Celecoxib-Loaded Cubosomal Nanoparticles as a Therapeutic Approach for Staphylococcus aureus In Vivo Infection.

There is a great need for novel approaches to treating bacterial infections, due to the vast dissemination of resistance among pathogenic bacteria. Staphylococcus aureus are ubiquitous Gram-positive pathogenic bacteria and are rapidly acquiring antibiotic resistance. Here, celecoxib was encapsulated into cubosomal nanoparticles, and the particle morphology, size distribution, zeta potential, entrapment efficiency, and celecoxib release were evaluated in vitro. Also, a systemic infection model in mice elucidated the in vivo antibacterial action of the celecoxib cubosomes. Cubosomes are a nanotechnology-based delivery system which can adhere to the external peptidoglycan layers of Gram-positive bacteria and penetrate them. The size distribution investigation revealed that the prepared celecoxib-loaded cubosomes had a mean particle size of 128.15 ± 3.04 nm with a low polydispersity index of 0.235 ± 0.023. The zeta potential measurement showed that the prepared cubosomes had a negative surface charge of -17.50 ± 0.45, indicating a highly stable nanodispersion formation with little susceptibility to particle aggregation. The cubosomal dispersion exhibited an entrapment efficiency of 88.57 ± 2.36%. The transmission electron micrograph for the prepared celecoxib-loaded cubosomes showed a narrow size distribution for the cubosomal nanoparticles, which had a spherical shape and were non-aggregated. The tested cubosomes diminished the inflammation in the treated mice's liver and spleen tissues, as revealed by hematoxylin and eosin stain and Masson's trichrome stain. The immunostained tissues with nuclear factor kappa B and caspase-3 monoclonal antibodies revealed a marked decrease in these markers in the celecoxib-treated group, as it resulted in negative or weak immunostaining in liver and spleen that ranged from 4.54% to 17.43%. This indicates their inhibitory effect on the inflammatory pathway and apoptosis, respectively. Furthermore, they reduced the bacterial burden in the studied tissues. This is alongside a decrease in the inflammatory markers (interleukin-1 beta, interleukin-6, cyclooxygenase-2, and tumor necrosis factor-alpha) determined by ELISA and qRT-PCR. The IL-1ß levels were 16.66 ± 0.5 pg/mg and 17 ± 0.9 pg/mg in liver and spleen, respectively. Also, IL-6 levels were 85 ± 3.2 pg/mg and 84 ± 2.4 pg/mg in liver and spleen, respectively. In conclusion, the current study introduced cubosomes as an approach for the formulation of celecoxib to enhance its in vivo antibacterial action by improving its oral bioavailability.

Fabrication of Celecoxib PVP Microparticles Stabilized by Gelucire 48/16 via Electrospraying for Enhanced Anti-Inflammatory Action.

Electrospraying (ES) technology is considered an efficient micro/nanoparticle fabrication technique with controlled dimensions and diverse morphology. Gelurice® 48/16 (GLR) has been employed to stabilize the aqueous dispersion of Celecoxib (CXB) for enhancing its solubility and oral bioavailability. Our formula is composed of CXB loaded in polyvinylpyllodine (PVP) stabilized with GLR to formulate microparticles (MPs) (CXB-GLR-PVP MPs). CXB-GLR-PVP MPs display excellent in vitro properties regarding particle size (548 ± 10.23 nm), zeta potential (-20.21 ± 2.45 mV), and drug loading (DL, 1.98 ± 0.059 mg per 10 mg MPs). CXB-GLR-PVP MPs showed a significant (p < 0.05) higher % cumulative release after ten minutes (50.31 ± 4.36) compared to free CXB (10.63 ± 2.89). CXB exhibited good dispersibility, proved by X-ray diffractometry (XRD), adequate compatibility of all components, confirmed by Fourier-Transform Infrared Spectroscopy (FTIR), and spherical geometry as revealed in scanning electron microscopy (SEM). Concerning our anti-inflammatory study, there was a significant decrease in the scores of the inflammatory markers' immunostaining in the CXB-GLR-PVP MPs treated group. Also, the amounts of the oxidative stress biomarkers, as well as mRNA expression of interleukins (IL-1ß and IL-6), considerably declined (p < 0.05) in CXB-GLR-PVP MPs treated group alongside an enhancement in the histological features was revealed. CXB-GLR-PVP MPs is an up-and-coming delivery system that could be elucidated in future clinical investigations.

Formulation of Lipid-Based Tableted Spray-Congealed Microparticles for Sustained Release of Vildagliptin: In Vitro and In Vivo Studies.

Spray-congealing (SPC) technology was utilized to prepare lipid-based microparticles (MP) capable of sustaining the release of Vildagliptin (VG) for use as a once-daily treatment for type 2 diabetes mellitus. VG microparticles were prepared using Compritol® and Gelucire®50/13 as lipid carriers in the presence of various amounts of Carbomer 934 NF. The lipid carriers were heated to 10 °C above their melting points, and VG was dispersed in the lipid melt and sprayed through the heated two-fluid nozzle of the spray congealer to prepare the VG-loaded MP (VGMP). The microparticles produced were then compressed into tablets and characterized for their morphological and physicochemical characteristics, content analysis, in vitro dissolution, and in vivo bioavailability studies in mixed-breed dogs. The VGMP were spherical with a yield of 76% of the total amount. VG was found to be in its semicrystalline form, with a drug content of 11.11% per tablet and a percentage drug recovery reaching 98.8%. The in vitro dissolution studies showed that VG was released from the tableted particles in a sustained-release fashion for up to 24 h compared with the immediate-release marketed tablets from which VG was completely released within 30 min. The in vivo pharmacokinetics studies reported a Cmax, Tmax, T1/2, and MRT of 118 ng/mL, 3.4 h, 5.27 h, and 9.8 h, respectively, for the SPC formulations, showing a significant difference (p < 0.05)) from the pk parameters of the immediate-release marketed drug (147 ng/mL, 1 h, 2.16 h, and 2.8 h, respectively). The area under the peak (AUC) of both the reference and tested formulations was comparable to indicate similar bioavailabilities. The in vitro-in vivo correlation (IVIVC) studies using multiple level C correlations showed a linear correlation between in vivo pharmacokinetics and dissolution parameters. In conclusion, SPC was successfully utilized to prepare a once-daily sustained-release VG oral drug delivery system.

The Influence of Oily Vehicle Composition and Vehicle-Membrane Interactions on the Diffusion of Model Permeants across Barrier Membranes.

In many instances, one or more components of a pharmaceutical or cosmetic formulation is an oil. The aims of this study were two-fold. First, to examine the potential of preferential uptake of one oily vehicle component over another into a model barrier membrane (silicone) from blended vehicles (comprising two from the common excipients isohexadecane (IHD), hexadecane (HD), isopropyl myristate (IPM), oleic acid (OA) and liquid paraffin). Second, to study the effect of membrane-vehicle interactions on the diffusion of model permeants (caffeine (CF), methyl paraben (MP) and butyl paraben (BP)) from blended vehicles. Selective sorption and partition of some oils (especially IHD and IPM) at the expense of other oils (such as OA) was demonstrated to take place. For example, the membrane composition of IHD was enriched compared to a donor solution of IHD-OA: 41%, 63% and 82% IHD, compared to donor solution composition of 25%, 50% and 75% IHD, respectively. Pre-soaking the membrane in IHD, HD or LP, rather than phosphate buffer, enhanced the flux of MP through the membrane by 2.6, 1.7 and 1.3 times, respectively. The preferential sorption of individual oil components from mixtures altered the barrier properties of silicone membrane, and enhanced the permeation of CF, MP and BP, which are typically co-formulated in topical products.

Multivariate Analytical Approaches to Identify Key Molecular Properties of Vehicles, Permeants and Membranes That Affect Permeation through Membranes.

There has been considerable recent interest in employing computer models to investigate the relationship between the structure of a molecule and its dermal penetration. Molecular permeation across the epidermis has previously been demonstrated to be determined by a number of physicochemical properties, for example, the lipophilicity, molecular weight and hydrogen bonding ability of the permeant. However little attention has been paid to modeling the combined effects of permeant properties in tandem with the properties of vehicles used to deliver those permeants or to whether data obtained using synthetic membranes can be correlated with those obtained using human epidermis. This work uses Principal Components Analysis (PCA) to demonstrate that, for studies of the diffusion of three model permeants (caffeine, methyl paraben and butyl paraben) through synthetic membranes, it is the properties of the oily vehicle in which they are applied that dominated the rates of permeation and flux. Simple robust and predictive descriptor-based quantitative structure-permeability relationship (QSPR) models have been developed to support these findings by utilizing physicochemical descriptors of the oily vehicles to quantify the differences in flux and permeation of the model compounds. Interestingly, PCA showed that, for the flux of co-applied model permeants through human epidermis, the permeation of the model permeants was better described by a balance between the physicochemical properties of the vehicle and the permeant rather than being dominated solely by the vehicle properties as in the case of synthetic model membranes. The important influence of permeant solubility in the vehicle along with the solvent uptake on overall permeant diffusion into the membrane was substantiated. These results confirm that care must be taken in interpreting permeation data when synthetic membranes are employed as surrogates for human epidermis; they also demonstrate the importance of considering not only the permeant properties but also those of both vehicle and membrane when arriving at any conclusions relating to permeation data.

Ethanol effect on acid resistance of selected enteric polymers.

The aim of this study was to investigate under in vitro conditions the influence of ethanol on acid resistance of four commercially-available enteric polymers (Acryl-EZE®, AQOAT®, Hypromellose phthalate, and Sureteric®). For this purpose, custom-prepared paracetamol tablets were coated with the enteric polymers and tested for release using the buffer-addition method. Ten different hydro-ethanolic media were used in the acid stage corresponding to five levels of ethanol (0, 5, 10, 20, and 40% v/v) in two acidic solutions representing low and high gastric pH (0.1 N HCl pH 1.2, LGpH, and phosphate buffer pH 4.0, HGpH, respectively). The coats were found to resist both types of acidic solution with ethanol percentages up to 10% leading to release profiles that conformed with the pharmacopeial requirements (<10% release after 2 h in acid stage) except for Acryl-EZE®, which showed a premature release in HGpH media. At the higher ethanol levels (20 and 40%), premature release associated with increased acid uptake by coated tablets was noticed for all polymers and more remarkably in HGpH media. ANOVA tests revealed significant effects of polymer type, acidic solution type, and ethanol level on the onset and extent of premature release.

Clarithromycin laurate salt: physicochemical properties and pharmacokinetics after oral administration in humans.

OBJECTIVE: To prepare and characterize the physicochemical and pharmacokinetic properties of clarithromycin laurate (CLM-L), a fatty acid salt of clarithromycin (CLM). METHODS: CLM-L was prepared by a simple co-melting process. The formation of CLM-L was confirmed using FTIR, 1H NMR, and 13C NMR. Solubility, intrinsic dissolution rate (IDR), and partitioning properties of CLM-L were determined and compared to those of CLM. Bioavailability of CLM from CLM-L tablets was evaluated in healthy volunteers and compared to immediate release CLM tablets. RESULTS: CLM-L showed lower aqueous solubility, higher partitioning coefficient, and slower dissolution rate. Tablets of CLM-L also showed a significantly slower in vitro release in comparison to CLM tablets. Cmax, Tmax and AUC0→∞ of CLM-L tablets and immediate release CLM tablets did not show a significant difference. However, the AUC0→∞ for the CLM-L tablets tended to be higher than that of CLM tablets at all-time points. CONCLUSION: CLM-L was successfully prepared and its formation was confirmed. CLM-L was more hydrophobic than CLM. It exhibited a slight in vivo absorption enhancement in comparison to CLM. However, its pharmacokinetic behavior was comparable to that of CLM.

Novel Salted Anionic-Cationic Polymethacrylate Polymer Blends for Sustained Release of Acidic and Basic Drugs.

BACKGROUND: Since a unique matrix tablet formulation that independently controls the release of various drug types is in a great demand, the objective of this research was to develop a sustained release matrix tablet as a universal dosage form using a binary mixture of the salt forms of Eudragit polymers rather than their interpolyelectrolyte complexes. METHODS: Tablets were prepared by wet granulation and compressed at different compression forces, depending on drug type. Dissolution tests were conducted using USP XXII rotating paddle apparatus at 50 rpm at 37°C in consecutive pH stages. RESULTS: Tablets containing Ibuprofen (IB) as a model acidic drug and Metronidazole (MD) as a model basic drug showed controlled/sustained release behavior. For IB tablets containing 80% Ibuprofen and 5% (w/w) polymeric combination; the time for 50% of the drug release was about 24 hours compared to 8.5 hours for plain tablets containing 80% IB. In case of MD, the drug release extended to about 7 hours for tablets containing 80% MD and 5% (w/w) polymeric combination, compared to about 1 hour for plain tablets containing 80% MD. In terms of extending the release of medications, the dissolution profiles of the tablets containing polymeric salts forms were found to be statistically superior to tablets prepared by direct compression of the polymers in their powdered base forms, and superior to tablets containing the same polymers granulated using isopropyl alcohol. CONCLUSION: The findings indicated the significance of combining the polymers in their salt forms in controlling the release of various drug types from matrices.

Establishing the importance of oil-membrane interactions on the transmembrane diffusion of physicochemically diverse compounds.

The diffusion process through a non-porous barrier membrane depends on the properties of the drug, vehicle and membrane. The aim of the current study was to investigate whether a series of oily vehicles might have the potential to interact to varying degrees with synthetic membranes and to determine whether any such interaction might affect the permeation of co-formulated permeants: methylparaben (MP); butylparaben (BP) or caffeine (CF). The oils (isopropyl myristate (IPM), isohexadecane (IHD), hexadecane (HD), oleic acid (OA) and liquid paraffin (LP)) and membranes (silicone, high density polyethylene and polyurethane) employed in the study were selected such that they displayed a range of different structural, and physicochemical properties. Diffusion studies showed that many of the vehicles were not inert and did interact with the membranes resulting in a modification of the permeants' flux when corrected for membrane thickness (e.g. normalized flux of MP increased from 1.25±0.13µgcm(-1)h(-1) in LP to 17.94±0.25µgcm(-1)h(-1)in IPM). The oils were sorbed differently to membranes (range of weight gain: 2.2±0.2% for polyurethane with LP to 105.6±1.1% for silicone with IHD). Membrane interaction was apparently dependent upon the physicochemical properties including; size, shape, flexibility and the Hansen solubility parameter values of both the membranes and oils. Sorbed oils resulted in modified permeant diffusion through the membranes. No simple correlation was found to exist between the Hansen solubility parameters of the oils or swelling of the membrane and the normalized fluxes of the three compounds investigated. More sophisticated modelling would appear to be required to delineate and quantify the key molecular parameters of membrane, permeant and vehicle compatibility and their interactions of relevance to membrane permeation.

Physicochemical characterization of emulgel formulated with SepineoP 600, SepineoSE 68 and cosolvent mixtures.

The combined properties of SepineoP 600 (S600), a self-gelling dispersion and SepineoSE 68 (M68), a natural liquid crystal forming surfactant, were utilized in the development of emulgel base for topical application. The emulgels were prepared in water alone or combined with propylene glycol (PG), polyethylene glycol 400 (PEG400) and glycerol (G) as cosolvents. Emulgels were characterized for their optical and flow behavior. Two model drugs: caffeine (CF) and methylparaben (MP) were used in the evaluation of drug permeation across the stratum corneum (SC). The results showed that emulgel prepared using 70% PG:water (1:1) and 30% S600 has the best flow behavior compared to other cosolvents. Also the permeability coefficient of CF was found to be higher than that of MP and the addition of 3% M68 improved the physical stability of the emulgel, but it did not affect the drug diffusion profile.

Effect of ethylcellulose and propylene glycol on the controlled-release performance of glyceryl monooleate-mertronidazole periodontal gel.

Controlled-release metronidazole, mucoadhesive gel proposed as a drug-delivery system for periodontal application was developed and characterized. The system was based on a mixture of glycerylmonooleate (GMO) and ethylcellulose (EC). The mechanism of release depends: firstly, on the ability of GMO to form a viscous liquid crystalline mesophases and secondly on the solubilized EC to form a hydrophobic network when the mixture comes into contact with water resulting in sustaining the release of the drug. Ethylcellulose dissolved in GMO had a profound influence on the rate of drug release, reduced the initial drug release and prolonged the sustained release of metronidazole. Propylene glycol (PG) was added to increase the solubility of the drug and water was added with PG to control the viscosity. A controlled release formulation containing w/w, 20% metronidazole, 10% PG, 5% water and 65% GMO that contains 7% EC was found to be mucoadhesive, easily injectable at room temperature, and to follow Fickian diffusion release mechanism. When the drug loading was increased the drug release was accelerated, and the mechanism followed anomalous controlled-release mechanism. Stability studies indicated that the formulation should be stored at 4 °C in a dark place.

Evaluation of tadalafil nanosuspensions and their PEG solid dispersion matrices for enhancing its dissolution properties.

The aim of this work was to prepare and evaluate Tadalafil nanosuspensions and their PEG 4000 solid dispersion matrices to enhance its dissolution rate. Nanosuspensions were prepared by precipitation/ultrasonication technique at 5°C where different stabilizers were screened for stabilization. Nanosuspensions were characterized in terms of particle size and charge. Screening process limited suitable stabilizers into structurally related surfactants composed of a mixture of Tween80 and Span80 at 1:1 ratio (in percent, weight/volume) in adjusted alkaline pH (named TDTSp-OH). The surfactant mixture aided the production of nanosuspensions with an average particle size of 193 ± 8 nm and with short-term stability sufficient for further processing. Solid dispersion matrices made of dried Tadalafil nanosuspensions or dried Tadalafil raw powder suspensions and PEG 4000 as a carrier were prepared by direct compression. Drying was performed via dry heat or via freeze dry. Drug release studies showed that, in general, tablet formulations made of freeze-dried product exhibited faster initial release rates than the corresponding tablets made of oven-dried products which could be attributed to possible larger crystal growth and larger crushing strengths of oven-dried formulations. At best, 60% of drug was released from solid dispersion matrices, while more than 90% of drug was released from TDTSp-OH nanosuspension within the first 5 min. In conclusion, Tadalafil nanosuspensions obtained using a mixed surfactant system provided rapid dissolution rates of Tadalafil that can theoretically enhance its bioavailability.

Sustained release tablets containing soluble polymethacrylates: comparison with tableted polymethacrylate IPEC polymers.

The objective of this study was to compare a novel sustained release tablet formulation that has the potential to be used for drugs of different physicochemical properties using a binary mixture of polymethacrylate polymers in their salt forms with the polymethacrylate interpolyelectrolyte complex (IPEC) tablets in terms of drug release and compactness. Also, we aimed to compare this formulation with an IPEC tablet in terms of drug release. Tablets prepared using Eudragit E-Citrate and Eudragit L-Sodium were more convenient, easier to prepare, and showed better sustained release and compactness characteristics compared to IPEC tablets of similar concentrations and preparation methods.

Novel combination of anionic and cationic polymethacrylate polymers for sustained release tablet preparation.

The objectives of this study were to prepare and evaluate a novel sustained release tablet formulation using a binary mixture of polymethacrylate polymers: Eudragit E-100 (EE) and Eudragit L-100 (EL) in their salt forms. Tablets prepared using EE-citrate and EL-Na showed the highest degree of swelling among other combinations of EE and EL. The drug release rates were independent of the pH of the dissolution medium as the release profiles exhibited a continuous release pattern with no burst effect when changing the pH of the medium. These results, along with other test results, indicated the presence of an ionic interaction between both polymers when combined in the salt forms.

Diclofenac-bismuth complex: synthesis, physicochemical, and biological evaluation.

Diclofenac-bismuth complexation was attempted by mixing diclofenac sodium (Na) and bismuth-subcitrate aqueous solutions at diclofenac:bismuth molar ratio of 3:1. A solid precipitate was obtained and isolated. The precipitate was characterized for stoichiometric ratio of diclofenac-bismuth complexation using capillary electrophoresis, which showed 1:1 complexation. In addition, nuclear magnetic resonance and Fourier transform infrared analysis were performed for the isolated solid complex and indicated that bismuth was in coordinate bond formation with the carboxylate group of diclofenac. In comparison with diclofenac Na powder, the complex was evaluated as an aqueous suspension for in vitro drug dissolution. The complex exhibited a faster dissolution rate than and similar dissolution extent as diclofenac Na. In comparison with an aqueous solution of diclofenac Na and an aqueous suspension of physical mixture of diclofenac acid (suspended) and bismuth-subcitrate (dissolved), the aqueous complex suspension was evaluated for ulcerogenic effect in rats upon oral administration. The complex led to more gastric ulceration than diclofenac Na, which was not in accordance with the antiulcer properties of bismuth. This antiulcer effect was shown as the physical mixture administration was accompanied with lower gastric ulceration than diclofenac Na administration. These gastric ulceration results were explained in terms of the difference in particle size between solid diclofenac acid formed as a result of the complex breakdown in an acidic medium (0.1 M HCl to simulate the gastric fluid) and that formed as a result of diclofenac Na neutralization. Diclofenac acid particles formed from the complex breakdown were of average size, three times smaller of those formed as a result of diclofenac Na protonation. This difference in particle size was correlated with the higher gastric ulceration associated with the complex than with diclofenac Na in terms of higher coverage of the gastric mucosa with diclofenac, and consequently, higher local ulceration.

Formulation of an oral dosage form utilizing the properties of cubic liquid crystalline phases of glyceryl monooleate.

Glyceryl monooleate is a Food and Drug Administration-approved food additive which has the ability to form various liquid crystalline phases in the presence of various amounts of water. The unique properties of the cubic liquid crystalline phase that result upon the presence of excess body fluids at body temperature were utilized to formulate an oral dosage form containing furosemide as the model drug. The aim was to develop a formula, which has both bioadhesive and sustained release properties of the resultant cubic phase, so that increasing gastric residence time to improve bioavailability of the drug and at the same time obtaining a sustained action. The system was found to be affected by the limited solubility of furosemide in both the carrier system and the pH of surrounding medium. As a consequence, the addition of some solubility modifiers was investigated in order to obtain the desired properties of the expected liquid crystalline system.