Development and characterization of bilayered tablets of diazepam for oral drug delivery: design, optimization and in vitro evaluation.

Aims: The oral bioavailability of drugs can be limited by their short residence time in the gastrointestinal tract. This study was performed to design bilayered floating tablets of diazepam comprising immediate-release and controlled-release layers. Methods: The tablets were prepared using sodium starch glycolate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and microcrystalline cellulose and evaluated for their characteristics. Results: The optimized formulation was found to be buoyant for 8 h on simulated gastric fluid. Hydroxypropyl methylcellulose K4M and microcrystalline cellulose sustained the release of diazepam from the controlled-release layer. The optimized formulation exhibited an extended release period of 8 h. Discussion/conclusion: It can be concluded that bilayered tablets of diazepam may extend the residence time of the drug at the site of absorption.

Development and characterization of a novel mucoadhesive sol-gel suppository of sumatriptan: design, optimization, in vitro and ex vivo evaluation for rectal drug delivery.

Aim: Sumatriptan (ST) is used for the treatment of migraine and cluster headaches. However, it exhibits low oral bioavailability (15%) due to the high first-pass metabolism. The aim of this work was to formulate an ST rectal hydrogel. Methods: Hydrogels were formulated according to a Box-Behnken design using pluronic F-127 (PF-127) and chitosan as thermogelling and mucoadhesive agents, respectively. The rectal permeability was examined using a sheep rectal mucosa. Results: Among all the formulations, the hydrogel S2 showed satisfactory drug content (4.50%), gelling temperature (32°C), pH (6.41), viscosity (105 cP) and strength (15.90 sec). Mucoadhesive strength was adequate to provide a prolonged residence time. The flux of hydrogel S2 was calculated to be 0.0003 µg/cm2.min. Conclusion: The ST hydrogel can provide a potential opportunity to overcome the first pass metabolism and reduce drug dose.

The Factors Determining the Skin Penetration and Cellular Uptake of Nanocarriers: New Hope for Clinical Development.

The skin provides a protective barrier against toxic environments and also offers a valuable route for topical drug delivery. The stratum corneum (SC) is the outermost layer of the skin and serves as the major barrier to chemical transfer through the skin. The human skin barrier is particularly difficult to overcome because of the complex composition and structure of the SC. Nanoparticulate carriers have gained widespread attention in topical drug delivery due to their tunable and versatile properties. The present review summarizes the main factors involved in skin penetration of nanocarriers containing the drug. Employment of nanotechnology in topical delivery has grown progressively during recent years; however, it is important to monitor the skin penetration of nanocarriers prior to their use to avoid possible toxic effects. Nanocarriers can act as a means to increase skin permeation of drugs by supporting direct interaction with the SC and increasing the period of permanence on the skin. Skin penetration is influenced by the physicochemical characteristics of nanocarriers such as composition, size, shape, surface chemistry, as well as skin features. Considering that the target of topical systems based on nanocarriers is the penetration of therapeutic agents in the skin layers, so a detailed understanding of the factors influencing skin permeability of nanocarriers is essential for safe and efficient therapeutic applications.

Preparation and optimization of fast disintegrating tablets of isosorbide dinitrate using lyophilization method for oral drug delivery.

Background: Orally disintegrating tablets rapidly disintegrate in saliva and then swallowed without the need for water. Materials & methods: The orally disintegrating tablets were prepared by freeze-drying of an aqueous dispersion of isosorbide dinitrate containing a matrix former (gelatin), a cryoprotectant (mannitol), a plasticizer (glycerin) and a dissolution enhancer (Tween/polyethylene glycol). Results: Results demonstrated that the selected formulation, Ft9, disintegrated within 1 min and showed faster dissolution rate compared with the commercial tablet. Conclusion: Having a fast disintegration time, the developed lyophilized tablet does not need to be swallowed as a whole. So, it is a convenient solid oral dosage form for the patients who have difficulty with swallowing such as the pediatric and elderly ones.

Preparation and in vitro evaluation of thermosensitive and mucoadhesive hydrogels for intranasal delivery of phenobarbital sodium.

Background: Recently, intranasal administration has been suggested as a potential direct route to transport pharmaceuticals into the brain through the olfactory and trigeminal nerves, bypassing the blood-brain barrier. Materials & methods: The nasal hydrogels were prepared by a cold method using pluronic F-12 and chitosan. Results: All the selected formulations were gelled at 30°C. The gelation time varied from 5 to 10 min. The mucoadhesive strength was adequate to provide prolonged mucosal adhesion. The formulations exhibited good drug content after stability period of 3 months. The permeability studies revealed a high permeation of the drug through the surgically removed nasal tissue. Conclusion: The results suggest that the obtained hydrogels might be suitable candidates for the nasal delivery of phenobarbital sodium.

Development and characterization of sublingual films for enhanced bioavailability of selegiline hydrochloride.

Low oral bioavailability of selegiline hydrochloride (SH) is primarily due to extensive first-pass metabolism and hence the need for an alternative pathway of administration. Herein, we report the development of sublingual SH films. The films were formulated with varying polymer composition (F1-F6) and evaluated for physicochemical characteristics, in vitro drug release and ex vivo permeation studies. The film F2 demonstrated satisfactory weight (10.60 mg), folding endurance (>200), drug content (11.44 mg/cm2), disintegration time (68 s), mucoadhesive strength (47.7 N/cm2), and controlled release for 30 min. The permeation studies exhibited a higher ex vivo sublingual flux than that of the plain drug. This study concludes that the SH film can provide a potential opportunity for sublingual drug delivery.

Expert Design and Optimization of Ethyl Cellulose-Poly (ε-caprolactone) Blend Microparticles For Gastro-Retentive Floating Delivery of Metformin Hydrochloride.

BACKGROUND: Metformin Hydrochloride (MH) is an oral anti-hyperglycemic agent belonging to the biguanide class of drugs. OBJECTIVE: The present study involves the formulation and evaluation of gastro-retentive floating microparticles containing MH as a model drug for the prolongation of absorption time. METHODS: Three levels of a three-factor, Box-Behnken design were used to evaluate the critical formulation variables. Microparticles were prepared using a water-in-oil-in-water double-emulsion solvent evaporation method and examined in terms of production yield, particle size, entrapment efficiency, floating ability, morphology, FTIR (Fourier transform infrared spectroscopy), and in vitro drug release. RESULTS: The optimum conditions for preparing MH microparticles were predicted to be the content of ethyl cellulose content (150 mg),poly (ε-caprolactone) (150 mg), and polyvinyl alcohol (1%w/v).The optimized MH microparticles were found to be spherical with a mean size of 350.2 µm. Entrapment efficiency was 58.62% for microparticles. 63.94% of microparticles showed floating properties. The FTIR analysis confirmed no chemical linkage between microparticle components. in vitro release study showed a controlled release for up to 8h. CONCLUSION: These results demonstrated that MH microparticles, as a drug delivery system, may be useful to achieve a controlled drug release profile suitable for oral administration and may help to reduce the dose of the drug and to improve patient compliance.

Expert design and optimization of a novel buccoadhesive blend film impregnated with metformin nanoparticles.

Aim: The purpose of this study was to design a metformin nanoparticles (NPs)-loaded buccoadhesive film for enhanced drug bioavailability. Materials & methods: The NPs were prepared and incorporated into a hydroxypropyl methylcellulose-chitosan blend film. Three levels of a three-factor, Box-Behnken design were used to evaluate the critical formulation variables. The drug permeation was also examined using sheep buccal mucosa. Results & conclusion: The results verified the formation of spherical NPs with an average size of 177.8 ± 6.42 nm and entrapment efficiency of 78.03 ± 0.23%. The optimum conditions for nanofilms were predicted to be: hydroxypropyl methylcellulose (700 mg), glycerol (50 mg) and chitosan (0.15 %w/v). The nanofilm showed a high drug permeation within 6 h. The metformin nanofilm offers an excellent opportunity for buccal drug delivery.

Preparation and characterization of cyclodextrin nanosponges for bortezomib delivery.

BACKGROUND: Bortezomib (BTZ) as an anticancer drug has been used through the injection pathway. RESEARCH DESIGN AND METHODS: Two types of Cyclodextrin nanosponges (CDNSs) were synthesized and studied by DLS, TEM, FTIR, and DSC instruments for BTZ delivery. Both carriers were analyzed for loading efficiencies and in-vitro release. Cell studies and intestinal permeability of selected CDNS were determined using MTT and SPIP method, respectively. RESULTS: Both types of CDNSs, encapsulated BTZ in their nano-porous structure, but better loading was shown in CDNS 1:4. FTIR and DSC results proved considerable encapsulation of BTZ into CDNSs. The slow and prolonged release profile was observed for CDNS 1:4 in comparison with CDNS 1:2. Based on in-vitro results, BTZ-CDNS 1:4 was chosen as a selected nanosystem for further analysis. This nontoxic carrier revealed considerable uptake (93.9% in 3 h) against the MCF-7 cell line but indicated higher IC50 in comparison with the plain drug. This carrier also could improve the rat intestinal permeability of BTZ almost 5.8 times. CONCLUSION: CDNS 1:4 has the ability to be introduced as a nontoxic carrier for BTZ delivery with its high loading, controlled release manner, high cellular uptake, and permeability improvement characteristics.

Desirability function approach for development of a thermosensitive and bioadhesive nanotransfersome-hydrogel hybrid system for enhanced skin bioavailability and antibacterial activity of cephalexin.

Cellulitis is a common bacterial infection of the skin and soft tissues immediately beneath the skin. Despite the successful use of antibiotics in the treatment of infectious diseases, bacterial infections continue to impose significant global health challenges because of the rapid emergence of antibiotic resistance. The aim of this work was to develop an in situ hydrogel forming system containing highly permeable cephalexin-loaded nanotransfersomes (NTs), suitable for antibacterial drug delivery. Response surface design was applied for the optimization of NTs. Cephalexin NTs were prepared using thin-film hydration method and then embedded into a 3D hydrogel network. The in vitro antibacterial activity of the optimized NTs was assayed against indicator bacteria of Staphylococcus aureus (S. aureus). The drug permeation was evaluated using an ex vivo rat skin model. The in vivo efficacy of the cephalexin NT hydrogel was also determined against rat skin infection. The resulting data verified the formation of NTs, the size of which was approximately 192 nm. The cephalexin NTs exhibited higher antibacterial activity against S. aureus as compared to the untreated drug. The NT hydrogel improved drug penetration through the skin after 8 h. When applied on the rat skin for 10 days, the cephalexin NT hydrogel exhibited superior antibacterial activity with normal hair growth and skin appearance as compared with the plain drug hydrogel. These findings suggest that the cephalexin NT-hydrogel system can serve as a valuable drug delivery platform against bacterial infections.

Preparation and characterization of a novel thermosensitive and bioadhesive cephalexin nanohydrogel: a promising platform for topical antibacterial delivery.

OBJECTIVE: Impetigo is a common and highly contagious bacterial skin infection that mostly affects young children and infants. Herein, we report the development of a thermosensitive and bioadhesive in-situ hydrogel-forming system containing cephalexin-loaded nanoparticles (NPs) suitable for antibacterial drug delivery. METHODS: The nanohydrogel was formulated using drug-loaded NPs and characterized by its physicochemical characteristics. Antibacterial activities of the cephalexin NPs and nanohydrogel were examined in vitro against Staphylococcus aureus (S. aureus). The ex vivo drug permeation study was performed using rat skin. Finally, this formulation was tested for in vivo antibacterial activity using superficial skin infections in rats. RESULTS: The mean size and entrapment efficiency of the NPs were found to be 178 nm and 58%, respectively. The transmission electron microscopy analysis verified the formation of spherical NPs. The drug-loaded NPs showed an enhanced eradication effect against S. aureus according to the declined MIC values in comparison with the untreated drug. The ex vivo permeation profile of the cephalexin nanohydrogel showed a slow release pattern for 8 h. When applied on rat skin for 6 days, the nanohydrogel exhibited a superior antibacterial activity with normal hair growth and skin appearance as compared to the plain drug hydrogel. CONCLUSIONS: These findings suggested that the nanohydrogel could serve as a valuable drug delivery platform against superficial bacterial infections.

PLA-PCL-PEG-PCL-PLA based micelles for improving the ocular permeability of dexamethasone: development, characterization, and in vitro evaluation.

The aim of the present research was to investigate the feasibility of developing polylactide-polycaprolactone-polyethylene glycol-polycaprolactone-polylactide (PLA-PCL-PEG-PCL-PLA) based micelles to improve ocular permeability of dexamethasone (DEX). PLA-PCL-PEG-PCL-PLA copolymers were synthesized by a ring-opening polymerization method. DEX was loaded into the developed copolymers. The DEX-loaded micelles were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS) methods. Cytotoxicity of the micelles obtained was investigated on L929 cell line. Cellular uptake was followed by fluorescence microscopy and flow cytometry analyses. The release behavior of DEX from the micelles as well as the drug release kinetics was studied. Corneal permeability was also evaluated using an ex vivo bovine model. The pentablock copolymers were successfully synthesized. The TEM results verified the formation of spherical micelles, the sizes of which was approximately 65 nm. The micelles exhibited suitable compatibility on L929 cells. The release profile showed an initial burst release phase followed by a sustained release phase, the kinetic of which was close to the Weibull's distribution model. The micelles showed higher corneal permeability in comparison to a marketed DEX eye drop. Taken together, the results indicated that the PLA-PCL-PEG-PCL-PLA micelles could be appropriate candidates for the ocular delivery of DEX, and probably other hydrophobic drugs.

Formulation and Evaluation of Eudragit RL-100 Nanoparticles Loaded In-Situ Forming Gel for Intranasal Delivery of Rivastigmine.

Purpose: Rivastigmine hydrogen tartrate (RHT) is commonly used for the treatment of mild to moderate Alzheimer's disease (AD). The aim of this work was to formulate in-situ pluronic F-127 (PF-127) hydrogels containing Eudragit RL-100 (EU-RL) nanoparticles (NPs) in order to improve the therapeutic efficacy of RHT through the nasal route. Methods: The NPs were prepared using different polymer to drug ratios and evaluated for their physicochemical characteristics, cellular uptake and in vitro cytotoxicity against lung adenocarcinoma cells (A459). PF-127 nanoformulations were prepared via cold method and analyzed in terms of physicochemical properties and drug release profiles. The nanoformulations and plain drug gel were then assessed by ex vivo permeation studies across the sheep nasal mucosa. Results: The EU-RL NPs exhibited a particle size within the range of 118 to 154 nm and positive zeta potential values of 22.5 to 30 mV with an approximately spherical shape. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) suggested no drug to polymer interaction through the preparation of nanoformulations. The RHT-loaded NPs exhibited an acceptable cytocompatibility with a time- and dose-dependent cellular internalization. Conclusion: Our results clearly indicated the potential of nanoformulations as controlled release systems to improve the therapeutic efficacy of RHT through the intranasal administration.

Expert design and desirability function approach for the development of diazepam thermally sensitive rectal gel.

Aim: The aim of the present work was to develop an in situ thermosensitive rectal gel for diazepam by using Expert-design for improving three factors and a three-level process was formed by using a cold method. Methods & materials: Response surface design was utilized to investigate the effect of independent variables like sodium chloride (NaCl, X1), poloxamer 407 (F-127, X2) and diazepam (X3), on different dependent variables such as gelation temperature, mucoadhesive strength, drug content, along with permeation and stability. Results: The obtained results revealed that the addition of diazepam enhanced the gelation temperature of hydrogel while it decreased the gel strength and mucoadhesive force. Conclusion: It is suggested that in situ hydrogels may be suitable candidates for rectal delivery.

A brief overview on nano-sized materials used in the topical treatment of skin and soft tissue bacterial infections.

Introduction: Skin and soft tissue infections are a significant clinical problem that can happen anywhere on the body. Bacteria are the most common cause of skin and soft tissue infections in humans. Despite the fact that there is a lot of antimicrobial agents and antibiotics for elucidating bacterial infections, the prevention and control of infectious diseases continue to be one of the greatest challenges for public health worldwide. At the present time, an alarming increase in multidrug resistance instantly requests to find suitable alternatives to current antibiotics. Therefore, drug resistance has been attempted to be resolved by the development of new classes of antimicrobial agents or targeted delivery systems for antibacterial drugs using nanotechnology.Area covered: The present review summarizes the emerging topical efforts to support the use of nano-sized materials as a new opportunity to combat today's skin infectious diseases.Expert opinion: Nano-sized materials can overcome the stratum corneum barrier and deliver drugs specifically to bacterial skin infections with trivial side effects. Depending on the physicochemical characteristics of nano-scaled materials, they can specifically be selected to target bacterial pathogens and also to get into the skin layers. These systems can overcome the antibiotic-resistance mechanisms and help us to the design of novel topical formulations that will make administration of antibacterial compounds safer, easier and more convenient.

Freeze-thaw-induced cross-linked PVA/chitosan for oxytetracycline-loaded wound dressing: the experimental design and optimization.

Oxytetracycline is an antibiotic for the treatment of the infections caused by Gram-positive and Gram-negative microorganisms. Among novel formulations applied for damaged skin, hydrogels have shown to be superior as they can provide a moist environment for the wound. The purpose of this study was to prepare and evaluate the hydrogels of oxytetracycline consisted of polyvinyl alcohol (PVA) and chitosan polymers. A study design based on 4 factors and 3 levels was used for the preparation and evaluation of hydrogels formed by freeze-thaw (F-T) cycle using PVA and chitosan as a matrix-based wound dressing system. Furthermore, an experimental design was employed in order to study the effect of independent variables, namely drug amount (X1, 500-1000 mg), the amount of PVA (X2, 3.33-7.5%), the amount of chitosan (X3, 0.5-1%), and F-T cycle (X4, 3-7 cycles) on the dependent variables, including encapsulation efficiency, swelling index, adsorption of protein onto hydrogel surface, and skin permeation. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation. Hydrogel microbial tests with sequential dilution method in Muller-Hinton broth medium were also carried out. The selected hydrogel (F6) containing 5% PVA, 0.75% chitosan, 1000 mg drug, and 3 F-T cycles was found to have increased encapsulation efficiency, gel strength, and higher skin permeation suitable for faster healing of wounds. Results showed the biological stability of oxytetracycline HCl in the hydrogel formulation with a lower dilution of the pure drug. Thus, oxytetracycline-loaded hydrogel could be a potential candidate to be used as a wound dressing system.

Cyclodextrin-based nanosponges as promising carriers for active agents.

INTRODUCTION: In recent years, new drug delivery systems have attempted to overcome the undesirable pharmacokinetic problems of various drugs. Among them, cyclodextrin nanosponges (CDNSs) attract great attention from researchers for solving major bioavailability problems such as inadequate solubility, poor dissolution rate, and the limited stability of some agents, as well as increasing their effectiveness and decreasing unwanted side effects. This novel system can also be prepared as different dosage forms. AREAS COVERED: This review will give an insight into the effects of CDNSs on the pharmacokinetic parameters and permeability of active agents. Different classes of drugs delivered by this system are mentioned and we designate which CD is used most widely in their production process. We also inform why this carrier can be introduced as a versatile carrying system in pharmaceutical fields. Registered patents about this novel system in various fields are also mentioned. EXPERT OPINION: The readers will be informed on CDNSs as a novel carrier especially for the delivery of drugs. Versatile characteristics and applications of them can also be known by this review. Finally, CDNSs may be introduced as a remarkable vehicle in the pharmaceutical market in coming years.

Evaluation of anti-inflammatory impact of dexamethasone-loaded PCL-PEG-PCL micelles on endotoxin-induced uveitis in rabbits.

The aim of this study was to investigate the capability of polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) micelles in improving the anti-inflammatory effects of dexamethasone (DEX). A film hydration method was used for the preparation of the DEX-loaded PCL-PEG-PCL micelles. In vitro cytotoxicity of the micelles obtained was investigated on L929 cells. Cellular uptake was studied by using flow cytometry and fluorescence microscopy. Anterior uveitis was induced in a group of rabbits by intravitreal injection of endotoxin from Salmonella typhimurium. The severity of inflammation-induced was clinically graded by using Hogan's classification method. Protein concentration in the aqueous humor was also measured. The micelles exhibited suitable compatibility on L929 cells and were taken up by the cells in a concentration- and time-dependent manner. The DEX-loaded micelles could reduce the clinical symptoms of uveitis after a lag-time. At 24 and 36 h after the LPS injection, the PCL-PEG-PCL micelles showed a better inhibitory effect on uveitis than the marketed eye drop, the differences did not reach significant levels though. This study demonstrated the potential of the PCL-PEG-PCL micelles as carriers for DEX in treating anterior uveitis. However, this concept is still to be further investigated.

Box-Behnken experimental design for preparation and optimization of the intranasal gels of selegiline hydrochloride.

Selegiline hydrochloride (SL) is chosen as an adjunct for the control of clinical signs of Parkinsonian patients. The aim of the present work is to develop and optimize thermosensitive gels using Pluronic (F-127) for enhancing transport of SL into the brain through the nasal route. SL gels were prepared using a cold method and the Box-Behnken experimental design methodology. Drug (SL), gelling agent (F-127), and emulsifier (Propylene glycol, PG) were selected as independent variables, while the gelation temperature, gel strength, pH, gel content, and gel erosion were considered as dependent variables. For further understanding of the interaction between the various variables, contour plots and surface plots were also applied. Selected formulations, like S10 (contain 25 mg SL, 20 g F-127, and 1 g PG) and S14 (contain 50 mg SL, 18 g F-127 and 1 g PG), had a clear appearance in the sol form, with gelling temperature of the nasal gel ranging between 33 and 34, respectively. The gel strength of the formulations varied from 4.67 and 0.68 mm and the drug content was 100%. The pH of the formulations ranged between 6.71 and 7.11. Detachment force was acceptable (63.69-244.16 N/cm2) to provide prolonged adhesion. In vitro, drug release studies showed that the prepared formulations could release SL for up to 8 h. Permeation flux for the S10 gel was 0.0002 mg/min/cm2. Results demonstrated that the potential use of SL gels can enhance the therapeutic effect of SL through the intranasal administration.

Preparation and evaluation of PCL-PEG-PCL micelles as potential nanocarriers for ocular delivery of dexamethasone.

OBJECTIVES: Micelles have been studied as nanoparticulate drug delivery systems for improving the topical ocular delivery of hydrophobic drugs. The objective of this study was to develop and characterize dexamethasone-loaded polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) micelles to improve patient compliance and enhance the ocular bioavailability of poorly water-soluble drugs. MATERIALS AND METHODS: The PCL-PEG-PCL copolymers were synthesized via the ring opening polymerization of ε-caprolactone in the presence of PEG. The resulting purified copolymers were characterized by GPC, NMR, FTIR, XRD and DSC. The critical micelle concentrations (CMCs) of the mentioned copolymers were determined. Dexamethasone was loaded into polymeric micelles by film hydration method, and dexamethasone-loaded micelles were characterized by TEM and DLS. Drug release kinetics and ex vivo corneal permeability were also determined. RESULTS: The CMC of the synthetized copolymers was approximately 0.03 mg/ml. Aqueous solutions of the resulting copolymers (400 mg/ml) rapidly formed a gel in situ at 34°C. The TEM results exhibited the successful formation of spherical micelles. The size of the prepared micelles was approximately 40 nm. Formulated micelles sustained the release of the incorporated dexamethasone for 5 days. CONCLUSION: Data from ex vivo permeability tests indicated that PCL-PEG-PCL micelles can be suitable candidates for the ocular delivery of dexamethasone and, likely, other hydrophobic drugs.