Lung Microbiota: Its Relationship to Respiratory System Diseases and Approaches for Lung-Targeted Probiotic Bacteria Delivery.

Microorganisms that make up the local microbiota (such as Lactobacillus sp. and Bifidobacterium sp.) play a crucial role in the modulation of diseases and health states by taking place not only in the gut but also in many parts of our body. There is also interference between the gut and the lung via the gut-lung axis. The relationship between respiratory diseases and lung microbiota, which become more of an issue of particular importance in recent years, shows that probiotics play an essential role in maintaining the balance of microorganisms in the respiratory tract. However, studies on probiotics' prophylactic or therapeutic application in chronic lung diseases are limited. In this review, the literature between 1977 and 2022 was surveyed. General information about human microbiota was accessed in earlier sources, and especially in the past decade, research on lung microbiota has been reached. The relationship between lung microbiota and important respiratory diseases such as bronchopulmonary dysplasia, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, allergy-asthma, influenza, lung cancer, and COVID-19 infection, was scrutinized after mentioning human microbiota, the gut-lung axis, and respiratory tract microbiota. The mechanism of action of probiotics and the formulation approaches of probiotics in terms of pharmaceutical technology were reviewed. Finally, future perspectives on lung-targeted administration of probiotic bacteria with prophylactic or therapeutic potential, or both, were presented.

Development and quality assessment of glutathione tripeptide loaded niosome containing carbopol emulgels as nanocosmeceutical formulations.

This study focuses on the preparation, physicopharmaceutical and mechanical characterization of reduced glutathione tripeptide loaded niosome containing emulgels as a novel nanocosmeceutical product. Prepared emulgel formulations were mainly composed of oily phase containing different lipids such as glycerine dibehenate, cetyl alcohol, cetearyl alcohol, etc., and aqueous phase containing Carbopol934® as gelling agent. Niosomal lipidic vesicles prepared from Span 60 and cholesterol were subsequently incorporated into optimum emulgel formulations. The pH, viscosity, and textural/mechanical properties of emulgels were examined before and after the incorporation of niosomes. The viscoelasticity and morphological characterization were performed on the final formulation before the packed formulation's microbiological stability test. The hardness and compressibility results ensured easy removal of the emulgel from the container. Due to the carboxyl groups of Carbopol934®, moderate adhesiveness with good cohesiveness was achieved. The rheological characteristics of the emulgels were estimated by oscillatory testing and the data fitted with the Herschel-Bulkley model. Thus, the viscoelastic properties and shear-thinning flow of emulgels were demonstrated. The final formulation was microbiologically stable, and pathogens or skin-irritating allergens were not detected. An anti-aging cosmeceutical preparation containing glutathione tripeptide loaded lipid-based niosome dispersion, suitable for topical use due to its textural and viscosity properties, was successfully produced.

Molecularly imprinted polymers: preparation, characterisation, and application in drug delivery systems.

Molecular imprinting technology defines the creation of molecularly imprinted polymer (MIP) molecules in which template molecules can place in a key-lock relationship through shape, diameter, and functional groups. Although molecular imprinting technology has been employed in different fields, its applications in drug delivery systems (DDSs) have gained momentum recently. The high loading efficiency, high stability, and controlled drug release are the primary advantages of MIPs. Here, the main components, preparation methods, and characterisation tests of MIPs are summarised, and their applications in DDSs administered by different routes are evaluated in detail. The review offers a perspective on molecular imprinting technology and applications of MIPs in drug delivery by surveying the literature approximately 1998-2021 together with the outlined prospects.

A study to enhance the oral bioavailability of s-adenosyl-l-methionine (SAMe): SLN and SLN nanocomposite particles.

The endogenous molecule, S-adenosyl-l-methionine (SAMe) is a key factor due to its role in the methylation cycle and modulation of monoaminergic neurotransmission. Since many mental disorders have linked to the monoaminergic system, the level of SAMe in blood and cerebrospinal fluid is important in the treatment of major depression. In this study, solid lipid nanoparticles (SLN) were prepared in order to increase the limited oral bioavailability of SAMe, and SLN based nanocomposite particles (SAMe-SLN-NC) were further developed using an enteric polymer for passive targeting of intestinal lymphatic system. In this manner, it was also aimed to protect SAMe loaded SLN from harsh gastric environment as well as hepatic first-pass metabolism. Dynamic light scattering (DLS) analysis of SLN was performed, drug content was measured, SAMe release patterns were examined and the permeation ability of SAMe was investigated by the Parallel Artificial Membrane Permeability Assay (PAMPA) to characterize SAMe loaded SLN formulation. According to the PAMPA results, SAMe-SLN with the average particle size of 242 nm showed enhanced SAMe permeability in comparison to pure drug. Delayed drug release obtained by SLN nanocomposite particles indicated the protection of drug-loaded SLN in the acidic gastric medium and their intact presence in the intestine. SAMe solution or particle suspensions were prepared using 0.45 (w/v) hydroxypropyl methylcellulose aqueous solution to be applied to groups of animals for pharmacokinetic studies. In vivo pharmacokinetic parameters revealed enhancement in relative bioavailability of SAMe upon oral administration of SLN based formulations. This was attributed to intact absorption of lipid matrix through lymphatic path. A statistically significant increase in SAMe plasma levels was obtained at 15th and 30th minutes with SAMe-SLN and at 2nd and 4th hours with SAMe-SLN-NC. Overall results suggest that SLN is a promising carrier to passive lymphatic targeting of SAMe and novel SLN nanocomposite particles which presented efficient oral bioavailability is a potential way for oral delivery of SAMe and treatment of major depression.

Development and In vitro Evaluation of Nifedipine Gel Formulations for Anorectal Applications.

OBJECTIVE: Current study focuses on the formulation and characterization of lipophilic and hydrophilic gel formulations of nifedipine to treat anal fissure via anodermal application. METHODS: Lipophilic gels were prepared with Aerosil grades as gelling agents in bulk oils. Polyethylene glycols, hydroxypropyl methylcellulose, and Carbopol® 974P were used as gelling agents in water and propylene glycol for forming hydrophilic gels. The effect of repeated Freeze-Thaw Cycles (FT-C) on microstructures of the gels was investigated by examining viscosity, rheology and textural properties. Aerosil 200 containing lipophilic gels exhibited thixotropic behavior with plastic flow properties and higher viscosities. RESULT: Accordingly, their compressibility and adhesiveness increased. FT-C caused notable changes in microstructures and textural properties of the lipophilic gels excluding the formulation containing Aerosil 200-in-isopropyl myristate. Among the hydrophilic gels, the viscosity of Carbopol® 974P gels increased depending on the amount of polymer, triethanolamine and water; these gels featured plastic flow without thixotropic behavior. Their compressibility and adhesiveness were higher than other gel formulations with stable post-FT-C characteristics. The higher flux values of nifedipine were observed from water containing Carbopol® 974P gel. CONCLUSION: The results of the stability tests showed that the Carbopol® 974P gel had a longer shelf life than the Aerosil 200-in-isopropyl myristate gel.

Investigations on clonazepam-loaded polymeric micelle-like nanoparticles for safe drug administration during pregnancy.

Medication during pregnancy is often a necessity for women to treat their acute or chronic diseases. The goal of this study is to evaluate the potential of micelle-like nanoparticles (MNP) for providing safe drug usage in pregnancy and protect both foetus and mother from medication side effects. Clonazepam-loaded MNP were prepared from copolymers [polystyrene-poly(acrylic acid) (PS-PAA), poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) and distearyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-poly(ethylene glycol) (PEG-DSPE)] with varying monomer ratios and their drug-loading efficiency, drug release ratio, particle size, surface charge and morphology were characterised. The cellular transport and cytotoxicity experiments were conducted on clonazepam and MNP formulations using placenta-choriocarcinoma-BeWo and brain-endothelial-bEnd3 cells. Clonazepam-loaded PEG5000-PLA4500 MNP reduced the drug transport through BeWo cells demonstrating that MNP may lower foetal drug exposure, thus reduce the drug side effects. However, lipofectamine modified MNP improved the transport of clonazepam and found to be promising for brain and in-utero-specific drug treatment.

In situ niosome forming maltodextrin proniosomes of candesartan cilexetil: In vitro and in vivo evaluations.

The aim of this study is to develop novel proniosomal tablets of candesartan cilexetil. Drug loaded proniosomes were prepared as dry powder by slurry method. The critical parameters of the production process were the type of the carrier (sorbitol, maltodextrin, and lactose), addition of charge inducers, rotation speed of the rotavapor and solvent evaporation temperature. The effects of these parameters on proniosome specifications such as the recovery, drug loading, drug release were investigated and also the influence on the particle size and surface charge of the niosomes derived by the hydration of proniosomes were evaluated. The mean particle size and drug loading of niosomes formed from the hydrated proniosomes were 204 ± 2 nm and 99.09 ± 0.04% respectively, with a negative charge -43.65 ± 0.54 mV. The proniosomes demonstrated good flowability, compressibility and consolidation properties both alone and together with the tableting agents (microcrystalline cellulose and cross-linked poly vinylpyrrolidone). The niosomes derived by the hydration of proniosomal tablets preserved their initial properties. Compatibly with the increased in vitro drug dissolution rate, the relative bioavailability of drug from proniosomal tablets increased 1.86-fold and 2.75-fold and higher candesartan plasma levels were achieved within shorter time compared to the pure drug.

Provesicles as novel drug delivery systems.

Vesicular systems exhibit many attractive properties such as controlled drug release, ability to carry both hydrophilic and hydrophobic drugs, targetability and good biocompatibility. With these unique properties they can provide improved drug bioavailability and reduced side effects. Until now, many vesicular formulations have been studied in clinical and preclinical stages. Nevertheless, the major concern about these systems is their low physicochemical stability and high manufacturing expenses. The stability problems (fusion, aggregation, sedimentation, swelling, and drug leakage during storage) associated with the aqueous nature of vesicular systems hinders their effective usage. The advances on improving the stability of vesicular systems led to the emergence of provesicular systems, which are commonly described as dry, free flowing preformulations of vesicular drug delivery systems. Provesicles form vesicular systems upon hydratation with water and exhibit the advantages of vesicular systems with improved stability. The present article briefly reviews vesicular systems (particularly liposomes and niosomes) and enlightens about the innovations in the field. Overall investigations are reviewed and the provesicle approach is explained by giving detailed information on the composition, preparation, administration and characterization methods of provesicular systems (proliposomes and proniosomes). The scope of this article is expected to give insight to the researchers and industrialists to perform further research in this area.

Stability studies on piroxicam encapsulated niosomes.

Drug delivery systems which yield ideal treatments are currently the center of interest for researchers. Niosomes have numerous advantages over other drug delivery systems. However, stability issue is not clear yet and is a serious drawback for niosomes. In this study, the stability of niosomes was the center of interest. Piroxicam which was chosen as the model drug was loaded to niosomes. Niosomes were prepared by thin-film method and different forms (aqueous dispersion, lyophilized powder and lyophilized powder with cryoprotectant) of the original niosome formulation were prepared. The samples were stored either at 5°C±3°C or 25°C±2°C/60% RH±5% RH for 3 months. The drug leakage percent, particle size and distribution, zeta potential, drug release profiles were determined and niosomes were visualized under optic microscope. Niosome formulation provided sustained release of piroxicam. The drug leakage from stored niosomes was observed at the level of 1.56-6.63 %. Individual vesicle images were obtained for all samples by optical microscope. However, particle size of niosomes was increased upon storage. The zeta potential values were neither related to time nor physical form. Drug release profiles and amounts were quite similar for all forms of niosomes and the original formulation but a slight decrease was noticed on drug release amounts by time. This indicates that niosomes become more rigid by time. Although the ideal storage was obtained with lyophilized niosomes at 5±3°C in this study, the usage of suitable cryoprotectant and optimized lyophilization process should be further evaluated.

Development and characterization of mixed niosomes for oral delivery using candesartan cilexetil as a model poorly water-soluble drug.

The aim of this study was to prepare candesartan cilexetil-loaded niosomes and mixed niosomes to enhance the aqueous solubility of the drug, thus improving its oral bioavailability. The formulations were prepared using various types and combinations of surfactants, copolymers, and charge-inducing agents. The candesartan cilexetil entrapment efficiency, particle size, and zeta potential of these niosomes varied within the range of 99.06 ± 1.74 to 36.26 ± 2.78, 157.3 ± 3.3 to 658.3 ± 12.7 nm, and -14.7 ± 2.8 to -44.5 ± 1.5 mV, respectively. The in vitro drug release from niosomes was improved after niosomal entrapment compared to pure candesartan cilexetil. The sedimentation behavior study and formulation stability tests against bile salt revealed that mixed niosomes prepared by combining Span 60 and Pluronic P85 demonstrated better stability. The differential scanning calorimetry analysis showed the conversion of crystal structure of candesartan cilexetil to the soluble amorphous form after niosomal encapsulation which induced the drug release. Consequently, oral drug delivery by Span 60/Pluronic P85-mixed niosomes seems feasible due to enhanced drug release and stability.

Paclitaxel-loaded niosomes for intravenous administration: pharmacokinetics and tissue distribution in rats.

BACKGROUND/AIM: The purpose of this study was to investigate and compare the pharmacokinetic behavior and tissue distribution of paclitaxel, delivered as commercial preparation Taxol or through Span 40 niosomes, after intravenous injection to rats. MATERIALS AND METHODS: Paclitaxel-loaded Span 40 niosomes were prepared using the thin-film method. An HPLC method was developed and validated for paclitaxel determination in rat plasma and tissues. RESULTS: The area under the curve value of the niosome-recipient group (3.22 ± 0.255 µg h/mL) was significantly higher compared to that of the Taxol group (0.725 ± 0.163 µg h/mL). The mean residence time and the elimination half-life of paclitaxel were 1.66 ± 0.133 h and 1.15 ± 0.085 h for Taxol administration, respectively. The elimination half-life (7.63 ± 0.380 h) and the mean residence time (11.0 ± 0.6 h) of paclitaxel were significantly increased, and a pronounced delay was observed in general excretion of paclitaxel from plasma (0.0925 ± 0.00490 h(-1)) after niosomal administration. The spleen was the main tissue that accumulated paclitaxel from both niosomes and Taxol. CONCLUSION: The findings of this study show that niosomal formulation might be a useful drug delivery system for intravenous administration of paclitaxel.

Niosomes encapsulating paclitaxel for oral bioavailability enhancement: preparation, characterization, pharmacokinetics and biodistribution.

In this study, niosome formulations were prepared and evaluated for their effects on improving the oral bioavailability of paclitaxel (PCT). Niosomes were prepared from Span 40 and coated with bioadhesive carbopol polymers. The niosomes encapsulated 98.7% ± 0.8 of the initially added PCT and their size ranged from 133 ± 6 nm to 320 ± 6 nm. The stability of Carbopol 974P coated niosomes in bile salts was better than uncoated niosomes. Extended release of PCT was observed. After oral administration of formulations to Wistar rats, higher drug plasma concentrations were observed for niosomes comparing to PCT suspension. The high PCT accumulation in intestine and liver obtained after Carbopol 974P coated niosomes administration indicated their potential regarding effective treatment of localized carcinomas in intestine and liver. The relative bioavailability of PCT was increased 3.8- and 1.4-fold by uncoated and Carbopol 974P coated niosomes emphasizing the ability of niosomes on improving the oral bioavailability of PCT.

Investigation of formulation variables and excipient interaction on the production of niosomes.

The aim of this study was to investigate the effects of formulation and process variables on the properties of niosomes formed from Span 40 as nonionic surfactant. A variety of formulations encapsulating Paclitaxel, a hydrophobic model drug, were prepared using different dicetyl phosphate (DCP) and Span 40-cholesterol (1:1) amounts. Formulations were optimized by multiple regression analysis to evaluate the changes on niosome characteristics such as entrapment efficiency, particle size, polydispersity index, zeta potential and in vitro drug release. Multiple regression analysis revealed that as Span 40-cholesterol amounts in the formulations were increased, zeta potential and percent of drug released at 24th hour were decreased. Besides, DCP was found to be effective on increasing niosome size. As a process variable, the effect of sonication was observed and findings revealed an irreversible size reduction on Span 40 niosomes after probe sonication. Monodisperse small sized (133 ± 6.01 nm) Span 40 niosomes entrapping 98.2% of Paclitaxel with a weight percentage of 3.64% were successfully prepared. The drug-excipient interactions in niosomes were observed by differential scanning calorimetry and X-ray powder diffraction analysis. Both techniques suggest the conversion of PCTs' crystal structure to amorphous form. The thermal analyses demonstrate the high interaction between drug and surfactant that explains high entrapment efficiency. After 3-month storage, niosomes preserved their stability in terms of drug amount and particle size. Overall, this study showed that Span 40 niosomes with desired properties can be prepared by changing the content and production variables.

Investigation of triacetin effect on indomethacin release from poly(methyl methacrylate) microspheres: evaluation of interactions using FT-IR and NMR spectroscopies.

The purpose of this study was to form indomethacin (IND)-loaded poly(methyl methacrylate) (PMMA) microspheres having an extended drug release profile over a period of 24h. Microspheres were prepared by solvent evaporation method using sucrose stearate as a droplet stabilizer. When PMMA was used alone for the preparation of microspheres, only 44% of IND could be released at the end of 8h. Triacetin was added to PMMA, as a minor phase, and the obtained microspheres showed a high yield process with recovery of 89.82% and incorporation efficiency of 102.3%. A desired release profile lasting 24h was achieved. Differential scanning calorimetry (DSC) analysis showed that IND was found to be in an amorphous state in the microspheres. Fourier transform infrared (FT-IR) and nuclear magnetic resonance ((1)H NMR) spectra suggested that there might be a hydrogen bond present between the IND hydroxyl group and PMMA. No interaction between triacetin and IND or PMMA as the formation of secondary bonds was observed. The release enhancement of IND from microspheres was attributed to the physical plasticization effect of triacetin on PMMA and, to some extent, the amorphous state of the drug.

Characterization of niosomes prepared with various nonionic surfactants for paclitaxel oral delivery.

Nonionic surfactant based vesicles (niosomes) are novel drug delivery systems formed from the self-assembly of nonionic amphiphiles in aqueous media. In the present study niosomal formulations of Paclitaxel (PCT), an antineoplastic agent, were prepared using different surfactants (Tween 20, 60, Span 20, 40, 60, Brij 76, 78, 72) by film hydration method. PCT was successfully entrapped in all of the formulations with encapsulation efficiencies ranging between 12.1 +/- 1.36% and 96.6 +/- 0.482%. Z-average sizes of the niosomes were between 229.3 and 588.2 nm. Depending on the addition of the negatively charged dicetyl phosphate to the formulations negative zeta potential values were obtained. High surface charges showed that niosomes can be suspended in water well and this is beneficial for their storage and administration. PCT released from niosomes by a diffusion controlled mechanism. The slow release observed from these formulations might be beneficial for reducing the toxic side effects of PCT. The niosome preparation method was found to be repeatable in terms of size distribution, zeta potential and % drug loading values. The efficiency of niosomes to protect PCT against gastrointestinal enzymes (trypsin, chymotrypsin, and pepsin) was also evaluated for PCT oral delivery. Among all formulations, gastrointestinal stability of PCT was well preserved with Span 40 niosomes.

Preparation and optimization of superabsorbent hydrogel micromatrices based on poly(acrylic acid), partly sodium salt-g-poly(ethylene oxide) for modified release of indomethacin.

The purpose of this study was to prepare modified-release dosage of indomethacin (IND) in the form of micromatrices based on a superabsorbent hydrogel (SAH), poly(acrylic acid), partly sodium salt-g-poly(ethylene oxide) (PAAc-Na-g-PEO). A soaking procedure was used for the preparation of drug-loaded hydrogel micromatrices. The amount of IND, volume of drug-loading solution, and amount of PAAc-Na-g-PEO granules used for preparing micromatrices were the independent factors. The dependent factors were the measured responses from micromatrices, that is, percent recovery, percent entrapment efficiency, and the time at which 63.2% of the drug was released (T(d), minutes). A three-factor, three-level full factorial design (33) was created to optimize formulations. Nonlinear regression analysis indicated a good correlation between the measured responses and the independent factors. Optimum responses were obtained from medium levels of IND and SAH and low level of drug-loading solution. Differential scanning calorimetry, X-ray diffraction analysis, and scanning electron micrography indicated that IND crystals are physically adsorbed into the pores and irregular spaces of the hydrogel.

Investigation of pluronic and PEG-PE micelles as carriers of meso-tetraphenyl porphine for oral administration.

Meso-tetraphenyl porphine (mTPP) is a highly lipophilic, fluorescent porphyrin derivate and it is used as photosensitizer on the treatment of malign neoplasms. The aim of this study was to prepare mTPP loaded pluronic F127 and polyethylene glycol-distearoyl phosphatidylethanolamine (PEG(2000)-DSPE) micelles to evaluate polymeric micelles potential for the transport of drugs through intestinal mucosa. Transport and bioadhesion behaviors of polymeric micelles was investigated using Caco-2 cell monolayer and everted rat intestine models. In order to show that Caco-2 cells can be used as a transport model cytotoxicity of formulations was tested. Cell viability was more than 80%, showing that Caco-2 cells will keep their viability during the transport studies demonstrating that prepared formulations can be securely used as oral drug carrier systems. Plain micelles were labeled with a fluorescent agent rhodamine-phosphatidylethanolamine (Rh-PE) and their transport through Caco-2 cells was investigated beside mTPP loaded micelles. At the end of 4h transport study through Caco-2 cells, cumulative transport (%) of fluorescent agents were around 14% and 1% in Rh-PE labeled and mTPP loaded micelles This difference was attributed to the different placement of mTPP and Rh-PE in the micellar core. Drug transport was not estimated in everted rat intestine model but the bioadhesion was 79% and 70% for mTPP loaded pluronic F127 and PEG(2000)-DSPE micelles. These good bioadhesion rates are promising for oral drug delivery.

Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs.

The objective of this study is to investigate the solubilization of poorly water-soluble anticancer drugs, octaethylporphine (OEP), meso-tetraphenyl porphine (mTPP) and camptothecin (CPT), in Pluronic and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) polymeric micelles. Three different Pluronic and PEG-DSPE polymers with various chain lengths were chosen and micelle formulations were prepared by using various drug:polymer ratios. Formulations were characterized by critical micellization concentration (CMC) values of copolymers, micelle particle size and distribution, zeta potential, loading efficiency and stability. Polymers formed very stable, low CMC micelles with smaller sizes than 100 nm. It was shown that drug loading efficiency highly depends on the polymer type, drug type and their ratios. The most efficient drug loading was obtained by loading mTPP in PEG2000-DSPE and Pluronic F127 micelles. This result is attributed to phenyl groups in mTPP might lead to attraction between alkyl groups in the polymer and increase drug incorporation. PEG-DSPE formulations had higher zeta potential values indicating that they would be more stable against aggregation than Pluronic micelles. From the drug assay aspect Pluronic micelles remained more stable in 3-month long stability test. These results showed that besides their solubilizing effects, polymeric micelles could be useful as novel drug carriers for hydrophobic drugs.