Drug Delivery Letters - Volume 8, Issue 3, 2018

Background and Objective: Intranasal drug delivery, being non-invasive in nature has turned out to be a promising option for drug administration. It is particularly valuable for drugs having low oral bioavailability due to degradation in Gastrointestinal Tract (GIT). Discussion: Nasal route provides a unique micro-environment due to absence of deactivating enzymes and abundant vascular tissues which bring about direct systemic display, along with these lines abstaining the first pass hepatic metabolism. Conclusion: The present article provides in-depth information about the physicochemical parameters associated with drug absorption in nasal mucosa and factors influencing it. The pathways and mechanisms associated with nasal drug uptake alongside current pharmaceutical applications are additionally summarized.

Background: Nano-crystalline suspensions obtained by top down process are used to overcome the poor water solubility of Active Pharmaceutical Ingredient (API). Discussion: Nano-crystalline suspensions are a versatile technology and can be used for administering drug via different application routes. They are manufactured mainly by using technologies like stirred bead milling and high pressure homogenization. To make nano-crystalline suspensions successful as drug delivery system, several aspects needs to be considered in terms of formulation composition, manufacturing process and the technology to be used for particles size reduction. Conclusion: This paper reviews all above aspects though eyes of engineer and industrial production feasibility. In addition to that, this review outlines importance of technology selection to obtain the desired particle size and product in compliance to pharmaceutical regulation. Finally, the important parameters and factors are outlined for the industrial manufacturing process.

Introduction: Intravaginal delivery is currently considered to be an important alternative route for poorly-absorbed, rapidly metabolised oral drugs. Objectives: The objective of this study was to evaluate (i) the preliminary feasibility of using the readyto- use vehicle Pentravan® to compound dienogest, gestrinone, nimesulide and piroxicam and (ii) the vaginal administration of theses formulations to patients with pelvic pain associated with endometriosis (PPRE). Methods: Intravaginal creams were compounded containing the active pharmaceutical ingredients (APIs) individually and with no addition of permeation enhancers (dienogest 0,2%, gestrinone 0,5%, nimesulide 2,0% and piroxicam 2,0%). For quality control, pH, drug content and particle size were determined. HPLC methods were developed and validated for each formulation. Vaginal permeation profiles were determined using porcine vaginal mucosa on Franz-type diffusion cells and then kinetics parameters were determined. Results: Quality control of the formulations showed that the products were convenient and easily prepared, with narrow size distribution. Diffusion experiments demonstrated fluxes of 15.98 μg.cm-2.h-1 for dienogest, 3.91 μg.cm-2.h-1 for piroxicam, 3.72 μg.cm-2.h-1 for gestrinone and 2.26 μg.cm-2.h-1 for nimesulide. Dienogest and gestrinone had permeation fluxes and quantities of drug absorbed hypothetically compatible with therapeutic effect in vivo (fluxes to attempt in order to deliver the recommended daily doses to treat PPRE were calculated as 0.87 μg.cm-2.h-1 for dienogest, 0.69 μg.cm-2.h-1 for gestrinone, 70.45 μg.cm-2.h-1 for nimesulide and 9.64 μg.cm-2.h-1 for piroxicam), whereas nimesulide and piroxicam studies showed a great amount of these drugs retained in the vaginal mucosa. This could account for a local effect for these two substances. Conclusion: Pentravan®, which already has an established role for transdermal delivery of drugs, seems to be a feasible intravaginal vehicle. Particularly in this study, we highlight its use for vaginal delivery of dienogest and gestrinone for the treatment of PPRE. In vivo studies must now be conducted to confirm these data.

Background: Tuberculosis (TB) is infectious, contagious and persistent infection caused by Mycobacterium tuberculosis. The treatment of TB is becoming more complex due to development of multidrug resistant tuberculosis hence, it requires daily administration of combined drug therapy for six or more months. It is rational to formulate controlled release formulation to reduce dosing frequency and drug toxicity. Chitosan Nanoparticles (CHNPs) are optimistic approach to treat tuberculosis. Objective: To formulate combined drug chitosan nanoparticles of antitubercular drugs (Isoniazid-INH and Pyrazinamide-PYZ) to get additive effect on Mycobacterium tuberculosis. Nanoparticles are colloidal system that enhances effective permeation through cell membrane, stability in blood stream and controlled release of drug. Hence, it is emerging as a new weapon in drug delivery field. Methods: The 32 factorial design was used to formulate nanoparticles by ionic gelation method using Chitosan (CS) and sodium tripolyphosphate (TPP) with ratio 3:1 (CS:TPP::v/v) in pH range 4.6 to 4.8. The effect of CS and TPP concentration on particle size, zeta potential, entrapment efficiency and in vitro drug release were studied. Results: Optimized batch 8N showed particle size 414.3 ± 2.71 nm, zeta potential 26.52 ± 0.67mV, PDI (poly dispersity index) 0.296 and entrapment efficiency of INH and PYZ 55.29 ± 0.06% and 63.14 ± 0.29% respectively. Dissolution release study of 8N formulation at pH 7.4 showed initial burst release of 20.28 ± 1.43% and 23.62 ± 1.07 at 0.25 hrs followed by controlled release up to 84.82 ± 2.54% and 61.48 ± 1.52% by INH and PYZ for 14 hrs. Conclusion: The study concluded that CS and TPP concentration were rate limiting factors in optimizing formulation development. Combined drug nanoparticle system has an innovative and optimistic approach towards the enhancement of therapeutic efficacy and reduction undesirable effects of antitubercular drug.

Background and Objective: Gold nanoparticles (AuNP) conjugated with either EpCAM or TARP antibodies and an anticancer agent, paclitaxel (PTX), for tumour targeting and therapy were synthesised using a simple chemistry. Methods: The AuNP surface was functionalised using a two-step modification approach. The conjugates were characterised using Transmission Electron Microscopy (TEM) and infrared spectroscopy. Results: The cytotoxicity assay of T47D cells treated with only antibodies conjugated to the gold nanoparticles did not show any cytotoxicity to the cells, which indicates these nanoconjugates are suitable for intracellular delivery of anticancer drugs. Conclusion: When using AuNPs with antibodies and the cancer chemotherapy agent PTX attached simultaneously to the functionalised AuNPs, the reduction of cell viability was significantly higher compared to PTX-thiol-AuNPs conjugate system where no antibodies were used.

Background and Objective: Non-melanoma Skin Cancer (NMSC) is the most common malignancy found in humans and currently 2-3 million cases occur globally and occur in the persons with light skin and less melanin content. It often appears as a painless, raised area of skin, which may be shiny or with the hard lump with a scaly top, but may also form an ulcer which may spread to other parts of the body. Nonsurgical management of NMSC could be a viable and effective treatment option, however, permeation of hydrophilic drugs such as 5-fluorouracil through the skin may hamper the success of topical application approach. Therefore, the aim of this work was to incorporate 5-fluorouracil in ethosomes using a Fractional Factorial Design in order to improve its skin permeation. Methods: The 5-fluorouracil ethosomes were prepared by cold method through 25-2 Fractional factorial design in which amount of Phospholipon®90H(A), Drug(B), Propylene Glycol(C), Ethanol(D) and Sonication time(E) was selected as independent variables and vesicle size(X1) and %Entrapment Efficiency (%EE)(X2) as dependent variables. Results: All the batches exhibited the vesicle size and %EE in the range of 74.43-653.8 nm and 34.64- 50.94%. The optimized batch of ethosomes (K3) exhibited 229.6nm vesicle size, 55.41%EE and 14.9mV zeta potential indicating suitability for skin permeation and stability of the formulation. During %In-vitro drug release study, Batch K3 indicated 69.30% and 59.18% of drug release after 12 hours as compared to 82.84% and 91.8% of pure drug in acetate Buffer pH 6.0 and phosphate buffer pH 7.4 respectively indicating the sustained release of drug. Conclusion: Thus, the prepared formulation might have potential applications of delivering the drug in controlled manner directly to the site of action by overcoming the limitations of conventional formulations and by enhancing drug penetration to deeper layers of skin, by reduce dosing frequency and thus with improved bioavailability for the treatment of non-melanoma skin cancer.

Introduction: Ultraviolet radiation from sunlight is the common cause for skin aging, premalignant skin lesions as well as melanoma and nonmelanoma skin cancer. Most skin cancers can be prevented by avoiding prolonged direct exposure to the sun or by treating the skin with antioxidants before sun exposure. Evidence demonstrates that natural compounds with anticancer properties may play a crucial role in cancer prevention, growth and progression. Vitamin E (VitE) was shown to possess antitumor activity in the skin with its skin barrier-stabilizing properties and protection against UV-induced skin photodamage through a combination of antioxidant and UV absorptive properties. In this study, we developed and investigated the potential of VitE encapsulation in monoolein and poloxamer-based cubosomes in topical administration. Physicochemical characterization and stability studies were evaluated to better predict their performance when applied to in vitro and in vivo studies. Materials and Methods: Cubosomes were prepared by the hydration of the thin lipid film. The particle sizes, polydispersity index, zeta potential were obtained by dynamic light scattering and the encapsulation degree by ultrafiltration process. Physical stability of the Cubosomes nanodispersions obtained herein were evaluated under accelerated conditions (low, high and room temperature) for 40 days while in vitro release, permeation and skin retention by Franz diffusion cell. Results: The formulations containing with or without VitE displayed homogeneous appearance, with sizes in the nano-range (around 200 nm), and low polydispersity index. There was no statistical difference between cubosomes only and VitE incorporated cubosomes (0.2 mg/g). The encapsulation degree of VitE in cubosomes was approximately 100%. The cubosomes were physically stable for 40 days even under semi-harsh conditions. VitE skin permeation studies showed increased VitE in the deeper layers of the skin, which is important for the success of the topical skin cancer treatment and prevention. Conclusion: Based on the physicochemical characteristics of the monoolein and poloxamer-based cubosomes nanodispersion results, we believe that cubosomes are potential delivery systems for topical administration of VitE. Further studies using melanoma cells line and animal cutaneous cancer models will be performed to verify VitE-loaded cubosomes nanodispersion treatment and efficacy.

Background and Objectives: Recently S-Allyl-L-Cysteine (SAC) (an organic compound that is a natural constituent of garlic, is a derivative of the amino acid cysteine) has been introduced as an agent of suppression of μ- and m-calpain activities and followed by that bright promising neuroprotective compound. The main objective of this research was to evaluate the biocompatibility and neuroprotective potential of the encapsulated S-Allyl-L-Cysteine (SAC) into polycaprolactone (PCL)-based nanocarriers (NCs). Methods: The copolymer-based SAC-loaded nanocarriers were prepared from coprecipitation method at constant temperature followed by evaporation of the organic solvent. To the best of our knowledge, it is the first time to investigate the biocompatibility and neuroprotective potential of SAC loaded into PEG-b-PCL (poly(ethylene glycol)-block-poly(−caprolactone) methyl ether). Results: The average size of the PEG-b- PCL/empty NCs was 108 nm and for PEG-b-PCL/SAC was 124 nm. The Drug Loading efficiency was 68%. The concentration of PCL-based NCs was 2 x 10 10 particles/ml and the zeta potential of PEG-b- PCL/empty and PEG-b-PCL/SAC NCs was -17 mV and - 23 mV respectively. Biocompatibility and Neuroprotective potential of NCs were evaluated in the SHSY5Y human neuroblastoma cell line using cell viability and toxicity assays. Conclusion: The concentration of PEG-b-PCL NCs below 1 x 10 10 particles/ml can be considered as a safe concentration for the cell line. Also, the SAC encapsulated into PEG-b-PCL NCs has the same neuroprotective effect as free SAC at lower concentration, and therefore, has a significant neuroprotective potential against Z-VAD-fmk and St-evoked SH-SY5Y cell damage.

Background and Objective: In the present study, a self-micro emulsifying drug delivery system (SMEDDS) has been developed and optimized to enhance solubility and bioavailability of poorly water soluble drug ezetimibe. Methods: Phase solubility studies and emulsification tests were performed for selection of a suitable oil, surfactant, and co-solvent. Ternary phase diagram was constructed to find out range of oil, surfactant and co-solvent required for microemulsion formation. A three-factor, two level, mixture design of experiments was used to optimize the concentration of components for SMEDDS formulation for achieving desirable physicochemical properties such as small globule size (<100nm) and high dissolution (more than 85% of drug released within 15 minutes). Lipolysis of optimized ezetimibe SMEDDS formulation by pancreatic lipase was done to investigate the effect on solubilizing capacity of dispersed colloid in aqueous phase. Pharmacodynamic study on hyperlipidaemic rat models was done to investigate the bioavailability of optimized ezetimibe SMEDDS formulation in comparison to pure drug. Results: The optimized ezetimibe loaded SMEDDS formulation containing 10.0% capmul MCM (oil), 70.0% tween 20 (surfactant) and 20.0% transcutol (co-solvent) offered smallest globule size (16.3 nm) and maximum drug release (97.8% in 15 minutes). Lipolysis has shown that the nature of colloidal species changed during lipolysis process does not affect solubilizing capacity of dispersed colloid. Pharmacodynamic investigation reveals that optimized formulation significantly reduced serum lipid levels when compared with ezetimibe drug and hence indicating improved bioavailability. Conclusion: The result of this study suggested that ezetimibe SMEDDS formulation developed using mixture design of experiment could potentially be used for improving the solubility and bioavailability of poorly water-soluble drugs.