The delivery of vaccines plays a pivotal role in influencing the strength and longevity of the immune response and controlling reactogenicity. Mucosal immunization, as compared to parenteral ...vaccination, could offer greater protection against respiratory infections while being less invasive. While oral vaccination has been presumed less effective and believed to target mainly the gastrointestinal tract, trans-buccal delivery using mucoadhesive films (MAF) may allow targeted delivery to the mucosa. Here we present an effective strategy for mucosal delivery of several vaccine platforms incorporated in MAF, including DNA plasmids, viral vectors, and lipid nanoparticles incorporating mRNA (mRNA/LNP). The mRNA/LNP vaccine formulation targeting SARS-CoV-2 as a proof of concept remained stable within MAF consisting of slowly releasing water-soluble polymers and an impermeable backing layer, facilitating enhanced penetration into the oral mucosa. This formulation elicited antibody and cellular responses comparable to the intramuscular injection, but also induced the production of mucosal IgAs, highlighting its efficacy, particularly for use as a booster vaccine and the potential advantage for protection against respiratory infections. The MAF vaccine preparation demonstrates significant advantages, such as efficient delivery, stability, and simple noninvasive administration with the potential to alleviate vaccine hesitancy.
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The purpose of this study was to examine skin irritation and phototoxicity potentials of several microemulsions (ME), all comprising approximately the same percentage of surfactant ...mixture, but varying oil/water content and consequently inner structure being either droplet-like (o/w ME, o/w ME carbomer, w/o ME and w/o ME white wax) or lamellar (gel-like ME). Two different in vitro methods were used: MTT assay (performed either on reconstructed human epidermis (RHE) or NCTC 2544 cells) and pig ear test. Neither assay revealed the difference among ME with droplet-like structure. Then again, pig ear test and MTT assay performed on RHE indicated that gel-like ME is more irritant compared to other tested ME, whereas no difference among formulations were observed by MTT assay on NCTC 2544 cells. The reasonable explanation is destruction and consequently uniform structure of ME upon dilution that is inevitable for testing on cell cultures. The results of phototoxicity test again indicated the increased potential of gel-like ME to cause adverse effects on skin. It can be concluded that for ME consisting of the same amount of identical surfactants but having different structure the latter represent a crucial factor that determines their dermal toxicity.
Context: Comparative evaluation of liquid and solid self-microemulsifying drug delivery systems (SMEDDS) as promising approaches for solubility enhancement.
Objective: The aim of this work was to ...develop, characterize, and evaluate a solid SMEDDS prepared via spray-drying of a liquid SMEDDS based on Gelucire® 44/14 to improve the solubility and dissolution rate of naproxen.
Material and methods: Various oils and co-surfactants in combination with Gelucire® 44/14 were evaluated during excipient selection study, solubility testing, and construction of (pseudo)ternary diagrams. The selected system was further evaluated for naproxen solubility, self-microemulsification ability, and in vitro dissolution of naproxen. In addition, its transformation into a solid SMEDDS by spray-drying using maltodextrin as a solid carrier was performed. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to evaluate the physical characteristics of the solid SMEDDS obtained.
Results: The selected formulation of SMEDDS was comprised of Miglyol 812®, Peceol™, Gelucire® 44/14, and Solutol® HS 15. The liquid and solid SMEDDS formed a microemulsion after dilution with comparable average droplet size and exhibited uniform droplet size distribution. In the solid SMEDDS, liquid SMEDDS was adsorbed onto the surface of maltodextrin and formed smooth granular particles with the encapsulated drug predominantly in a dissolved state and partially in an amorphous state. Overall, incorporation of naproxen in SMEDDS, either liquid or solid, resulted in improved solubility and dissolution rate compared to pure naproxen.
Conclusion: This study indicates that a liquid and solid SMEDDS is a strategy for solubility enhancement in the future development of orally delivered dosage forms.
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•Fluid-bed granulation enables production of s-SMEDDS with complete drug release.•Type and concentration of binder and binder/SMEDDS ratio are important variables.•s-SMEDDS tablets ...with preserved self-emulsifying properties and fast drug release.
Solidification of self-microemulsifying drug delivery systems (SMEDDS) is a rising experimental field with important potential for pharmaceutical industry, however fluid-bed granulation with SMEDDS is yet an unexplored solidification technique. The aim of the study was to solidify carvedilol-loaded SMEDDS utilizing fluid bed granulation process and to investigate how the formulation variables (type of solid carrier, optimization of granulation dispersion) and fluid-bed granulation process variables can be optimized in order to achieve suitable agglomeration process, high drug loading and appropriate product characteristics. Obtained granulates exhibited complete drug release, comparable to liquid SMEDDS and superior to crystalline carvedilol, nevertheless compromise between large SMEDDS loading and appropriate flow properties of the granules has to be made. Representative granulates with highest drug loading were further compressed into tablets. It was shown that the optimal excipient selection of compression mixture and compression force can lead to fast carvedilol release even from the tablets. Selfmicroemulsifying properties were not impaired neither after the solidification process and nor after the compression of solid SMEDDS into tablets. This suggests that fluid-bed granulation with SMEDDS offers a perspective alternative for solidification of the SMEDDS, enabling preservation of self-microemulsifying properties, acceptable drug loading and complete drug release.
The aim of this study is to develop a self‐microemulsifying drug delivery system (SMEDDS) for the model active pharmaceutical ingredient (API) dipyridamole using exclusively excipients suitable for ...oral administration and nonvolatile cosolvents. Dipyridamole is a poorly water‐soluble and poorly oil‐soluble compound, which made it an atypical candidate for development of a lipid‐based drug delivery system (LBDDS). Four SMEDDS are successfully formulated, and dipyridamole has up to 1750‐fold higher solubility in the SMEDDS compared to water. Incorporation of 0.6–1% of dipyridamole into the SMEDDS does not considerably affect the droplet size, uniformity of droplet size distribution, and self‐emulsifying properties of the SMEDDS. The applicability of hard capsules for developing a final solid dosage form is tested by dissolution studies of dipyridamole from SMEDDS filled in gelatin and hydroxypropyl methylcellulose (HPMC) hard capsules. In addition, empty SMEDDS are filled into gelatin and HPMC hard capsules. They are stored for 16 weeks at ambient conditions and at 40 °C and 75% relative humidity. The dissolution properties and solubility of dipyridamole are considerably enhanced by incorporating dipyridamole into the SMEDDS; however, development of a final dosage form with hard capsules that are leak‐free for an extended period and at higher temperatures/humidity is still pending.
Practical Applications: This study suggests that substances with low water solubility and low oil solubility can also benefit from incorporation into SMEDDS. Excipient selection needs to be considered carefully for such cases to maximize API incorporation and to ensure the self‐emulsifying properties of the formulation. In addition, only nonvolatile and orally acceptable excipients are used for preparation of SMEDDS, which is important when developing a formulation aimed for oral application. Hard capsules are a common approach for preparation of final dosage forms; however, obtaining leak‐free capsules can be challenging when liquid SMEDDS are used as filling. Storage for prolonged period and at higher temperatures/humidity is necessary for evaluation of liquid SMEDDS‐filled hard capsules.
A self‐microemulsifying drug delivery system (SMEDDS) for a model poorly water‐soluble and poorly oil‐soluble active pharmaceutical ingredient (API) is developed using exclusively nonvolatile and orally acceptable excipients. Incorporation into the SMEDDS greatly improves the solubility and dissolution rate, and lowers pH dependence of the model API dissolution.
Antioxidant vitamins have been proven to be highly efficient in treatment of skin impaired by oxidative stress, but challenges regarding stability and skin penetration limit their therapeutic effect. ...Lipid-based drug delivery systems offer great potential for overcoming these drawbacks. This work aimed to identify the most promising system for combined antioxidant therapy. A comparative assessment of several systems, containing the same ingredients but differing in their microstructure, was therefore performed. Namely, microemulsions (MEs) of both types (W/O and O/W) and lyotropic liquid crystals (LLCs), simultaneously loaded with vitamin C or ascorbyl palmitate and vitamin E, were assessed. Stability, antioxidant capacity (DPPH assay), and release (Franz diffusion cells) of the vitamins incorporated was examined. The results obtained were supported with the systems' thermal and rheological (rotational and oscillatory tests) evaluation. In addition, biological acceptability (MTS assay) of the systems studied was investigated. The findings demonstrate that the microstructure of MEs and LLCs studied has a decisive impact on the stability, antioxidant activity, and release of the vitamins incorporated. The highest stability was preserved in LLCs for both pairings, with vitamins C and E being a more stable combination. LLCs also provided suitable vitamins' antioxidant activity and release characteristics. In addition, the system exhibited preferable rheological features for dermal administration. Furthermore, cytotoxicity studies on a keratinocyte cell line demonstrated the highest biocompatibility for LCCs with the cell proliferation being greater than 85%. In conclusion, LLCs were confirmed as the most favorable lipid-based drug delivery system for combined antioxidant treatment.
Several different methods for production of liposomes incorporating resveratrol were investigated and compared from the aspect of size distribution, surface charge, entrapment efficiency, phase ...behavior and stability. Thin film method and proliposome method provided high entrapment efficiency (92.9% and 97.4%, respectively). Extrusion and sonication techniques were applied to obtain particles of the average diameter between 120 and 270nm. The sonicated liposomes incorporated resveratrol (44–56%) fewer than extruded vesicles (92–96%). Antioxidative activity of resveratrol was retained upon encapsulation. Differential scanning calorimetry was performed in order to study the interaction of liposomal membranes with resveratrol, and their physical state. The release studies performed in Franz diffusion cell showed that liposomes impart slow diffusion of resveratrol, where diffusion resistance derived from liposomal membrane ranged from 5.90∙105 to 9.55∙105s/m depending on the size of particles. Cytotoxicity of the formulations was evaluated via morphological changes of keratinocytes treated by liposomes.
Resveratrol displays many health-beneficial properties and possesses a remarkably strong antioxidant activity. Although often consumed in food, the positive effects of resveratrol are restricted because it is prone to oxidation, poorly absorbed when orally administrated, and cytotoxic in higher total dosages (though relatively high local concentrations are required for an effect). Encapsulation is one way to improve bioavailability and stability of resveratrol; herein the main challenge is to find a suitable solution, as resveratrol is weakly water soluble. This has motivated us to design new formulations based on liposomes for delivering of resveratrol.
In the food sector, liposomes have been investigated for delivering proteins, enzymes, antioxidants, flavors and vitamins. The mean advantage of liposomes over other encapsulation technologies (spray-drying, extrusion, and fluidized beds) is the stability that liposomes impart to water-soluble compounds in aqueous surroundings. Liposomes are able to stabilize the encapsulated materials against a range of environmental and chemical changes. Another important characteristic of liposomes is that, unlike many other existing encapsulants, they can be utilized in the entrapment, delivery, and release of poorly water soluble compounds, such as resveratrol, and they are also convenient for water-soluble, lipid-soluble, and amphiphilic compounds. As liposomes could be produced from naturally occurring components, regulatory issues that may prevent the application in food systems are potentially diminished, and new formulations could be quickly implemented. Despite benefits described here, up to date little use of liposomes in food systems has been made, as current manufacturing processes are mainly time consuming, often consisting of several steps with high costs of raw materials. Another problem is that devices available commercially which are utilized for production of liposomes are able to process only small quantities. Therefore, our research is devoted to the development of the process for liposome production which is easy to scale up, and at the same time, is effective as the common way based on thin film hydration process. The process elaborated in our study utilizes a commercial lipid mixture. The method used called proliposome method is based on replacement of ethanol solvent by aqueous media. For liposome downsizing, sonication (which can be easily modified to increase sample volume capability) is tested versus membrane extrusion (equipment for small–large batches is readily available). The goal of this article is to provide evidence for food manufacturers and food scientists to make broader use of resveratrol-loaded liposomes that can add value and improve the quality of existing food products.
•Resveratrol was encapsulated in liposomes.•Thin film method and proliposome method were used for production of liposomes.•The size of liposomes was reduced by extrusion and sonication.•Antioxidative activity of resveratrol was retained upon encapsulation.•Liposomes impart slow diffusion of resveratrol.
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Insight into the microstructure of lyotropic liquid crystals (LCs) is of crucial importance for development of novel dermal delivery systems. Our aim was to evaluate the phase ...behaviour of dermally applicable LCs composed of isopropyl myristate/Tween 80/lecithin/water, along the dilution line, where phase transitions are predominantly driven by increased water content. Additionally, identification of LC temperature dependence is of great importance for skin application. Selected LCs were evaluated using electron paramagnetic resonance (EPR) plus conventionally used methods of polarization microscopy, small-angle X-ray scattering, differential scanning calorimetry, and rheological measurements. Depending on water content, LCs formed diverse microstructures, from (pseudo)hexagonal (LC1) and lamellar (LC2-LC7) liquid crystalline phases that possibly co-exist with rod-like micelles (LC4-LC7), to a transitional micellar phase (LC8). Furthermore, the LCs microstructure remained unaltered within the tested temperature range. EPR was shown to detect microstructural transitions of LCs and to provide complementary data to other techniques. These data thus confirm the applicability of EPR as a complementary technique for better understanding of LC microstructural transitions that are expected to contribute greatly to studies oriented towards the drug release characteristics from such systems.
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To elaborate the decisive role of surfactants in promotion of aceclofenac’ skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or ...synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester- over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81±5.97 and 60.86±3.67 vs. 27.00±5.09μg/cm2, and its maximum plasma concentrations 275.57±109.49 and 281.31±76.76 vs. 150.23±69.74ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery.
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•Films and wafers from water-soluble chitosan were compared to conventional chitosan.•Different solvents and manufacturing techniques affected physicochemical properties.•Fast drug ...release from film formulations and steadier from wafer formulations.•Consistent permeability through monolayers of mucus-producing HT29-MTX cells.•Superior patient-centric qualities for formulations based on water-soluble chitosan.
Oromucosal films and wafers are user-friendly solid dosage forms offering easy and convenient administration, as well as rapid or controlled drug delivery. The aim of this study was to develop prednisolone containing child-friendly chitosan-based mucoadhesive films and wafers with a prolonged residence time on the buccal mucosa. Four different chitosan types (different molecular weights, degree of deacetylation (DDA), pattern of deacetylation) were studied for films prepared by solvent-cast-evaporation and wafers by freeze-drying. Mucoadhesive properties correlated with swelling abilities and were dependent on the chitosan type, the solvent, and the preparation method. Mucoadhesive forces were higher for formulations containing chitosan with higher DDA and for wafers compared to films. The drug release was relatively fast, especially for films (approx. 90 % in 15 minutes) and steadier for wafers (90 % in 45–120 minutes). Permeability was evaluated using artificial membranes and HT29-MTX cell-monolayers. The developed formulations exhibited good biocompatibility. Organoleptic properties can be improved by choosing a homogenously deacetylated chitosan type that provides a more neutral pH. Using hydroxypropyl-beta-cyclodextrin-complexation for taste masking of bitter drugs also reduced wafers’ drug release rate. Mucoadhesive wafers are promising alternatives to films with a slower drug release rate and stronger mucoadhesion.
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