Current Drug Delivery - Volume 17, Issue 4, 2020

Nanotechnology is currently a hot topic in dermatology and nutraceutical/cosmeceutical delivery, owing to the advantages it provides in terms of enhancing the skin permeation of drugs, as well as increasing their therapeutic efficacy in the treatment of different dermatological diseases. There is also a great interest in the topical delivery of nutraceuticals; which are natural compounds with both therapeutic and cosmetic benefits, in order to overcome the side effects of topically applied chemical drugs. Quercetin is a key nutraceutical with topical antioxidant and anti-inflammatory properties which was reported to be effective in the treatment of different dermatological diseases, however, its topical therapeutic activity is hindered by its poor skin penetration. This review highlights the topical applications of quercetin, and summarizes the nanocarrier-based solutions to its percutaneous delivery challenges.

The collection of different bulk materials forms the nanoparticles, where the properties of the nanoparticle are solely different from the individual components before being ensembled. Selfassembled nanoparticles are basically a group of complex functional units that are formed by gathering the individual bulk components of the system. It includes micelles, polymeric nanoparticle, carbon nanotubes, liposomes and niosomes, etc. This self-assembly has progressively heightened interest to control the final complex structure of the nanoparticle and its associated properties. The main challenge of formulating self-assembled nanoparticle is to improve the delivery system, bioavailability, enhance circulation time, confer molecular targeting, controlled release, protection of the incorporated drug from external environment and also serve as nanocarriers for macromolecules. Ultimately, these self-assembled nanoparticles facilitate to overcome the physiological barriers in vivo. Self-assembly is an equilibrium process where both individual and assembled components are subsisting in equilibrium. It is a bottom up approach in which molecules are assembled spontaneously, non-covalently into a stable and welldefined structure. There are different approaches that have been adopted in fabrication of self-assembled nanoparticles by the researchers. The current review is enriched with strategies for nanoparticle selfassembly, associated properties, and its application in therapy.

Background: Liposomes are mostly known to be prepared from phospholipids and lipids and have a remarkable capacity to encapsulate both lipophobic and lipophilic molecules. However, there is little research on developing fatty acid liposomes for chemotherapy. Objective: We have successfully prepared mixed fatty acid liposomes from two monounsaturated fatty acids, namely oleic acid and erucic acid, which stabilised by DOPEPEG2000. The Critical Vesicular Concentration (CVC) of liposomes was found to be within 0.09 to 0.21 mmol dm^-3, with an average particle size of 400 nm. Methods: Encapsulation of various anticancer drugs such as folinic acid, methotrexate, doxorubicin, or irinotecan resulted in Encapsulation Efficiency (%EE) of up to 90%. Using a 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the median Inhibitory Concentration (IC50) values of mixed oleic acid-erucic acid encapsulating hydrophilic drugs was remarkably reduced at the end of 24 hours of incubation with the human lung carcinoma cell line A549. Results: The results suggest that mixed oleic acid-erucic acid liposomes are a potential new approach to further develop as an alternative vehicle of various drugs for cancer treatment.

Aim: The work’s aim was the preparation and characterization of a hydrogel based on gelatin and glycerine, useful for site-specific release of benzydamine, an anti-inflammatory drug, able to attenuate the inflammatory process typical of the vaginal infection. Objective: The obtained hydrogel has been characterized by Electronic Scanning Microscopy (SEM) and Differential Scanning Calorimetry (DSC). In addition, due to the precursor properties, the hydrogel exhibits a relevant mucoadhesive activity. Methods: The swelling degree was evaluated at two different pHs and at defined time intervals. In particular, phosphate buffers were used at pH 6.6, in order to mimic the typical conditions of infectious diseases at the vaginal level, particularly for HIV-seropositive pregnant women, and pH 4.6, to simulate the physiological environment. Results: The obtained results revealed that the hydrogel swells up well at both pHs. Conclusion: Release studies conducted at both pathological and physiological pHs have shown that benzydamine is released at the level of the vaginal mucosa in a slow and gradual manner. These data support the hypothesis of the hydrogel use for the site-specific release of benzydamine in the vaginal mucosa.

Background: Recently we developed a scalable scheme of synthesis of melphalan ester conjugate with 1,2-dioleoyl-sn-glycerol (MlphDG) and a protocol for the fabrication of its lyophilized liposomal formulation. Objective: Herein we compared this new convenient in use formulation of MlphDG with parent drug Alkeran® in rats concerning several toxicological parameters and evaluated its antitumor efficacy in the model of breast cancer in mice. Method: Liposomes of approximately 100 nm in diameter, consisting of egg phosphatidylcholine, soybean phosphatidylinositol, and MlphDG, or placebo liposomes without the drug were produced by extrusion and lyophilized. Alkeran® or liposomes recovered by the addition of water were injected into the tail vein of animals. Clinical examination of rats consisted of detailed inspection of the behavior, general status, and hematological parameters. Mice with transplanted breast cancer WNT-1 were subjected to multiple treatments with the drugs; tumor growth inhibition was assessed, together with cellular immunity parameters. Results: Liposomes showed approximately two times lower acute toxicity and better tolerability than Alkeran® in terms of behavioral criteria. The toxic effects of liposomes on hemopoiesis were manifested at higher doses than in the case of Alkeran®, proportionally to the difference in LD50 values. The formulation inhibited tumor growth significantly more effectively than Alkeran®, delaying the start of the exponential growth phase and exhibiting no additional toxic effects toward bone marrow. Conclusion: Lower toxicity of the liposomal formulation of MlphDG promises improved quality of life for cancer patients in need of treatment with melphalan. Presumably, the list of indications for melphalan therapy could be extended.

Background: Adjuvants have been obtained empirically by trial and error experiments and today, there is a tendency to the rational design of adjuvants candidates, which will increasingly achieve effective and safe products. The aim of this work was to design and evaluate the compound IMR-23 derived from nitroimidazole as an immunomodulatory molecule. Materials and Methods: The IMR-23 molecule was obtained by a condensation reaction, cytotoxicity was tested by the sulforhodamine B assay. Adjuvanticity was evaluated in vivo and in vitro in J774A.1 cells and in the mouse model, respectively. Results: IMR-23 that did not show cytotoxicity on HeLa, Vero cells and macrophages J774A.1, was able to induce the production of molecules involved in the inflammatory process, such as cytokines and chemokines determined by ELISA, to induce the production of antibodies and to generate antigenspecific cells to ovalbumin and against the antigen GST-L1b. Conclusion: These results open the possibility of further studies to obtain a proper balance of immunogenicity- toxicity in the use of IMR-23 as an adjuvant molecule.

Background: Hydrogels are excellent drug carriers, but their inability to retain hydrophilic drugs for a prolonged period of time has greatly limited their usage. Research has mostly focused on intricate designs and manipulations of hydrogels to expand their applications in drug delivery. Objective: In this study, a simple approach by incorporating a hydrophobic agent, octadecyltrichlorosilane (OTS), to alginate hydrogel micro-granules (Alg-Ms), was investigated as an effective technique to prolong the release of small hydrophilic drugs. Methods: Sodium Benzoate (SB), a highly water-soluble antimicrobial and anti-inflammatory compound, was used as a model drug. The presence of hydrophobic OTS impeded swelling of these OTS incorporated Alg-Ms (OTS-Alg-Ms), hence sustaining the release of SB. Result: The release data was fitted with Ritger-Peppas and Peppas-Sahlin models and the results showed that SB released from OTS-Alg-Ms with higher OTS content was mainly controlled by Fickian diffusion; with a lower OTS content, OTS-Alg-Ms swelled more easily, the combined diffusion and swelling led to a faster SB release. Conclusion: Thus, by simply tuning the OTS concentration in the solution where Alg-Ms were briefly submerged in a predefined release period, from hours to a few days, small hydrophilic drugs from these OTS-Alg-Ms could be successfully achieved.

Background: Rifampicin is known to degrade at the acidic pH of the stomach, especially in the presence of isoniazid. Although isoniazid also degrades partially, its degradation is reversible. Objective: Presently, we provide a proof of the fact that the simultaneous oral administration of rifampicin (RIF), upon incorporation into solid lipid nanoparticles (RIF-SLNs), with isoniazid (INH) overcomes its INH-induced degradation and improves its oral bioavailability in rats. Methods: Solid lipid nanoparticles of RIF (RIF-SLNs) were prepared using a novel and patented method. The effect of INH was investigated on in vivo bioavailability of RIF both in its free and encapsulated (RIF-SLNs) form, after oral administration to rats. Results: Cmax and AUC0-∞ of RIF increased 158 % and 125 %, respectively, upon incorporation into SLNs versus free RIF when combined with INH. The Tmax decreased from 5.67 h to 3.3 h, and the plasma concentration of RIF remained above its MIC (8 μg/ml) at all the tested time points starting with 15 min, when administered as RIF-SLNs in combination with INH. Conclusion: The results confirm the scope of combining RIF-SLNs with INH to overcome the bioavailability of free RIF when combined with INH, especially in fixed dose combinations.

Background: Orodispersible Tablets (ODTs) are an option to facilitate the intake of pharmaceutical solid dosage forms, which dissolve in the mouth within 30 seconds releasing the drug immediately with no need for water intake or chewing. Objective: The main goal of our study is the technological development of lactose-free orodispersible tablets that contain ketoprofen. Methods: We assessed different variables during the pharmaceutical development of ODTs: compression techniques conducted after a wet granulation process, aiming to optimize the flow properties of the formulation, and a suspension freeze-drying molded in blisters. We developed three formulations for each method, each containing one of the superdisintegrants: croscarmellose, crospovidone, or starch glycolate. Results: During the production of ODTs, we performed quality control of the granulation process, since the production of pellets contributed to the enhancement of the disintegration time and content homogeneity. Quality control tests for ODTs produced by freeze-drying were also satisfactory, despite significant changes in the final physical aspect of these products when compared to that of ODTs produced by compression. In addition, the disintegration times of ODTs produced by freeze-drying were substantially higher. Furthermore, these tablets displayed greater friability and pose a challenge to the control of a standard individual weight. Conclusion: Among the superdisintegrants, croscarmellose contributed most significantly to reduce the disintegration time and to dissolve KTP effectively in 20 minutes.