or gel-like vesicle formulations, both based on monoolein and lauroylcholine chloride. In vitro skin penetration and permeation studies proved these formulations efficiently overcome the barrier represented by the stratum corneum, delivering 3-hydroxycoumarin to the deeper skin layers. The effect of applying for different times the liquid and the gel formulation was also evaluated. Results revealed that application of the gel formulation for 2 h favored the drug accumulation into the skin with low transdermal delivery, thus indicating this combination of administration time and formulation as ideal to locally inhibit tyrosinase activity with minimal systemic absorption. Moreover, when incubated with B16F10 melanoma cells, the liquid vesicle formulations did not show cytotoxic activity

Production of nanosuspensions as a tool to improve drug bioavailability: focus on topical delivery

Over the past two decades nanosizing technology has become one of the most successful formulation approaches for improving the bioavailability of poorly soluble drugs, which show a low oral absorption due to low dissolution velocity. Nanocrystals are nanoparticles of pure drug, without any matrix material, with an average diameter below 1 μm (typically in the range of 200-500 nm), which can be prepared in both water and non-water media as colloidal nanosuspensions stabilized using surfactants or polymers. The reduction of the drug particle diameter below 1 μm increases the dissolution velocity by increasing the particle surface and decreasing the diffusion layer thickness. Nanosuspension production processes involve two different approaches such as bottom-up (drug nanocrystal precipitation) and top-down (drug particle disintegration) technologies or a combination of two. Within these main approaches, a variety of possible techniques to achieve particle size reduction have been proposed by different research groups from both industry and academia. Even though nanosuspensions formulations have been especially studied for oral and parenteral administration, nanocrystals have showed a great potential also for topical delivery through alternative routes such as dermal, pulmonary and ocular route. The purpose of this review is to describe the main technologies used to produce nanosuspensions as well as to explore the most significant results and progresses obtained by application of drug nanocrystal formulations through topical routes