A New Insight to Silver Sulfadiazine Antibacterial Dressings: Nanoparticle-Loaded Nanofibers for Controlled Drug Delivery.

The aim of this study was formulating a new-generation antibacterial dressing in a form of polymer-based hybrid nanofiber-nanoparticles, effective on Gram-negative and Gram-positive bacteria using silver sulfadiazine (SSD), an FDA-approved topical antibiotic. In this study, SSD nanoparticles were prepared with chitosan for taking the advantage of antibacterial and wound healing properties. Chitosan nanoparticles of SSD were prepared by using tripolyphosphate (TPP) or sulfobutylether-ß-cyclodextrin (SBE-ß-CD) as crosslinkers via ionic gelation method and then loaded to PVP-K30 and PVP-K90 nanofibers to obtain polymer-based nanofiber-nanoparticles. SSD-loaded chitosan nanoparticles prepared with SBE-ß-CD had lower particle size (359.6 ± 19.9 nm) and polydispersity index (0.364 ± 0.113) as well, indicating a more desired particle size distribution but lower encapsulation efficiency (56.04% ± 4.33). It was found that loading drug in SBE-ß-CD crosslinked nanoparticles and dispersing in nanofiber matrix lowered SSD release compared to  TPP crosslinked nanoparticle-loaded nanofibers. Drug release obtained by both TPP or SBE-ß-CD crosslinked nanoparticle-loaded PVP-K30 nanofibers is significantly higher than nanoparticle-loaded PVP-K90 nanofibers, indicating that SSD release was mainly affected by polymer type. SSD nanoparticle-loaded PVP-K30 nanofibers were found to be effective against Gram-negative (Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii) and Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis). SSD release was sustained by PVP-K90, resulting in lower antibacterial efficiency especially against Gram-positive bacteria. PVP-K30-based nanofiber-CS nanoparticle hybrids offer a new platform by combining and improving advantages of nanofibers and nanoparticles for obtaining controlled drug release and antibacterial efficacy.

Three-dimensional printed dosage forms based on disease-focussed perspectives.

OBJECTIVES: Three-dimensional printing (3DP) has gained importance worldwide recently as a novel drug manufacturing technology. 3DP technologies are suitable in the pharmaceutical field because of having the potential in personalized medicine. The aim of this review is to present an overview of the use of 3DP technologies in pharmaceutical area, their working principles and critical process parameters. In addition, this review presents an innovative approach that evaluates the use of 3DP technologies on disease to disease. KEY FINDINGS: This review covers the potential use of 3DP technologies in different diseases by evaluating them on a research basis. These diseases can be summarized as cardiovascular, neurological, respiratory, oncological, inflammatory, vaginal, dermatological and other diseases. It has been focussed on manuscripts that published after 2015. Studies on the use of 3DP in each disease group have been systematically reviewed by considering the methods, types of printers used and the prepared dosage forms. Oral formulations (tablets and films), implants, topical systems and vaccines are some of the examples of the mentioned dosage forms. SUMMARY: This review presented a systematic and novel overview of the use of 3DP in the treatment of different clinical disorders.

Etodolac nanosuspension based gel for enhanced dermal delivery: in vitro and in vivo evaluation.

AIM: The objective of this study was to develop dermal nanosuspension (NS) based gel formulation of etodolac (ETD). METHODS: Etodolac nanosuspension (ETD-NS) was prepared by wet milling method and dispersed in hydroxypropyl methylcellulose (NS-HPMC) or hydroxyethyl cellulose (NS-HEC) gels. Rheologic and mechanical properties were investigated. In vitro and ex vivo permeability studies were performed. Topical anti-inflammatory and analgesic activity were evaluated in regard to carrageenan-induced inflammatory paw oedema and radiant heat tail-flick method, respectively. RESULTS: The ETD-NS with approximately 190 nm particle size (PS), 0.16 polydispersity index (PDI), and -15 mV zeta potential (ZP) values were obtained. The work of bioadhesion values of NS-HEC and NS-HPMC gels were 0.229 mJ/cm2 for both gels. Dermal permeation of ETD from NS-HEC gel (7.18%) was found significantly higher than the NS-HPMC gel (4.56%). Enhanced anti-inflammatory and analgesic activity of NS-HEC gels were observed in comparison with micronised ETD. CONCLUSIONS: ETD-NS based gel formulation is promising for topical delivery of ETD.

3D printed extended release tablets for once daily use: An in vitro and in vivo evaluation study for a personalized solid dosage form.

Fused deposition modeling (FDM)-3D printing enables the manufacturing of dosage forms with personalized doses and controllable release profiles. Parkinson's disease is a neurodegenerative disorder that causes motor complications. In the treatment of the disease, the nonergot dopamine receptor agonist pramipexole is used in gradually increasing doses depending on patient's needs. Hence, there are various dosed commercial products of pramipexole and it is a suitable model drug for the preparation of personalized-dose 3D printed dosage forms. In this study, we prepared extended release 3D tablets of pramipexole for once daily use in Parkinson's disease. Herein, 12 different 3D tablet formulations were prepared and in vitro characterizations were performed on these formulations. The formulations were compared with the marketed tablet and the optimum formulation was selected. The chosen formulation was prepared with commercially available doses of pramipexole and also with intermediate doses which are not available in the market to demonstrate the applicability of 3D printing in personalized dosing. Stability studies, which have innovative features for 3D tablets, were conducted in optimum 3D tablet formulation for 6 months at 25 °C/60% relative humidity (RH) and 40 °C/75% RH conditions. After oral administration of the optimum 3D tablets and the marketed tablets (in the same dose) to the rats, 24-hour plasma profiles were obtained and pharmacokinetic parameters were calculated. 3D tablets were successfully prepared in personalized doses and their properties were similar for almost all doses. The optimum 3D tablet formulation was found to be stable during the stability tests. 3D tablet and marketed tablet performed similar plasma profiles. The relative bioavailability of 3D tablet formulation was calculated as 107.6% compared with the marketed tablet. Briefly, in vitro and in vivo evaluations demonstrated that FDM-3D printing is a promising technology for the development of personalized dosage forms with extended release property and comparable to conventional ones.

Preparation, characterization and antimicrobial activity evaluation of electrospun PCL nanofiber composites of resveratrol nanocrystals.

The objective of this study was to develop resveratrol nanocrystals to solve low water solubility issues of resveratrol and adsorb them to the polycaprolactone nanofibers. Nanocrystals were prepared by microfluidization. Particle size, polydispersity index and zeta potential values were evaluated as dependent variables. Polycaprolactone (PCL) nanofibers were prepared via electrospinning method and the flow rate, electrical voltage and tip-to-collector distance were set to 3 mL/h, 13 kV and 15 cm, respectively. Optimum resveratrol nanocrystals were lyophilized and re-suspended in water and physically adsorbed to PCL nanofibers with two different concentrations (0.2 and 1 mg/cm2). Bioadhesion, wettability, solubility, drug loading and antimicrobial activity against Propionibacterium acnes studies were carried out. Final nanocrystals showed 800 nm of particle size, 0.4 of polydispersity index, and -8 mV of zeta potential. Nanocrystals successfully adsorbed to PCL nanofibers proven on SEM images with adsorption efficiencies >70%. Adsorption of resveratrol nanocrystals decreased the contact angle of PCL from 128° to 50°. The solubility of resveratrol nanocrystals enhanced ∼5-fold in comparison with coarse powder. Effective antimicrobial activity against P. acnes was observed. It is concluded that nanocrystal loading on nanofibers brings advantage into preparing easy to use dermal patches for acne treatment or skin disorders.

In vitro and in vivo evaluation of microneedles coated with electrosprayed micro/nanoparticles for medical skin treatments.

AIM: Microneedles (MNs) create micropunctures and deliver drugs or nutrients deep into skin layer. We demonstrated that MNs, coated with electrosprayed nanoparticles loaded with functional molecules, are useful for transdermal delivery. METHODS: Electrospraying was utilised to generate drug-loaded nanoparticles and to create uniform coating on MNs. Process parameters and release kinetics were evaluated in vitro. The in vivo efficacy of insulin-coated MNs was investigated using diabetic rats. RESULTS: Electrosprayed micro/nanoparticles loaded with dye or insulin were coated on MNs with particle size of 515 ± 286 and 522 ± 261 nm, respectively. Optimally coated MNs resulted in >70% transfer rate into porcine skins. Insulin-coated MNs were applied to diabetic rats resulting in reduction of blood glucose levels fluctuations, compared to subcutaneous injections. CONCLUSIONS: Electrospraying is shown to be an effective method to coat MNs with drug-loaded nanoparticles. Coated MNs provide a promising platform for cosmetic, drug and protein delivery applications.

Electrospun metronidazole-loaded nanofibers for vaginal drug delivery.

Objective: To develop and characterize innovative vaginal dosage forms for the treatment of bacterial vaginosis (BV).Significance: This study is the first comparative evaluation of the metronidazole (MET)-loaded polyvinylpyrrolidone (PVP) nanofiber formulations on BV treatment. Vaginal nanofibers are one of the potential innovative dosage forms for BV treatment because of their flexible, mucoadhesive, and easy application in vaginal application which can be applied by the mucosal route.Methods: Blank and MET-loaded PVP solutions were prepared at three different concentrations (10, 12.5, 15%) for produce nanofiber. The suitability of the viscosities, surface tensions, and conductivity values of the solutions used to produce nanofibers for the electrospinning process has been evaluated. Scanning electron microscopy, mucoadhesion, permeability, Fourier transform infrared spectroscopy, differential scanning calorimetry, and drug release tests were performed to reveal the physical, chemical, and pharmaceutical properties of the nanofibers. Mechanical properties, and contact angle of the fibers were also determined. Gel and solution formulations containing MET were prepared for comparative studies.Results: All polymer solutions were found to be suitable for electrospinning process. PVP concentration directly affected nanofiber diameter, mechanical, and mucoadhesion properties of nanofibers. The release profiles of the drug from the nanofibers were similar for all concentration of PVP and release from the fibers was rapid. The permeability coefficient of MET from nanofibers was increased more than gel and solution formulations.Conclusions: Vaginal use of MET-loaded nanofibers has been shown to be a potential drug delivery system for the treatment of BV.

Self-inflating floating nanofiber membranes for controlled drug delivery.

Floating gastro-retentive delivery systems can prolong the gastric residence providing sustained drug release. In this study, we report on self-inflating effervescence-based electrospun nanofiber membranes embedding polyethylene oxide/sodium bicarbonate cast films. In this system, sodium bicarbonate results in an effervescence effect by creating carbon dioxide gas upon contacting an acidic gastric fluid, with the resulting gas bubbles being entrapped within the swollen network of nanofibers. Eudragit RL and RS polymers are utilized as a host material to manipulate release kinetics of incorporated drugs. Pramipexole, a common medication for chronic Parkinson's disease (PD), is used as a model drug. Uniform and bead-free nanofibers with diameters of ~300 nm were obtained. Although floating nanofibers initially exhibited high water contact angles (WCA), water droplets were quickly absorbed into the surface and the WCA decreased to ~0° within 60 s. Floating lag time, total floating time, swelling properties and drug release profiles were investigated both in a simulated gastric fluid (pH 1.2 buffer solution) and in a simulated intestinal fluid (pH 6.8 buffer solution) at 37 °C. All floating nanofiber formulations began to float instantly with nearly zero floating lag time and did not sink into the solution even after 24 h. By comparison, the same formulations without sodium bicarbonate cast films could not maintain continuous floating beyond 15 min. The floating nanofiber pouches presented lower initial release of between 20 and 57 %, compared to that of non-floating nanofiber pouches (40-82% within 2 h). Clearly, floating nanofibers reduced the initial burst release and provided sustained drug release. This demonstrates the potential to result in 'once-a-day' oral introduction of drugs that normally must be taken frequently. Effervescence-based floating nanofibers present a novel and promising prototype delivery system for the drug delivery in the upper gastro-intestinal (GI) tract.

The effect of a new wound dressing on wound healing: Biochemical and histopathological evaluation.

Electrospinning process has gained importance in the production of wound dressings in recent years. The wound dressings prepared by electrospinning method provide many advantages over conventional wound dressings. The aim of this study was to assess the histological, biochemical, and immunohistochemical evaluation of collagen/doxycycline loaded nanofiber wound dressing in both acute and chronic wound healing. Full-thickness wound model was created on rats and rats were divided in two main groups: normoglycemic (acute) and hyperglycemic (chronic) groups. Each group was divided into three sub groups: not treated (control) group, treated with nanofiber wound dressing group and treated with commercial product group. Wound closure rates were measured. Oxidative events were investigated by biochemical analyses. In addition to histological studies, matrix metalloproteinase, tissue inhibitor of metalloproteinase, vascular endothelial growth factor, basic-fibroblast growth factor, and von Willebrand factor levels were investigated with immunohistochemical studies. According to the biochemical analyses, it was concluded that the nanofiber wound dressing helps to increase antioxidant capacity and decrease lipid peroxidation. Immunohistochemical studies showed that nanofiber wound dressing enhanced angiogenesis and shortened the inflammatory phase. It was concluded that an effective and safe prototype nanofiber wound dressing, which has similar wound healing effect to the commercial product, has been developed to be used in acute or chronic wound treatment.

An Effective Technology for the Development of Immediate Release Solid Dosage Forms Containing Low-Dose Drug: Fused Deposition Modeling 3D Printing.

PURPOSE: Fabrication of immediate release (IR) tablet formulations with rapid release profile via fused deposition modeling 3D printing (FDM 3DP) is a challenge. The aims of this study were to prepare IR tablets with different dissolution profiles and to increase their in vitro dissolution rates by making physical modifications on them. Pramipexole was used as the model low-dose drug. METHODS: Polymeric filaments were prepared with six different combinations of Eudragit EPO and poly(ethylene) oxide by hot melt extrusion and 3D tablets were produced using an FDM printer. Characterization studies for the filaments and tablets were carried out. The printability of the filaments was also evaluated using a novel mechanical characterization method. Tablet formulation with optimum dissolution profile was chosen and physical modifications (infill %, shape change and thickness) on this formulation were made. RESULTS: Low-dose pramipexole loading filaments and 3D tablets were homogenously prepared. The printability of the filaments was related to their flexibility. With the physical modifications, the drug release completion time of the tablets reduced to 5 min. CONCLUSIONS: The same rapid release profiles with conventional IR tablets can be reached by making only physical changes on 3D tablets without using any filling or disintegrating agents.

Fabrication of doxycycline-loaded electrospun PCL/PEO membranes for a potential drug delivery system.

Potential usage of biodegradable and biocompatible polymeric nanofibers is the most attention grabbing topic for the drug delivery system. In order to fabricate ultrafine fibers, electrospinning, one of the well-known techniques, has been extensively studied in the literature. In the present study, the objective is to achieve the optimum blend of hydrophobic and hydrophilic polymers to be used as a drug delivery vehicle and also to obtain the optimum amount of doxycycline (DOXH) to reach the optimum release. In this case, the biodegradable and biocompatible synthetic polymers, poly(ε-caprolactone) (PCL) and poly(ethylene oxide) (PEO), were blended with different ratios for the production of DOXH-loaded electrospun PCL/PEO membranes using electrospinning technique, which is a novel attempt. The fabricated membranes were subsequently characterized to optimize the blending ratio of polymers by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD) and water contact angle analysis. After the characterization studies, different amounts of DOXH were loaded to the optimized blend of PCL and PEO to investigate the release of DOXH from the membrane used as a drug delivery vehicle. In vitro drug release studies were performed, and in vitro drug release kinetics were assessed to confirm the usage of these nanofiber materials as efficient drug delivery vehicles. The results indicated that 3.5% DOXH-loaded (75:25 w/w) PCL/PEO is the most acceptable membrane to provide prolonged release rather than immediate release of DOXH.

Development and characterization of rapid dissolving ornidazole loaded PVP electrospun fibers.

Gingivitis is a common and mild form of periodontal disease and can be described as a limited inflammation of the gingiva. This study aims to develop and characterize rapid releasing mucoadhesive fibers containing ornidazole with electrospinning process for the treatment of gingivitis. Polyvinylpyrrolidone (PVP) was chosen as a polymer and used at different concentrations of 10%, 12.5%, and 15%. Scanning electron microscopy images showed that fiber diameters increased with increasing polymer concentrations. Tensile strength and elongation at break values of fibers increased with increasing PVP amount, whereas the loading of ornidazole into the fibers decreased these parameters. The contact angle values of all fibers were found to be 0° due to the hydrophilic nature of PVP. Ornidazole was released within 5 min and diffused from all of the fibers faster than that of gel and solution formulations. Electrospun ornidazole fibers were found efficient against Porphyromonas gingivalis in antimicrobial activity studies. The results demonstrated that ornidazole loaded fibers could be a potential drug delivery system for the treatment of gingivitis.

Evaluation of three-layered doxycycline-collagen loaded nanofiber wound dressing.

Nanofiber wound dressings have great potential for both acute and chronic wound healing. The aim of this study is to develop a wound dressing by the electrospinning method and to determine its in vitro characteristics. The viscosity and the surface tension values of the polymer solutions used in the electrospinning were measured and their suitability for electrospinning was evaluated. Nanofiber wound dressing consists of three layers. The first and the second layers are sodium alginate and chitosan nanofibers, respectively. The core of the coaxial nanofibers that comprises the third layer of the wound dressing contains 1% polycaprolactone and 4.5% collagen, the shell comprises 2.5% doxycycline and 2.5% polyethylene oxide. The developed wound dressing comprises aligned nanofibers, with a contact angle of 38°, a work of bioadhesion value of 0.485mJ/cm2 on rat skin, a tensile strength of 2.76MPa, an elongation at break value of 7.65%, a specific surface area of 9.65m2/g and a porosity of 52.3%. The amount of doxycycline content was found to be 260µg/cm2 and the complete drug release was achieved in 15min. No cytotoxic effect was shown in cell culture studies with keratinocyte cell lines. As a result of the stability studies, it was found that the morphological, mechanical, bioadhesion and wettability properties and the amount of doxycycline remained stable for a period of 12 months at 4°C/ambient humidity condition. The developed three-layered wound dressing could be an alternative for wound healing applications.

Preparation and characterization of electrospun nanofibers containing glutamine.

Oral mucositis is a painful inflammation of mucous membranes commonly after chemotherapy or radiotherapy. The aim of this study was to develop mucoadhesive nanofibers containing glutamine via electrospinning and to characterize them for the treatment of oral mucositis. Different mucoadhesive polymers were tried for preparing nanofibers and sodium alginate nanofibers were chosen after the characterization studies. Glutamine-loaded nanofibers were produced and characterized. Glutamine loaded onto nanofibers was confirmed by differantial scanning calorimetry and fourier transform infrared spectroscopy analyses. As a result, scanning electron microscopy observations showed that the glutamine loaded nanofibers had average diameter of 160nm. Glutamine amount was found to be 0.452mg/cm(2). Work of mucoadhesion, tensile strength and elongation at break values of the glutamine loaded nanofibers were found to be 0.165mJ/cm(2), 2.61mPa and 6.62% respectively. In vitro dissolution tests showed that more than 85% of the drug was diffused from the nanofibers at the end of 4h. Stability studies showed that there was no significant changes at 4 and 25°C/65% relative humidity storage conditions. Therefore, these results demonstrate that glutamine loaded nanofibers could have potential as an oromucosal drug delivery system for the treatment oral mucositis.