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Jahanzeb Mudassir1,2, Yusrida Darwis,1 Suriani Muhamad,1 Arshad Ali Khan1,31Discipline of Pharmaceutical Technology, School of Pharmaceutical Sciences, Universiti Sains, Malaysia, 11800, Penang Malaysia; 2Department of Pharmaceutics, Faculty of Pharmacy, Bahanuddin Zakariya, Multan, Pakistan; 3Faculty of Engineering Technology, Universiti Malaysia Pahang, Kuantan, Pahang, MalaysiaIntroduction: Insulin is given by injection, because when administered orally, it would be destroyed by enzymes in the digestive system, hence only about 0.1% reaches blood circulation. The purpose of the present study was to use pH sensitive polyelectrolyte methyl methacrylate (MMA)/itaconic acid (IA) nanogels as carriers in an attempt to improve absorption of insulin administered orally.Methods: Insulin (Ins) was incorporated into the MMA/IA nanogels (NGs) using the polyelectrolyte complexation (PEC) method to form Ins/NGs-PEC. Several parameters, includingIns:NGs ratio, pH, incubation time and stirring rate were optimized during preparation of InsNGs-PEC. The prepared formulations were characterized in terms of particle size (PS), polydispersity index (PdI), zeta potential (ZP) and percent entrapment efficiency (% EE).Results: The optimized InF12 nanogels had a PS, PdI, ZP and %EE of 190.43 nm, 0.186, −16.70 mV and 85.20%, respectively. The InF12 nanogels were lyophilized in the presence of different concentrations of trehalose as cryoprotectant. The lyophilized InF12 containing 2%w/v trahalose (InF12-Tre2 nanogels) was chosen as final formulation which had a PS, PdI, ZP and %EE of 430.50 nm, 0.588, −16.50 mv and 82.10, respectively. The in vitro release of insulin from InF12-Tre2 nanogels in the SGF and SIF were 28.71% and 96.53%, respectively. The stability study conducted at 5±3°C for 3 months showed that lnF12-Tre2 nanogels were stable. The SDS-PAGE assay indicated that the primary structure of insulin in the lnF12-Tre2 nanogels was intact. The in-vivo study in the diabetic rats following oral administration of InF12-Tre2 nanogels at a dose of 100 IU/kg body weight reduced blood glucose level significantly to 51.10% after 6 hours compared to the control groups.Conclusions: The pH sensitive MMA/IA nanogels are potential carriers for oral delivery of insulin as they enhanced the absorption of the drug.Keywords: acrylic monomers, peptides self assembly, lyophilization, hypoglycemic effect, polymeric nanogels

Ethosomal systems are novel lipid vesicular carriers containing a relatively high percentage of ethanol. These nanocarriers are especially designed for the efficient delivery of therapeutic agents with different physicochemical properties into deep skin layers and across the skin. Ethosomes have undergone extensive research since they were invented in 1996; new compounds were added to their initial formula, which led to the production of new types of ethosomal systems. Different preparation techniques are used in the preparation of these novel carriers. For ease of application and stability, ethosomal dispersions are incorporated into gels, patches, and creams. Highly diverse in vivo models are used to evaluate their efficacy in dermal/transdermal delivery, in addition to clinical trials. This article provides a detailed review of the ethosomal systems and categorizes them on the basis of their constituents to classical ethosomes, binary ethosomes, and transethosomes. The differences among these systems are discussed from several perspectives, including the formulation, size, ζ-potential (zeta potential), entrapment efficiency, skin-permeation properties, and stability. This paper gives a detailed review on the effects of ethosomal system constituents, preparation methods, and their significant roles in determining the final properties of these nanocarriers. Furthermore, the novel pharmaceutical dosage forms of ethosomal gels, patches, and creams are highlighted. The article also provides detailed information regarding the in vivo studies and clinical trials conducted for the evaluation of these vesicular systems.

Nanogels are polymeric nanoparticles that have similar characteristic to hydrogels, but have the size in nano range. The pH-sensitive nanogel have gained much interest in the field of pharmaceutical nanotechnology as they have potential to be used as nanocarriers in drug delivery system. The aim of the present study was to synthesize pH-sensitive polyelectrolyte MMA/IA nanogels using free radical polymerization containing methyl methacrylate (MMA), itaconic acid (IA), and a crosslinker ethylene glycol dimethacrylate (EGDMA). In the synthesis of nanogels four parameters i.e. ethanol/water ratios (v/v), dilution volume using ethanol/water (v/v), crosslinker EGDMA concentration, and monomers MMA/IA ratios were optimized. Their effect on particle size, PdI, zeta potential and swelling ratio were evaluated. The swelling behaviour of the nanogels was studied by measuring swelling ratio using gravimetric method. The optimized nanogels were characterized by proton nuclear magnetic resonance (1H NMR), Fourier transform infrared spectroscopy (FTIR), liquid chromatography/time-of-flight/mass spectrometry (LC-TOF-MS), X-ray powder diffraction (X-RD) and transmission electron microscopy (TEM). Polyelectrolyte characteristic was confirmed by measuring isoelectric point using aqueous electrophoresis. The in-vitro and in-vivo toxicity studies were performed by MTT assays using Caco-2 cells and Limit test using female Sprague Dawly rats, respectively. The nanogels were amorphous in nature, exhibited pH-responsive property and polyelectrolyte characteristics, which showed an isoelectric point at pH 2.78. They had an average particle size

A new, simple, rapid, sensitive and specific isocratic RP–LC–UV method was developed and validated for the determination of ondansetron in pharmaceutical dosage forms of orally disintegrating tablets, oral solution and injection. The LC separation was achieved on a Hypersil C4 column (250 × 4.6 mm, 5 μm) using a mobile phase of 50 mM potassium dihydrogen phosphate anhydrous adjusted to pH 3.5 with orthophosphoric acid and acetonitrile (30:70, v/v) at a flow rate of 1.0 mL min−1 and UV detection at 310 nm. The method was validated for specificity, linearity, precision, accuracy, limit of quantification, limit of detection, robustness and solution stability. The calibration curve was linear over a concentration range of 100–1,000 ng mL−1 (r 2 = 0.9996) with limit of detection and limit of quantification 50 and 100 ng mL−1, respectively. The intra-day and inter-day precision and accuracy were between 0.79 and 2.37% and −0.64 and 1.65%, respectively. The method was successfully applied for analysis of ondansetron in the presence of excipients in commercially available pharmaceutical dosage forms.

A simple, sensitive high performance liquid chromatographic method with UV detection was developed and validated for determination of insulin in rat plasma, using methyl paraben as an internal standard. Insulin was extracted from plasma by a liquid–liquid extraction with a mixture of dichloromethane and n-hexane (1:1, v/v) followed by an acidic back extraction. Chromatographic separation was achieved isocratically with a Phenomenex® C18 analytical column (150 × 4.6 mm ID, 5 μm) at ambient room temperature. The calibration curves were linear within a concentration range of 0.7–8.4 μg mL−1 (r 2 = 0.9994). The inter-day and intra-day accuracy and precision were ≤3.33 and ≤5.55%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.35 and 0.7 μg mL−1. The average recovery was 87.86% for insulin and 83.52% for methyl paraben. Insulin containing plasma samples were stable at −20 °C for 7 days. Validated HPLC method was successfully applied to a pharmacokinetic study of insulin in streptozotocin induced diabetic rats.

The potential of using poly-(ethylene oxide)-block-distearoyl phosphatidyl-ethanolamine (mPEG-DSPE) polymer to prepare BDP-loaded micelles with high entrapment efficiency and mass median aerodynamic diameter of less than 5 μm demonstrating sustained release properties was evaluated. The result showed that lyophilized BDP-loaded polymeric micelles with entrapment efficiency of more than 96% could be achieved. Entrapment efficiency was affected by both the drug to polymer molar ratio and the amount of drug used. Investigation using FTIR and DSC confirmed that there was no chemical or physical interaction and the drug was molecularly dispersed within the micelles. TEM images showed that the drug-loaded polymeric micelles were spherical in shape with multivesicular morphology. Further analysis by photon correlation spectroscopy indicated that the particle size of the BDP-loaded micelles was about 22 nm in size. In vitro drug release showed a promising sustained release profile over six days following the Higuchi model. The mass median aerodynamic diameter and fine particle fraction were suitable for pulmonary delivery. Moreover, the small amount of deposited drug in the induction port (throat deposition) suggested possible reduction in incidence of oropharyngeal candidiasis, a side effect normally associated with inhaled corticosteroids therapy. The high encapsulation efficiency, comparable inhalation properties, sustained release behavior together with biocompatibility nature of the polymer support the potential of BDP-loaded polymeric micelles as a versatile delivery system to be used in the treatment of asthma and chronic obstructive pulmonary disease.

Mohanad Naji Sahib, Yusrida Darwis, Kok Khiang Peh, Shaymaa Abdalwahed Abdulameer, Yvonne Tze Fung TanSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, MalaysiaBackground: Inhaled corticosteroids provide unique systems for local treatment of asthma or chronic obstructive pulmonary disease. However, the use of poorly soluble drugs for nebulization has been inadequate, and many patients rely on large doses to achieve optimal control of their disease. Theoretically, nanotechnology with a sustained-release formulation may provide a favorable therapeutic index. The aim of this study was to determine the feasibility of using sterically stabilized phospholipid nanomicelles of budesonide for pulmonary delivery via nebulization.Methods: PEG5000-DSPE polymeric micelles containing budesonide (BUD-SSMs) were prepared by the coprecipitation and reconstitution method, and the physicochemical and pharmacodynamic characteristics of BUD-SSMs were investigated.Results: The optimal concentration of solubilized budesonide at 5 mM PEG5000-DSPE was 605.71 ± 6.38 µg/mL, with a single-sized peak population determined by photon correlation spectroscopy and a particle size distribution of 21.51 ± 1.5 nm. The zeta potential of BUD-SSMs was -28.43 ± 1.98 mV. The percent entrapment efficiency, percent yield, and percent drug loading of the lyophilized formulations were 100.13% ± 1.09%, 97.98% ± 1.95%, and 2.01% ± 0.02%, respectively. Budesonide was found to be amorphous by differential scanning calorimetry, and had no chemical interaction with PEGylated polymer according to Fourier transform infrared spectroscopy. Transmission electron microscopic images of BUD-SSMs revealed spherical nanoparticles. BUD-SSMs exhibited prolonged dissolution behavior compared with Pulmicort Respules® (P , 0.05). Aerodynamic characteristics indicated significantly higher deposition in the lungs compared with Pulmicort Respules®. The mass median aerodynamic, geometric standard deviation, percent emitted dose, and the fine particle fraction were 2.83 ± 0.08 µm, 2.33 ± 0.04 µm, 59.13% ± 0.19%, and 52.31% ± 0.25%, respectively. Intratracheal administration of BUD-SSMs 23 hours before challenge (1 mg/kg) in an asthmatic/chronic obstructive pulmonary disease rat model led to a significant reduction in inflammatory cell counts (76.94 ± 5.11) in bronchoalveolar lavage fluid compared with administration of Pulmicort Respules® (25.06 ± 6.91).Conclusion: The BUD-SSMs system might be advantageous for asthma or chronic obstructive pulmonary disease and other inflammatory airway diseases.Keywords: micelles, PEGylated polymer, aerodynamics, pharmacodynamics

The aim of this study was to formulate cost effective taste-masked orally disintegrating tablets of ondansetron, a bitter drug using different superdisintegrants by a wet granulation technique. Microcrystalline cellulose (Avicel) as a diluent and disintegrant in addition to aspartame as a sweetener were used in all formulations. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. The tablets’ hardness was maintained in the range of 2–3 kg and friability was

The delivery of drugs and bioactive compounds via the lymphatic system is complex and dependent on the physiological uniqueness of the system. The lymphatic route plays an important role in transporting extracellular fluid to maintain homeostasis and in transferring immune cells to injury sites, and is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism. The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system. Lymphatic imaging is useful in evaluating disease states and treatment plans for progressive diseases of the lymph system. Novel lipid-based nanoformulations, such as solid lipid nanoparticles and nanostructured lipid carriers, have unique characteristics that make them promising candidates for lymphatic delivery. These formulations are superior to colloidal carrier systems because they have controlled release properties and provide better chemical stability for drug molecules. However, multiple factors regulate the lymphatic delivery of drugs. Prior to lymphatic uptake, lipid-based nanoformulations are required to undergo interstitial hindrance that modulates drug delivery. Therefore, uptake and distribution of lipid-based nanoformulations by the lymphatic system depends on factors such as particle size, surface charge, molecular weight, and hydrophobicity. Types of lipid and concentration of the emulsifier are also important factors affecting drug delivery via the lymphatic system. All of these factors can cause changes in intermolecular interactions between the lipid nanoparticle matrix and the incorporated drug, which in turn affects uptake of drug into the lymphatic system. Two lipid-based nanoformulations, ie, solid lipid nanoparticles and nanostructured lipid carriers, have been administered via multiple routes (subcutaneous, pulmonary, and intestinal) for targeting of the lymphatic system. This paper provides a detailed review of novel lipid-based nanoformulations and their lymphatic delivery via different routes, as well as the in vivo and in vitro models used to study drug transport in the lymphatic system. Physicochemical properties that influence lymphatic delivery as well as the advantages of lipid-based nanoformulations for lymphatic delivery are also discussed.

The aim of this study was to prepare insulin-loaded poly(lactic acid)-polyethylene glycol microspheres that could control insulin release at least for 1 week and evaluate their in vivo performance in a streptozotocin-induced diabetic rat model.The microspheres were prepared using a water-in-oil-in-water double emulsion solvent evaporation technique. Different formulation variables influencing the yield, particle size, entrapment efficiency, and in vitro release profiles were investigated. The pharmacokinetic study of optimized formulation was performed with single dose in comparison with multiple dose of Humulin 30/70 as a reference product in streptozotocin-induced diabetic rats.The optimized formulation of insulin microspheres was nonporous, smooth-surfaced, and spherical in structure under scanning electron microscope with a mean particle size of 3.07 microm and entrapment efficiency of 42.74% of the theoretical amount incorporated. The in vitro insulin release profiles was characterized by a bimodal behavior with an initial burst release because of the insulin adsorbed on the microsphere surface, followed by slower and continuous release corresponding to the insulin entrapped in polymer matrix.The optimized formulation and reference were comparable in the extent of absorption. Consequently, these microspheres can be proposed as new controlled parenteral delivery system.