Self-emulsifying micelles as a drug nanocarrier system for itraconazole oral bioavailability enhancement; in vitro and in vivo assessment.

Itraconazole (ITZ) is a renowned antifungal medication, however its therapeutic efficacy is limited by low solubility and oral bioavailability. The current research work attempted to augment the oral bioavailability of ITZ by incorporating into self-emulsifying micelles (SEMCs). To fabricate the SEMCs, various preparation techniques including physical mixture, melt-emulsification, solvent evaporation and kneading, were opted by using different weight ratio of drug and solubilizers i.e. Gelucire-50/13 or Gelucire-44/14 and characterized both in vitro and in vivo. The prepared SEMCs were found to be in the size range from 63.4 ± 5.2 to 284.2 ± 19.5 nm with surface charges ranging from -16 ± 1.2 to -27 ± 2.0 mV. The drug solubility was improved to a reasonable extent with all investigated formulations, however, SEMCs in group 6 prepared by kneading method (KMG6) using Gelucire-44/14: drug (10:1 presented 87.6 folds' increase (964.93 ± 2 µg/mL) compared to solubility of crystalline ITZ (11 ± 2 µg/mL) through kneading method. In addition, KMG6 SEMCs shows the fast drug release compared to other SEMCs. Further, KMG6 SEMCs also exhibited 5.12-fold higher relative intestinal serosal fluid absorption compared to crystalline ITZ. The pharmacokinetic parameters such Cmax, AUC and Tmax of KMG6 SEMCs significantly improved compared to crystalline ITZ. In conclusion, the manipulation of ITZ solubility, dissolution rate and absorption using SEMCs is a promising strategy for bioavailability enhancement.

Piperine phytosomes for bioavailability enhancement of domperidone.

The markedly low oral bioavailability of domperidone (anti-emetic drug) is associated with rapid first-pass metabolism in the intestine and liver. To counteract such affects, there is a need to devise a strategy to enhance absorption and subsequently bioavailability. Thus, the current study was aimed at synthesizing phytosomes consisting of phosphatidylcholine and piperine (a P-glycoprotein inhibitor). Phytosomes were prepared by salting-out method. The developed phytosomes were extensively characterized for size, zeta potential, polydispersity index, entrapment efficiency (EE %), infra-red spectroscopy, X-ray diffraction, in vitro drug release, ex vivo permeation, in vivo pharmacokinetic and toxicity. The engineered formulations of phytosomes with piperine exhibited a significant improvement in oral bioavailability of domperidone (79.5%) in comparison with the pure drug suspension under the same conditions. Pharmacokinetic parameters such as maximal plasma concentration (Cmax) and the plasma concentration (estimated from area under the curve; AUC) of domperidone have been greatly increased relative to drug alone. The improved drug absorption was attributed to inhibition of P-glycoprotein transporter. The findings of current research work suggest that the optimized phytosomes based drug delivery containing phytochemicals as bioenhancers have the potential to improve bioavailability of poorly bioavailable drugs that are substrate to P-glycoprotein.

Novasomes as Nano-Vesicular Carriers to Enhance Topical Delivery of Fluconazole: A New Approach to Treat Fungal Infections.

The occurrence of fungal infections has increased over the past two decades. It is observed that superficial fungal infections are treated by conventional dosage forms, which are incapable of treating deep infections due to the barrier activity possessed by the stratum corneum of the skin. This is why the need for a topical preparation with advanced penetration techniques has arisen. This research aimed to encapsulate fluconazole (FLZ) in a novasome in order to improve the topical delivery. The novasomes were prepared using the ethanol injection technique and characterized for percent entrapment efficiency (EE), particle size (PS), zeta potential (ZP), drug release, Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and antifungal activity. The FN7 formulation with 94.45% EE, 110 nm PS and -24 ZP proved to be the best formulation. The FN7 formulation showed a 96% release of FLZ in 8 h. FTIR showed the compatibility of FLZ with excipients and DSC studies confirmed the thermal stability of FLZ in the developed formulation. The FN7 formulation showed superior inhibition of the growth of Candida albicans compared to the FLZ suspension using a resazurin reduction assay, suggesting high efficacy in inhibiting fungal growth.

Improved solubility and stability of aripiprazole in binary and ternary inclusion complexes using methyl-ß-cyclodextrin and L-arginine.

The aim of this study was to improve the solubility of aripiprazole (ARP) by fabricating binary and ternary inclusion complexes with methyl-ß-cyclodextrin (MßCD) and L-Arginine (LA). Physical mixing and lyophilization were used in the following molar ratios: 1:1, 1:2.5, 1:4, 1:9, 1:1:1, 1:1:0.27, 1:4:1, 1:9:1, 1:3.6:3.6. The developed formulations were analyzed by solubility and dissolution. They were characterized by FTIR, XRD, DSC, SEM and TGA. Ternary formulations prepared by the lyophilization method showed improved dissolution rates in simulated gastric fluid (SGF). The results showcased that the addition of MßCD and LA in inclusion complexes enhanced the solubility and decreased crystallinity. The amorphous nature of Aripiprazole in lyophilization was confirmed by XRD diffractograms. Drug release was dominated by the first-order kinetics (R2 = 0.9932) with the Fickian type of diffusion mechanism (n<0.450). LY18, LY19, LY20 and LY21 have the highest solubility (30, 35, 43 and 48 times higher than the pure drug respectively). Furthermore, it was observed that the method of preparation, as well as a specific drug to polymer and amino acid ratio, are critical for achieving high drug solubility and stability. These complexes appeared to be a promising product for the development of new drug delivery systems.

Synthesis and characterization of self-assembling chitosan-based nanoparticles.

Chitosan (CHT) based biodegradable nanovectors were synthesized and modified with poly ethylene glycol 4000 (PEG-4000). CHT having medium molecular weight with 75% to 85% deacetylation was phthaloylated with phthalic anhydride, followed by PEGylation using PEG-4000. After confirmation of successful PEGylation by fourier transforminfra red spectroscopy (FTIR), the modified polymer was further processed to develop the nanocarrier using ionic gelation method by the addition of sodium tripolyphosphate (NaTPP). The prepared nanocarriers were subjected to physicochemical evaluation. The surface morphology of the particles was observed under scanning electron microscope (SEM), and particle size by dynamic light scattering (DLS) method, which was about 159-170nm in diameter. The zeta potential of the prepared nanovectors was +0.907mV which was due to cationic nature of nanovectors. The cell viability studies were also conducted to find the suitability of the carrier for in-vivo application, using liver cancerous cells (Hep G2). The findings have disclosed the concentration dependent activities of the particles, as viability of the cell was shown to be decreased with the increase in the concentration of the particles. Conclusively, the study was successful in determining the toxicity profile of these nanovectors as these were proved non-toxic at specific concentration.

Oral bioavailability studies of niosomal formulations of Cyclosporine A in albino rabbits.

Cyclosporine A (CsA) is an immunosuppressant agent. Two niosomal formulations of CsA, FTS and FSB were formulated. Both formulations were studied in terms of size, polydispersity index (PDI), morphology and entrapment efficacy etc. Niosomal formulations FTS and FSB and plain aqueous dispersion were given to three assemblies of Albino rabbits (n=8 per group). CsA levels in plasma were determined at appropriate time intervals and pharmacokinetic parameters were evaluated. The percentage entrapment efficiencies of FTS and FSB were found to be 77.29 and 89.31% for respectively. Transmission electron microscopy results indicated spherical nature of niosomes. In vivo studies demonstrated that the value of Cmax for the FSB formulation was 1968.419 ng/ml and it was 1498.951 ng/ml and 1073.87 ng/ml for FTS and aqueous dispersion of CsA (control) respectively. It was found that both niosomal formulation FTS & FSB presented significantly high (p<0.05) Cmax, AUC0-t, MRT 0-inf and half-life (t1/2) as associated to plain drug dispersion. However niosomal formulation FSB exhibited better in-vivo performance as compared to FTS. It was established that CsA can be successfully entrapped in niosomes. So niosomes are promising vehicle for CsA oral delivery.

Improvement of solubility and dissolution of ebastine by fabricating phosphatidylcholine/ bile salt bilosomes.

Although ebastine (EBT) can impede histamine-induced skin allergic reaction and persuade long acting selective H1 receptor antagonistic effects but its poor water solubility circumscribed its clinical application. The main objective of this research work was to improve the aqueous solubility and oral bioavailability of EBT by preparing EBT-loaded bilosomes (EBT-PC-SDC-BS). A thin film hydration method was used to prepare ebastine loaded bilosomes. The prepared-formulations were optimized considering size, morphology and entrapment efficiency. The SEM images revealed regular and spherical shape of bilosomes. Average size of the prepared EBT-PC-SDC-BS was 665.8 nm and zeta potential was around-32.9 mV with 89.05 % average entrapment efficiency (EE).Importantly, the solubility of EBT in water was amplified up to 17.9 µg/ml compared to pure drug (2 µg/mL) reflecting a highest solubility increase of 751 %. In vitro drug release results of prepared EBT-PC-SDC-BS exhibited improved release behavior. Finally, it is established from the results that the EBT-PC-SDC-BS could function as a favorable nano-carrier system to improve the solubility as well as dissolution of EBT.

Evaluation of solubility and dissolution of lamotrigine using lipid based microparticulate carriers: An in-vitro analysis.

The present study was designed to develop novel lipid microparticles in order to improve solubility, dissolution and bioavailability of a lipophilic drug of BCS class II, lamotrigine. For that purpose, increase in solubility of the model drug was investigated using different lipids and the promising lipids were further used for the fabrication of microparticles. Solid lipid (GMS) and liquid lipid (olive oil) were used along with an emulsifier (Tween 80) and a stabilizer (Poloxamer 188) to prepare mircoparticles by melt emulsification method. Prepared formulations were characterized for physicochemical properties such as solubility, particle size, zeta potential, polydispersity index and entrapment efficiency. In vitro dissolution studies were carried out in 0.01 N HCl for 24 h. The findings provided that the solubility of lamotrigine was reasonably increased in GMS, olive oil, Tween 80 and poloxamer 180. The lamotrigine solubility was increased 4.92 fold with G4 microparticles formulation. Size analysis revealed that the microparticles were in range of 11.1 to 178.8 µm and the zeta potential values were from -13 to -20 mV. Microparticles prepared with solid and liquid lipids exhibited satisfactory entrapment efficiency ranging from 59 to 87%. Conclusively, the outcomes of the studies suggest the appropriateness of selected ingredients for improving solubility as well as loading of lamotrigine in microparticles for its sustained and effective delivery.

Loratadine oral bioavailability enhancement via solid dispersion loaded oro-dispersible films: Formulation, characterization and pharmacokinetics.

Loratadine (LRD) belongs to second-generation tricyclic H1 antihistamine class, known for its non-sedating properties in allergic reactions. H1 antihistamines avoid and block the responses to allergens or histamine in nose and conjunctivae, thereby abolishing itching, congestion and sneezing. LRD is a Biopharmaceutical Class System (BCS) class II drug with dissolution or solubility limited absorption which limited the oral bioavailability and therapeutic efficacy of LRD. To improve the oral bioavailability of LRD for allergic disease (urticaria) treatment, LRD solid dispersions (LRD-SDs) were integrating into oro-dispersible films (ODFs). LRD-SDs were prepared through hot-melt extrusion method (HME) using d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS-1000), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SP). Subsequently, LRD-SDs were incorporated in ODFs by solvent casting method. The physicochemical and mechanical properties of LRD solid dispersions-loaded oro-dispersible films (LRD-SDs-ODFs), were evaluated. The in-vitro dissolution, ex-vivo permeation, oral bioavailability, and pharmacodynamics studies were conducted to evaluate LRD-SDs-ODFs efficiency. LRD-SDs-ODFs showed superior solubility and in-vitro dissolution results compared to that of pure LRD (p < 0.05). The solubility of the LRD-SD coded as LTS-4 was 190 times higher than the pure drug in aqueous media. The average hydrodynamic particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of SD particles were 76 ± 2.1 nm, 0.20 ± 0.08 and - 19.16 ± 1.4 mV, respectively. Moreover, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results confirmed the amorphousness of LRD in LRD-SDs-ODFs. The permeability flux of LRD was 44.6 ± 3.1 µg/cm2/h from DPF-5 formulation. Likewise, in vivo oral bioavailability of DPF-5 in Sprague-Dawley rats was significantly increased (p < 0.05) compared to free LRD. Further, wheal area was reduced 20 % higher than LRD in 8 h (p < 0.05). Overall, LRD-SDs-ODFs considerably enhanced LRD solubility, dissolution rate, bioavailability, and antihistaminic efficacy. Our findings show that SDs-ODFs is an effective carrier system for delivering poorly soluble LRD.

Fabrication, In Vitro and In Vivo Evaluation of Non-Ordered Mesoporous Silica-Based Ternary Solid Dispersions for Enhanced Solubility of Flurbiprofen.

The aim of this study was to improve the solubility and prevent the ulcerogenic effect of flurbiprofen. Initially, binary and ternary solid dispersions (BSDs and TSDs) of flurbiprofen were prepared by using non-ordered mesoporous silica and gelucire. After preformulation testing (solubility, flow properties, % yield, and entrapment efficiency), four formulations were selected for further detailed studies. Solid-state characterization of optimized formulations (S1, S6, S7, and S12) showed successful drug incorporation in the solid dispersion at the molecular state without any noticeable interactions. The in vitro solubility and release study showed an increase in solubility and 98-100% of drug release in 30-45 min. The in vivo gastro-protective effect of the optimized formulations containing flurbiprofen and silica (1:1) with 25% w/w gelucire (S6 and S12) showed a reduction in the gastric lesion index (GLI) after four days of treatment. Moreover, histological images of the stomach lining (S6 and S12) illustrated normal epithelial cells and a partially protected mucosal membrane. Thus, TSD exhibited a significant increase in solubility and the dissolution rate and reduced the gastric ulceration. Therefore, TSDs are dubbed as efficacious carriers to enhance the bioavailability of flurbiprofen while simultaneously reducing its side effects.

Solubility and Dissolution Enhancement of Dexibuprofen with Hydroxypropylbetacyclodextrin (HPßCD) and Poloxamers (188/407) Inclusion Complexes: Preparation and In Vitro Characterization.

The objective of this study was to improve the dissolution and solubility of dexibuprofen (DEX) using hydroxypropyl beta cyclodextrin (HPßCD) inclusion complexes and also to evaluate the effect of presence of hydrophilic polymers on solubilization efficiency of HPßCD. Three different methods (physical trituration, kneading and solvent evaporation) were used to prepare binary inclusion complexes at various drug-to-cyclodextrin weight ratios. An increase in solubility and drug release was observed with the kneading (KN) method at a DEX/HPßCD (1:4) weight ratio. The addition of hydrophilic polymers poloxamer-188 (PXM-188) and poloxamer-407 (PXM-407) at 2.5, 5.0, 10.0 and 20% w/w enhanced the complexation efficiency and solubility of DEX/HPßCD significantly. Fourier-transform infrared (FTIR) analysis revealed that DEX was successfully incorporated into the cyclodextrin cavity. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) revealed less crystallinity of the drug and its entrapment in the cyclodextrin molecular cage. The addition of PXM-188 or PXM-407 reduced the strength of the DEX endothermic peak. With the addition of hydrophilic polymers, sharp and intense peaks of DEX disappeared. Finally, it was concluded that PXM-188 at a weight ratio of 10.0% w/w was the best candidate for improving solubility, stability and release rate of DEX.

Poloxamer-188 and d-α-Tocopheryl Polyethylene Glycol Succinate (TPGS-1000) Mixed Micelles Integrated Orodispersible Sublingual Films to Improve Oral Bioavailability of Ebastine; In Vitro and In Vivo Characterization.

Orodispersible sublingual films (OSFs) composed of hydrophilic polymers were loaded with poloxamer-188 and d-α-tocopheryl polyethylene glycol succinate (TPGS-1000) mixed micelles to improve the oral bioavailability of a poorly soluble drug, ebastine (EBT). Mixed micelles formed by thin-film hydration method were incorporated into orodispersible sublingual film, consisting of HPMC and glycerol, using solvent casting technique. The mixed micelles and films were thoroughly evaluated for physicochemical characterization (size, polydispersity index, zeta potential, entrapment efficiency, thickness, weight, surface pH studies, disintegration time, swelling indices, mechanical properties, FTIR, PXRD, DSC, SEM, AFM, in vitro drug release, in vivo bioavailability, and toxicological studies). The results showed that the average particle size of mixed micelles was 73 nm. The mean zeta potential and PDI of the optimal mixed micelles formulation were -26 mV and 0.16, respectively. Furthermore, the maximum entrapment efficiency 82% was attained. The film's disintegration time was in the range of 28 to 102 s in aqueous media. The integrity of micelles was not affected upon incorporation in films. Importantly, the micelles-loaded films revealed rapid absorption, high permeability, and increased bioavailability of EBT as compared to the pure drug. The existence of ebastine loaded mixed micelles in the films enhanced the bioavailability about 2.18 folds as compared to pure drug. Further, the results evidently established in-vitro and in-vivo performance of bioavailability enhancement, biocompatibility, and good safety profile of micelles-loaded orodispersible EBT films. Finally, it was concluded that film loaded with poloxamer-188/TPGS-1000 mixed micelles could be an effective carrier system for enhancing the bioavailability of ebastine.

Improved Bioavailability of Ebastine through Development of Transfersomal Oral Films.

The main objective of this research work was the development and evaluation of transfersomes integrated oral films for the bioavailability enhancement of Ebastine (EBT) to treat allergic rhinitis. The flexible transfersomes, consisting of drug (EBT), lipid (Phosphatidylcholine) and edge activator (EA) Polyoxyethylene sorbitan monooleate or Sorbitan monolaurate, were prepared with the conventional thin film hydration method. The developed transfersomes were further integrated into oral films using the solvent casting method. Transfersomes were evaluated for their size distribution, surface charge, entrapment efficiency (EE%) and relative deformability, whereas the formulated oral films were characterized for weight, thickness, pH, folding endurance, tensile strength, % of elongation, degree of crystallinity, water content, content uniformity, in vitro drug release and ex vivo permeation, as well as in vivo pharmacokinetic and pharmacodynamics profile. The mean hydrodynamic diameter of transfersomes was detected to be 75.87 ± 0.55 nm with an average PDI and zeta potential of 0.089 ± 0.01 and 33.5 ± 0.39 mV, respectively. The highest deformability of transfersomes of 18.52 mg/s was observed in the VS-3 formulation. The average entrapment efficiency of the transfersomes was about 95.15 ± 1.4%. Transfersomal oral films were found smooth with an average weight, thickness and tensile strength of 174.72 ± 2.3 mg, 0.313 ± 0.03 mm and 36.4 ± 1.1 MPa, respectively. The folding endurance, pH and elongation were found 132 ± 1, 6.8 ± 0.2 and 10.03 ± 0.4%, respectively. The ex vivo permeability of EBT from formulation ETF-5 was found to be approximately 2.86 folds higher than the pure drug and 1.81 folds higher than plain film (i.e., without loaded transfersomes). The relative oral bioavailability of ETF-5 was 2.95- and 1.7-fold higher than that of EBT-suspension and plain film, respectively. In addition, ETF-5 suppressed the wheal and flare completely within 24 h. Based on the physicochemical considerations, as well as in vitro and in vivo characterizations, it is concluded that the highly flexible transfersomal oral films (TOFs) effectively improved the bioavailability and antihistamine activity of EBT.