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This article reports on the micro- and nanonization of meloxicam (MEL) with the aim of developing pre-dispersions as intermediates for the design of intranasal formulations. As a new approach, combined wet milling technology was developed in order to reduce the particle size of the MEL. Different milling times resulted in micro- or nanosized MEL in the pre-dispersions with polyvinyl alcohol as stabilizer agent, which were directly used for preparing intranasal liquid formulations with the addition of sodium hyaluronate as mucoadhesive agent. Reduction of the MEL particle size into the nano range led to increased saturation solubility and dissolution velocities, and increased adhesiveness to surfaces as compared with microsized MEL particles. A linear correlation was demonstrated between the specific surface area of MEL and the AUC. The in vitro and in vivo studies indicated that the longer residence time and the uniform distribution of nano MEL spray throughout an artificial membrane and the nasal mucosa resulted in better diffusion and a higher AUC. Nanosized MEL may be suggested for the development of an innovative dosage form with a different dose of the drug, as a possible administration route for pain management. [ABSTRACT FROM AUTHOR]

The ophthalmic formulations on the market suffer from poor bioavailability, and it would therefore be useful to design a new formulation which is able to prolong the residence time and reduce the administration frequency. Polymer matrices which exhibit strong mucoadhesion are promising platforms in ocular drug delivery from the aspect of improved bioavailability. In the present study, an in situ gelling, mucoadhesive drug delivery system was fabricated from thiolated poly(aspartic acid) (ThioPASP). The thiol groups of ThioPASP are able to form disulphide linkages with the mucin glycoproteins and prolong the residence time on the eye. The effects of the thiol groups on the structure, swelling behaviour and mucoadhesive character of the gel and on the drug release profile were determined. The gel structure was characterized by means of rheology. The ThioPASP gel was demonstrated by rheology, tensile test and ‘wash away’ measurements to display strong mucoadhesion. The drug release from the ThioPASP gel was studied on a vertical Franz diffusion cell: a burst release of sodium diclofenac occurred in the first hour, followed by sustained release of the encapsulated drug for up to 24 h. The results proved the importance of the presence of the thiol groups and suggested that a ThioPASP formulation can be useful as an in situ gelling, ocular dosage form. [ABSTRACT FROM AUTHOR]

This article reports on particle engineering by a top-down method involving organic solvent-free acoustic cavitation as a wet-grinding procedure. The effects of static and dynamic sonication on particle size reduction methods were compared to each other. The most effective process parameters were determined by a factorial design plan for the particle size distribution of an important active pharmaceutical ingredient, meloxicam, as response factor after sonication. Samples sonicated with appropriate process parameters were dried and investigated. Scanning electron microscopy images showed that the sonication resulted in a rounded shape and micronized size of the particles. Differential scanning calorimetry and X-ray powder diffraction examinations revealed the crystalline structure of the produced meloxicam by both sonication methods. Fourier transform infrared spectroscopy demonstrated that no chemical degradation occurred. Static sonication is recommended primarily for particle size reduction in preclinical samples, where the amount of the drug candidate is very small (e.g. nasal formulation), while dynamic sonication may be suitable for wet-grinding of different active substances to prepare pre-suspension (e.g. micronization and nanonization). [ABSTRACT FROM AUTHOR]

• The nanoemulsion formulations enhanced drug permeation of meloxicam. • Meloxicam-loaded nanoemulsions provided rapid drug release. • The dilutable nanoemulsion formulation is applicable for the nasal administration. • Meloxicam-loaded nasal nanoemulsions can be a future remedy in pain management. Intranasally administered non-steroidal anti-inflammatory drugs (NSAIDs) offer an innovative opportunity in the field of pain management. Combination of the nasal physiological advantages such as the rich vascularization and large absorption area along with novel nanomedical formulations can fulfill all the necessary criteria of an advanced drug delivery system. Nanoemulsions represent a versatile formulation approach suitable for nasal drug delivery by increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery due to their stability, small droplet size and optimal solubilization properties. In this study we aimed to develop meloxicam (MX)-loaded mucoadhesive nanoemulsions and to investigate the nasal applicability of the optimized formulations. Our results indicated the optimized nanoemulsion formulation (MX-NE3) had a droplet size of 158.5 nm in monodisperse droplet size distribution (polydispersity index of 0.211). The surface charge was −11.2 mV, which helped with the colloidal stability upon dilution at simulated nasal conditions and storage. The high encapsulation efficiency (79.2%) mediated a 15-fold drug release and a 3-fold permeability increase at nasal conditions compared to the initial MX. Proper wetting properties associated with high mucoadhesion prosper the increased residence time on the surface of the nasal mucosa. No cytotoxic effect of the formulations was observed on NIH/3T3 mouse embryonic fibroblast cell lines, which supports the safe nasal applicability. [Display omitted] [ABSTRACT FROM AUTHOR]

Psoriasis is a T lymphocyte-mediated inflammatory disorder that affects the skin. A number of studies have demonstrated the occurrence of lipid alterations in psoriatic skin, resulting in a highly perturbed stratum corneum (SC). Relatively little attention has been paid to the protein conformation of the SC. In this study, the attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrum of the untreated psoriatic patients' unharmed SC was obtained after tape stripping. We focused on the amide-I band components in order to establish whether there are any protein alterations in the intact areas of psoriatic skin. Fourier self-deconvolution (FSD) of the amide-I band was followed by curve-fitting to generate the underlying components. Integration of band areas provided an estimate of the secondary structure. The results indicated decreases in all amide-I band components, the peak at 1660 cm-1 revealing the most dramatic change. This peak is characteristic of the turn structure in the protein chain. The decrease is marked in the case of the β-sheet structure at 1630 cm-1 too. This ATR-FTIR imaging is a rapid and simple noninvasive method, promotes a better understanding of the disease, and would be helpful in following the treatment. [ABSTRACT FROM AUTHOR]

Sucrose fatty acid esters are increasingly used as excipients in pharmaceutical products, but few data are available on their toxicity profile, mode of action, and efficacy on intestinal epithelial models. Three water-soluble sucrose esters, palmitate ( P-1695), myristate ( M-1695), laurate ( D-1216), and two reference absorption enhancers, Tween 80 and Cremophor RH40, were tested on Caco-2 cells. Caco-2 monolayers formed a good barrier as reflected by high transepithelial resistance and positive immunostaining for junctional proteins claudin-1, ZO-1, and β-catenin. Sucrose esters in nontoxic concentrations significantly reduced resistance and impedance, and increased permeability for atenolol, fluorescein, vinblastine, and rhodamine 123 in Caco-2 monolayers. No visible opening of the tight junctions was induced by sucrose esters assessed by immunohistochemistry and electron microscopy, but some alterations were seen in the structure of filamentous actin microfilaments. Sucrose esters fluidized the plasma membrane and enhanced the accumulation of efflux transporter ligands rhodamine 123 and calcein AM in epithelial cells, but did not inhibit the P-glycoprotein ( P-gp)-mediated calcein AM accumulation in MES- SA/ Dx5 cell line. These data indicate that in addition to their dissolution-increasing properties sucrose esters can enhance drug permeability through both the transcellular and paracellular routes without inhibiting P-gp. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3107-3119, 2014 [ABSTRACT FROM AUTHOR]

The use of dry powder formulations presents an alternative through which to achieve better deposition and residence time in the nasal cavity, increased stability and possible absorption enhancement. The most important factors involved in the preformulation are particle size and physical stability. Propranolol hydrochloride a model drug was subjected to spray-drying technology to form an intranasal dry powder. Particle size reduction of the drug was carried out by integration (spray-drying) methods, using different excipients. The micrometric properties were characterized by size and morphology. The structure was determined through the use of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy investigations. It was concluded that the intranasal dry powder formulation of propranolol hydrochloride can be achieved with a suitable particle size without polymorph modification or chemical decomposition. [ABSTRACT FROM AUTHOR]

Particle size reducing methods demand high energy input, so during these procedures crystallinity change always can occur. These changes can be enhanced by additives, which are often used to improve the dissolution, the powder rheological properties or the processability of the API (active pharmaceutical ingredient), or to support the particle size reduction. Different materials act differently during these crystallinity changing methods: some materials are easy to amorphize, while some of them can be really resistant. In this work, two chemically equivalent sugar alcohols as model materials-β- d-mannitol as poor glass former and d-sorbitol as good glass former-were chosen to be co-ground with polymeric additives (PVP C30 and PEG 6000). During the 120 min milling process mannitol showed just minor change in crystallinity alone or with PEG. But milled with PVP some amorphization was found. Sorbitol suffered noteworthy changes in crystallinity: raw sorbitol lost its crystallinity during the milling, and also polymorphic transition was displayed. Same transition happened during the milling with PVP: the whole crystallinity of the sorbitol decreased, while the amount of gamma polymorph increased. During the co-grinding with PEG, the polymer prevented the amorphization of sorbitol and kept the well-ordered crystal structure of the material. [ABSTRACT FROM AUTHOR]

Dermal or transdermal medication may lead to irritant contact dermatitis. However, little information is available on the irritant effect of surfactants which are applied in topical formulations. Our aim was to examine the irritant effect of the most frequent compounds in topical products. A murine model was applied. The following compounds were examined: sodium lauryl sulphate (SLS), polyethoxylated (40EO) hydrogenated castor oil and sucrose laurate. SLS led to severe erythema, increase in transepidermal water loss (TEWL) and induced necrosis and accumulation of neutrophylic granulocytes and lymphocytes. Exposure to sucrose laurate resulted in an elevation of TEWL, but histology did not reveal impairment of the skin structure. Application of polyethoxylated (40EO) hydrogenated castor oil was not accompanied by tissue damage. Special attention should be paid to the irritant effect of SLS. Polyethoxylated (40EO) hydrogenated castor oil seems to be a non-irritant agent and sucrose laurate is also a promising candidate for application in topical preparations. [ABSTRACT FROM AUTHOR]

Abstract: The nasal pathway represents a non-invasive route for delivery of drugs to the systemic circulation. Nanonization of poorly soluble drugs offers a possibility to increase dissolution properties, epithelial permeability or even bioavailability. The aim of the present study was to use in vitro methods to screen formulations which were intended for nasal application, and to perform animal experiments for recognizing the differences in plasmakinetics of intranasal- and oral-administered meloxicam nanoparticles. Due to nanonization the solubility of meloxicam elevated up to 1.2mg/mL, additionally the extent of dissolution also increased, complete dissolution was observed in 15min. Favorable in vitro diffusion profile of meloxicam nanoparticles was observed and their epithelial permeability through human RPMI2650 cells was elevated. The pharmacokinetic parameters were significantly increased when meloxicam was administered as nanoparticles to rats either nasally (increase of C max 2.7-fold, AUC 1.5-fold) or orally (increase of C max 2.4-fold, AUC 2-fold) as compared to physical mixture of the drug and the excipients. [Copyright &y& Elsevier]

Highlights: [•] Meloxicam crystals were transformed into mannitol-based respirable microcomposites. [•] The influence of polymers (PVP, PVA) was studied on properties of the composites. [•] The polymers modified the surface of the meloxicam co-sprayed with mannitol. [•] The polymers resulted in the different aggregation inhibitory effect. [•] The composites had a spherical form and the respirable size range (3–5μm). [ABSTRACT FROM AUTHOR]

Highlights: [•] Cross-linked HA-based semisolid preparation was investigated in comparison with a hydrogel containing linear HA. [•] The rheological properties, hydration, irritation effect, in vitro and in vivo skin penetration abilities were studied. [•] The hydration effect was preserved. [•] The rheological and penetration parameters were changed after the cross-linking procedure. [ABSTRACT FROM AUTHOR]

Highlights: [•] Polymers were used to reduce the grinding energy during co-grinding process to produce nanoparticles. [•] PEG did not have a significant effect on the crystallinity of meloxicam but the PVP decreased it drastically. [•] Weak secondary bonding between meloxicam and the PVP was found by FT-IR. [•] SEM images confirmed the major particle size decrease and the differences in crystal habit of meloxicam. [ABSTRACT FROM AUTHOR]

Highlights: [•] The biorelevant solubility of compounds with different acid–base properties were measured using validated saturation shake-flask method. [•] The precise evaluation of the ionization/solubilization effect on BRM solubility is done. [•] The biorelevant solubility of ampholyte niflumic acid is explained with the microspeciation of the molecule. [•] The relationship between the administration and the biorelevant solubility of drugs is discussed. [Copyright &y& Elsevier]

Cremophor EL and RH40 are widely used excipients in oral and intravenous drug formulations such as Taxol infusion to improve drug dissolution and absorption. Studies indicate that Cremophors, especially EL, have toxic side effects, but few data are available on endothelial and epithelial cells, which form biological barriers and are directly exposed to these molecules. Human hCMEC/D3 brain endothelial and Caco-2 epithelial cells were treated with Cremophor EL and RH40 in the 0.1-50 mg/mL concentration range. Cell toxicity was monitored by real-time cell microelectronic sensing and verified by lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and morphological methods. Cremophors caused dose- and time-dependent damage in both cell types. In endothelial cells, 0.1 mg/mL and higher concentrations, in epithelial cells, concentrations of 5 mg/mL and above were toxic, especially at longer incubations. Cell death was also proven by double fluorescent staining of cell nuclei. Immunostaining for tight junction proteins claudin-4 and -5 showed barrier disruption in cells treated by surfactants at 24 h. In conclusion, Cremophor EL and RH40 in concentrations corresponding to clinical doses caused endothelial and epithelial toxicity. Endothelial cells were more sensitive to surfactant treatment than epithelial cells, and Cremophor EL was more toxic than RH40 in both cell types. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1173-1181, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Interest in submicron-sized drug particles has emerged from both laboratory and industrial perspectives in the last decade. Production of crystals in the nano size scale offers a novel way to particles for drug formulation solving formulation problems of drugs with low solubility in class II of the Biopharmaceutical Classification System. In this work niflumic acid nanoparticles with a size range of 200–800nm were produced by the novel crystallization method, electrospray crystallization. Their properties were compared to those from evaporative and anti-solvent crystallizations, using the same organic solvent, acetone. There is a remarkable difference in the product crystal size depending on the applied methods. The size and morphology were analyzed by scanning electron microscopy and laser diffraction. The structure of the samples was investigated using differential scanning calorimetry, Fourier-transformed infrared spectroscopy and X-ray powder diffraction. The particles produced using electrospray crystallization process were probably changing from amorphous to crystalline state after the procedure. [Copyright &y& Elsevier]

Abstract: Sucrose esters are effective solubilizers and there is an interest to use them as pharmaceutical excipients for nasal drug delivery. We have determined for the first time the non-toxic doses of laurate and myristate sucrose esters by four independent methods, and their effects on epithelial permeability using RPMI 2650 human nasal epithelial cell line. Based on real-time cell electronic sensing, MTT dye conversion and lactate dehydrogenase release methods reference surfactant Cremophor RH40 proved to be the least toxic excipient, and could be used at 5mg/mL concentration for 1h in epithelial cells without cellular damage. The non-toxic dose of Tween 80 was 1mg/mL, while the dose of laurate and myristate sucrose esters that could be safely used on cells for 1h was 0.1mg/mL. Both the reference surfactants and the sucrose esters significantly enhanced the permeability of epithelial cell layers for the paracellular marker FITC-labelled 4.4kDa dextran at 0.1mg/mL concentration. The effects of sucrose esters on epithelial permeability were dose-dependent. These data indicate that laurate and myristate sucrose esters can be potentially used as permeability enhancers in nasal formulations to augment drug delivery to the systemic circulation. [Copyright &y& Elsevier]

Abstract: The crystal size, form, wettability and rate of dissolution of a drug are factors limiting its nasal or pulmonary administration. The aim of this work was to achieve an ideal crystal habit, good wettability and the rapid release of meloxicam (MEL), a poorly water-soluble non-steroidal anti-inflammatory drug. The structures of MEL and the carrier-based systems were analysed by differential scanning calorimetry, X-ray diffractometry and Fourier transform infrared spectroscopy. The particle size and morphology were investigated by laser diffraction and SEM analyses. The novelty of this work was the use of a co-spray-drying technique, which resulted in mannitol-based crystalline microcomposites (1–6μm) containing MEL microcrystals (1–5μm). The particle size and form of the MEL microcrystals were adjusted by a top-down method. The presence of mannitol (with a MEL:mannitol mass ratio of 1:1) with additives ensured the homogeneous distribution of MEL in the microcomposites with good wettability and rapid release (100% MEL within 5min). [Copyright &y& Elsevier]

Abstract: The present paper describes the preparation and characterization of hydrophilic hyaluronan nanoparticles formed by cross-linking of hyaluronic acid (HA) with 2,2′(ethylenedioxy)bis(ethylamine) in the presence of water-soluble carbodiimide (CDI) in aqueous media. The particle size of cross-linked nanosystems was measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), transmittance by UV–VIS spectrophotometry, gel permeation chromatography (GPC) and rheology to characterize the physico-chemical properties. The aqueous nanosystems prepared were stable, transparent or mildly opalescent with values of transmittance above 91%. It was observed, that a fraction of particles with size less than 20nm, has been released during the purification by diafiltration. It was established that the hydrodynamic size of cross-linked HA nanoparticles can be controlled by variation of the reaction conditions such as concentration of HA, salt concentration of media, ratio of cross-linker and the final pH of the reaction mixture. [Copyright &y& Elsevier]

Our aim was to develop potential dermal drug delivery systems (DDSs) with a good and lasting moisturizing effect. Lyotropic liquid crystals (LLCs), gel-emulsions and hydrogels were investigated by means of thermogravimetry, which can give information about the structure of these preparations, and we could study the water binding mechanisms indirectly in them. We found that the preparations with a complex structure and strong water bonds hydrate the skin well and lastingly by in vivo tests. Since the thermoanalytical results correlate with the in vivo test results, this method could be suited for predicting the moisturizing effect of the vehicles and provide the possibility to select the potential semisolid DDSs for in vivo tests cost and time effectively. [ABSTRACT FROM AUTHOR]

Sucrose esters (SEs) are biodegradable surfactants that can be manufactured in various hydrophilic-lipophilic balances (HLB) through the use of different fatty acids. They are used in food and in industries, such as the cosmetics, detergents and pharmaceutical industries. In aqueous media they can form gels, which can affect various industrial processes. The pharmaceutical industry is currently showing an increasing preference for biomaterials and environmentally sensitive gels, and in particular thermo-sensitive gels. By virtue of the nontoxic, biodegradable and gel-forming properties of SEs, they are promising materials with which to form thermo-sensitive delivery systems. In this study, the gelling properties of some sucrose stearates were investigated by rheological measurements, and compared with each other. The effects of the release of gel-forming SEs on a model drug (paracetamol) were evaluated through in vitro drug release studies. The rheological results indicated that the sucrose stearates with lower HLB values have higher gel strengths than those of the more hydrophilic sucrose stearates. The gelling of the SEs is concentration- and temperature-dependent, and this gelling behaviour is responsible for the great effect of sucrose stearates on drug release. [ABSTRACT FROM AUTHOR]

(1) Intranasal administration is a non-invasive and effective way for the delivery of drugs to brain that circumvents the blood–brain barrier. The aims of the study were to test a nasal delivery system for human β-amyloid (Aβ) peptides, to measure the delivery of the peptides to brain regions, and to test their biological activity in rats. (2) Aβ1-42, in the form of a mixture of oligomers, protofibrils, and fibrils was dissolved in a nasal formulation containing hydrophobic, hydrophylic, and mucoadhesive components. The peptide solution was administered intranasally to rats as a single dose or in repeated doses. (3) Nasally injected Aβ labeled with the blue fluorescent dye amino-methyl coumarinyl acetic acid (AMCA) could be detected by fluorescent microscopy in the olfactory bulb and frontal cortex. The concentration of the peptide was quantified by fluorescent spectroscopy, and a significant amount of AMCA-Aβ peptide could be detected in the olfactory bulb. Unlabeled Aβ also reached the olfactory bulb and frontal cortex of rats as evidenced by intense immunostaining. (4) In behavioral experiments, nasal Aβ treatment did not affect anxiety levels (open-field test) and short-term memory (Y-maze test), but significantly impaired long-term spatial memory in the Morris water maze. The treatments did not result in Aβ immunization. (5) The tested intranasal delivery system could successfully target a bioactive peptide into the central nervous system and provides a basis for developing a non-invasive and cost effective, new model to study amyloid-induced dysfunctions in the brain. [ABSTRACT FROM AUTHOR]

Abstract: Intranasal administration of molecules has been investigated as a non-invasive way for delivery of drugs to the brain in the last decade. Circumvention of both the blood–brain barrier and the first-pass elimination by the liver and gastrointestinal tract is considered as the main advantages of this method. Because of the rapid mucociliary clearance in the nasal cavity, bioadhesive formulations are needed for effective targeting. Our goal was to develop a formulation containing sodium hyaluronate, a well-known mucoadhesive molecule, in combination with a non-ionic surfactant to enhance the delivery of hydrophilic compounds to the brain via the olfactory route. Fluorescein isothiocyanate-labeled 4kDa dextran (FD-4), used as a test molecule, was administered nasally in different formulations to Wistar rats, and detected in brain areas by fluorescent spectrophotometry. Hyaluronan increased the viscosity of the vehicles and slowed down the in vitro release of FD-4. Significantly higher FD-4 transport could be measured in the majority of brain areas examined, including olfactory bulb, frontal and parietal cortex, hippocampus, cerebellum, midbrain and pons, when the vehicle contained hyaluronan in combination with absorption enhancer. The highest concentrations of FD-4 could be detected in the olfactory bulbs, frontal and parietal cortex 4h after nasal administration in the mucoadhesive formulation. Intravenous administration of a hundred times higher dose of FD-4 resulted in a lower brain penetration as compared to nasal formulations. Morphological examination of the olfactory system revealed no toxicity of the vehicles. Hyaluronan, a non-toxic biomolecule used as a mucoadhesive in a nasal formulation, increased the brain penetration of a hydrophilic compound, the size of a peptide, via the nasal route. [Copyright &y& Elsevier]

The purpose of this investigation was to further elucidate calorimetric properties of cartilage samples from femoral head necrosis and osteoarthritis from live surgeries. The natural course of this disease is one of steady progression with eventual collapse of the femoral head, followed by secondary osteoarthritis in the hip joint. All samples showed a clear denaturation peak on the calorimetric curve. Cartilage obtained from necrotic femoral head required the lowest amount of energy for decomposition. The use differential scanning calorimetry as part of thermal analysis was a reliable method for differentiating. [ABSTRACT FROM AUTHOR]

The glenohumeral joint is not a classical mass bearing joint, the treatment of primary osteoarthritis is conservative. In all other cases, when the arthritis is associated with unbalance of the soft tissues, the treatment solution of this pathology is arthroplasty. The purpose of this study was to examine the altered metabolism in human degenerated cartilage of the shoulder joint. With the rise of temperature an endothermic reaction was observed in all cases. The use differential scanning calorimetry as part of thermal analysis was a reliable method for differentiating normal hyaline cartilage from degenerated samples. [ABSTRACT FROM AUTHOR]

Sugar esters (SEs) have a wide range of hydrophilic-lipophilic balance (HLB) values (1–16) and hence can be applied as surfactants or as solubility or penetration enhancers. They can be used for hot melt technology and solvent method which are frequently applied techniques to preparation of solid dispersions. In this study drug-SE products were prepared by physical mixing, melt technology and solvent methods. The products were investigated by DSC, X-ray powder diffraction and dissolution tests. Diclofenac sodium (DS) as model drug and two SEs, P1670 (HLB=16) and S970 (HLB=9) were used for the preparation of the products. DSC curves revealed considerable melting range and enthalpy decreases for the DS-SE products. The dissolved drug molecules broke down the structures of the SEs but were not built into the crystalline phase of the carrier. The melt technology led to a solid dispersion while in the case of the solvent methods the DS was in molecularly dispersed form which resulted in faster dissolution. The drug release was influenced by the structures resulting from the various treatments, by the HLB and by the gel-forming behaviour of the SEs. [ABSTRACT FROM AUTHOR]

In this study, the effect of Cremophor® RH 40 (CR 40) classic micelles and Soluplus® (SP) polymeric micelles were investigated on a novel granule-type drug-delivery system containing megestrolacetate (MGA). Using a risk assessment-based approach on the formulation via melt technology resulted in the formation of these granules, presented as the dosage, with proper particle size and flow characteristics. Due to the application of a eutectic carrier base composition, gentle process conditions were reached, retaining the crystalline structure of the carrier system and allowing for the proper distribution of MGA in the granules. The increased water solubility (0.111 mg/mL to 2.154 mg/mL), and the decreased nano particle size (102.27 nm) with uniform distribution (polydispersity index of 0.259) and colloid stability (zeta potential of −12.99 mV) resulted in SP polymeric micelles prevailing over CR 40 micelles in this gastric dissolution study, performed in biorelevant fasted and fed state drug-release media. Mathematical characterization and kinetic model fitting supported the fast drug-release mechanism of polymeric micelles over micelles. The value-added polymeric micelle-containing formulation developed can be successfully administered perorally and the enhanced drug release offers the possibility of greater drug absorption in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Abstract: Sucrose esters (SEs) have a wide range of hydrophilic–lipophilic balance (HLB) values (1–16), and hence can be applied as surfactants, or as solubility or penetration enhancers. In general, SEs are used in hot-melt technology, because of their low melting points, but literature data are not available on the effects of active agents on the structures of SEs and the possible solid-state interactions. In this study, drug–SE products were prepared by melt technology and investigated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), rheological measurements and dissolution tests. The model drugs meloxicam and diclofenac sodium and three SEs with different polarities (P1670, S970 and B370) were chosen for the preparation of the products. The DSC and XRPD results revealed that the structures of the SEs were rearranged, with a decrease in the degree of crystallinity. The dissolved drug molecules broke down the structures of the SEs, but were not built into the crystalline phase of the carrier. The dissolution of the drugs was influenced by the different HLB values and gel-forming behaviour of the SEs, and also by the polarity of the drug and the interactions between the drug and the SEs. [Copyright &y& Elsevier]

Abstract: The purpose of our study was to investigate the applicability of isostatic ultra high pressure (IUHP) for the aim of drug formulation. Aqueous suspensions of potato and maize starches containing theophylline as a model drug were subjected to IUHP. The changes in the structure and morphology of potato and maize starches were investigated. The release profile of theophylline from the pressurized samples was also studied. The aqueous suspensions subjected to IUHP turned into highly viscous gels. The crystalline structure of maize starch was changed, while PS pressurized in aqueous medium retained its original X-ray pattern. The sample containing potato starch as a gel-forming polymer exhibited faster drug dissolution compared to an aqueous theophylline suspension used as a reference, while the pressurization of maize starch resulted in a gel exhibiting sustained drug release. The results of the dissolution study can be explained with the changes in structure and morphology of the starches caused by IUHP processing and with the different pressure sensitivities of PS and MS. [Copyright &y& Elsevier]

Abstract: The objective of the work was to assess the possible interactions between the model drug diclofenac sodium (DS) and the water-insoluble ammonio methacrylate copolymer (AMC). Films with different drug/polymer ratios were therefore prepared by the solvent casting method and investigated as a preformulation study towards sustained release microparticles. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to investigate the dispersed/dissolved state of the DS in the preparation, the thermal stability and the properties of DS-containing AMC films; and Raman spectroscopy was used to confirm the possible interactions between DS and AMC. Thermoanalytical studies confirmed that the DS could behave as a plasticizer, which was indicated by decreasing glass transition temperature (T g) of the AMC, depending on its dispersity level in the AMC matrix. Partially solid solutions were formed at DS/AMC ratios of 1:12, 1:8 and 1:6. The DS was mainly crystalline at DS/AMC ratio of 1:4, while it remained crystalline at a ratio of 1:2. The Raman spectra confirmed that none of the major structural changes revealed any significant difference, which can indicate a strong ionic interaction between the DS and the AMC. The investigations provided good facilities for the selection of a DS/AMC ratio, in the preformulation study of the microsphere preparation process, in conformity with the therapeutic aim. [Copyright &y& Elsevier]

Abstract: A small amount of solvents applied at the production of solid drugs is retained in the porous structure of the crystalline product. The regulatory guidelines require that the impurity due to the remaining solvent content of drugs should be a matter for serious concern toward marketing drugs; hence the reduction of the solvent amount is an important task of the technology of production. A steroid drug was crystallized and the correlation between the pore structure of the crystalline product and its residual solvent content was investigated. It was stated that the drug examined has a characteristic meso- and macropore structure, which distribution has a major contribution on the amount of the residual solvent content. [Copyright &y& Elsevier]

We studied the application of pulsed laser ablation (PLA) for particle size reduction in non-steroidal anti-inflammatory drugs (NSAIDs). Grinding of the poorly water-soluble NSAID crystallites can considerably increase their solubility and bioavailability, thereby the necessary doses can be reduced significantly. We used tablets of ibuprofen, niflumic acid and meloxicam as targets. Nanosecond laser pulses were applied at various wavelengths (KrF excimer laser, λ = 248 nm, FWHM = 18 ns and Nd:YAG laser, λ1 = 532 nm/λ2 = 1064 nm, FWHM = 6 ns) and at various fluences. FTIR and Raman spectra showed that the chemical compositions of the drugs had not changed during ablation at 532 nm and 1064 nm laser wavelengths. The size distribution of the ablated products was established using two types of particle size analyzers (SMPS and OPC) having complementary measuring ranges. The mean size of the drug crystallites decreased from the initial 30–80 µm to the submicron to nanometer range. For a better understanding of the ablation mechanism we made several investigations (SEM, Ellipsometry, Fast photography) and some model calculations. We have established that PLA offers a chemical-free and simple method for the size reduction of poorly water-soluble drugs and a possible new way for pharmaceutical drug preformulation for nasal administration. [ABSTRACT FROM AUTHOR]

The increasing prevalence of water insoluble or poorly soluble drugs calls for the development of new formulation methods. Common approaches include the reduction of particle size and degree of crystallinity. Pulsed laser ablation is a clean technique for producing sub-micrometre sized drug particles and has the potential to induce amorphization. We studied the effect of femtosecond pulsed laser ablation (ELI ALPS THz pump laser system: λ c  = 781 nm, τ = 135 fs) on meloxicam in distilled water and in air. The ablated particles were characterized chemically, morphologically and in terms of crystallinity. We demonstrated that femtosecond laser ablation can induce partial amorphization of the particles in addition to a reduction in particle size. In the case of femtosecond pulsed laser ablation in air, the formation of pure meloxicam spheres showed that this technique can produce amorphous meloxicam without the use of excipients, which is a unique result. We also aimed to describe the ablation processes in both investigated media., (© 2023. The Author(s).)

A fatal hereditary condition, cystic fibrosis (CF) causes severe lung problems. Ibuprofen (IBU), a non-steroidal anti-inflammatory drug, slows the progression of disease without causing significant side effects. Considering the poor water-solubility of the drug, IBU nanoparticles are beneficial for local pulmonary administration. We aimed to formulate a carrier-free dry powder inhaler containing nanosized IBU. We combined high-performance ultra-sonication and nano spray-drying. IBU was dissolved in ethyl acetate; after that, it was sonicated into a polyvinyl alcohol solution, where it precipitated as nanoparticles. Mannitol and leucine were added when producing dry particles using nano-spray drying. The following investigations were implemented: dynamic light scattering, laser diffraction, surface tension measurement, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy, in vitro dissolution test, and in vitro aerodynamic assessment (Andersen Cascade Impactor). The particle diameter of the IBU was in the nano range. The spray-dried particles showed a spherical morphology. The drug release was rapid in artificial lung media. The products represented large fine particle fractions and proper aerodynamic diameters. We successfully created an inhalable powder, containing nano-sized IBU. Along with the exceptional aerodynamic performance, the ideal particle size, shape, and drug-release profile might offer a ground-breaking local therapy for CF.

Background: Cystic fibrosis (CF) is a life-threatening multiorgan genetic disease, particularly affecting the lungs, where recurrent infections are the main cause of reduced life expectancy. In CF, mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein impair transepithelial electrolyte and water transport, resulting in airway dehydration, and a thickening of the mucus associated with abnormal viscoelastic properties. Our aim was to develop a rheological method to assess the effects of hypertonic saline (NaCl) and NaHCO 3 on CF sputum viscoelasticity in vitro, and to identify the critical steps in sample preparation and in the rheological measurements., Methods: Sputum samples were mixed with hypertonic salt solutions in vitro in a ratio of either 10:4 or 10:1. Distilled water was applied as a reference treatment. The rheological properties of sputum from CF patients, and the effects of these in vitro treatments, were studied with a rheometer at constant frequency and strain, followed by frequency sweep tests, where storage modulus (G'), loss modulus (G″) and loss factor were determined., Results: We identified three distinct categories of sputum: (i) highly elastic (G' > 100,000 Pa), (ii) elastic (100,000 Pa > G' > 1000 Pa), and (iii) viscoelastic (G' < 1000). At the higher additive ratio (10:4), all of the added solutions were found to significantly reduce the gel strength of the sputum, but the most pronounced changes were observed with NaHCO 3 (p < 0.001). Samples with high elasticity exhibited the greatest changes while, for less elastic samples, a weakening of the gel structure was observed when they were treated with water or NaHCO 3 , but not with NaCl. For the viscoelastic samples, the additives did not cause significant changes in the parameters. When the lower additive ratio (10:1) was used, the mean values of the rheological parameters usually decreased, but the changes were not statistically significant., Conclusion: Based on the rheological properties of the initial sputum samples, we can predict with some confidence the treatment efficacy of each of the alternative additives. The marked differences between the three categories suggest that it is advisable to evaluate each sample individually using a rheological approach such as that described here., (© 2021. The Author(s).)

Nowadays, the intranasal route has become a reliable alternative route for drug administration to the systemic circulation or central nervous system. However, there are no official in vitro diffusion and dissolution tests especially for the investigation of nasal formulations. Our main goal was to study and compare a well-known and a lesser-known in vitro permeability investigation method, in order to ascertain which was suitable for the determination of drug permeability through the nasal mucosa from different formulations. The vertical diffusion cell (Franz cell) was compared with the horizontal diffusion model (Side-Bi-Side). Raw and nanonized meloxicam containing nasal dosage forms (spray, gel and powder) were tested and compared. It was found that the Side-Bi-Side cell was suitable for the investigation of spray and powder forms. In contrast, the gel was not measurable on the Side-Bi-Side cell; due to its high viscosity, a uniform distribution of the active substance could not be ensured in the donor phase. The Franz cell, designed for the analysis of semi-solid formulations, was desirable for the investigation of nasal gels. It can be concluded that the application of a horizontal cell is recommended for liquid and solid nasal preparations, while the vertical one should be used for semi-solid formulations.

Recent in vitro and in vivo studies highlight the strong potential of dimethyl trisulfide (DMTS) as an antidote for cyanide (CN) intoxication. Due to its high oxygen demand, the brain is one of the main target organs of CN. The blood-brain barrier (BBB) regulates the uptake of molecules into the brain. In the literature, there is no data about the ability of DMTS to penetrate the BBB. Therefore, our aim was to test the in vitro BBB penetration of DMTS and its in vivo pharmacokinetics in blood and brain. The in vitro BBB penetration of DMTS was measured by using a parallel artificial membrane permeability assay (BBB-PAMPA), and a triple BBB co-culture model. The pharmacokinetics was investigated in a mouse model by following the DMTS concentration in blood and brain at regular time intervals following intramuscular administration. DMTS showed high penetrability in both in vitro systems (apparent permeability coefficients: BBB-PAMPA 11.8 × 10-6 cm/s; cell culture 158 × 10-6 cm/s) without causing cell toxicity and leaving the cellular barrier intact. DMTS immediately absorbed into the blood after the intramuscular injection (5 min), and rapidly penetrated the brain of mice (10 min). In addition to the observed passive diffusion in the in vitro studies, the contribution of facilitated and/or active transport to the measured high permeability of DMTS in the pharmacokinetic studies can be hypothesized. Earlier investigations demonstrating the antidotal efficacy of DMTS against CN together with the present results highlight the promise of DMTS as a brain-protective CN antidote., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Mefenamic acid (MA) is a widely used non-steroidal antiinflammatory (NSAID) drug. The adverse effects typical of NSAIDs are also present in the case of MA, partly due to its low water solubility. The aim of this study was to increase the water solubility of MA in order to influence its absorption and bioavailability. Solid dispersions of MA were prepared by the melting method using polyethylene glycol 6000 and different types (laurate, D-1216; palmitate, P-1670; stearate, S-1670) and amounts of sucrose esters as carriers. The X-ray diffraction results show that MA crystals were not present in the products. Dissolution tests carried out in artificial intestinal juice showed that the product containing 10 % D-1216 increased water solubility about 3 times. The apparent permeability coefficient of MA across human Caco-2 intestinal epithelial cell layers was high and, despite the difference in solubility, there was no further increase in drug penetration in the presence of the applied additives.

The nasal pathway represents an alternative route for non-invasive systemic administration of drugs. The main advantages of nasal drug delivery are the rapid onset of action, the avoidance of the first-pass metabolism in the liver and the easy applicability. In vitro cell culture systems offer an opportunity to model biological barriers. Our aim was to develop and characterize an in vitro model based on confluent layers of the human RPMI 2650 cell line. Retinoic acid, hydrocortisone and cyclic adenosine monophosphate, which influence cell attachment, growth and differentiation have been investigated on the barrier formation and function of the nasal epithelial cell layers. Real-time cell microelectronic sensing, a novel label-free technique was used for dynamic monitoring of cell growth and barrier properties of RPMI 2650 cells. Treatments enhanced the formation of adherens and tight intercellular junctions visualized by electron microscopy, the presence and localization of junctional proteins ZO-1 and β-catenin demonstrated by fluorescent immunohistochemistry, and the barrier function of nasal epithelial cell layers. The transepithelial resistance of the RPMI 2650 cell model reached 50 to 200 Ω × cm(2), the permeability coefficient for 4.4 kDa FITC-dextran was 9.3 to 17 × 10(-6) cm/s, in agreement with values measured on nasal mucosa from in vivo and ex vivo experiments. Based on these results human RPMI 2650 cells seem to be a suitable nasal epithelial model to test different pharmaceutical excipients and various novel formulations, such as nanoparticles for toxicity and permeability.

Enhancement of the transdermal penetration of different active agents is an important research goal. Our aim was to establish a novel in vivo experimental model which provides a possibility for exact measurement of the quantity of penetrated drug. The experiments were performed on SKH-1 hairless mice. A skin fold in the dorsal region was fixed with two fenestrated titanium plates. A circular wound was made on one side of the skin fold. A metal cylinder with phosphate buffer was fixed into the window of the titanium plate. The concentration of penetrated drug was measured in the buffer. The skin fold was morphologically intact and had a healthy microcirculation. The drug appeared in the acceptor buffer after 30 min, and its concentration exhibited a continuous increase. The presence of ibuprofen was also detected in the plasma. In conclusion, this model allows an exact in vivo study of drug penetration and absorption.

Application of a solid dispersion system is one of the methods used to increase the bioavailability of poorly water-soluble drugs. Adaptation of the dropping method from the chemical industry as a formulation procedure may help the scaling-up process and simplify the formulation of poorly water-soluble compounds. Meloxicam (ME), a nonsteroidal anti-inflammatory drug that is poorly soluble in water, and polyethylene glycol (PEG) 4000, a water-soluble carrier, were formulated by using a dropping method in an attempt to improve the dissolution of ME. Pure ME and physical mixtures and tablets of ME-PEG 4000 (1:3 ratio) were compared as regards their dissolution with samples formulated by the dropping method. The results revealed that the round particles (solid drops) exhibited a higher dissolution rate than those of the physical mixtures, tablets, and pure ME. Self-modeling curve resolution (SMCR) as a chemometric method was used to evaluate X-ray powder diffractometry (XRPD) data. The results demonstrated the presence of a new crystalline phase in the solid dispersion, which can help the fast and quantitative dissolution from the solid drops. The round particles can be adapted to individual therapy by using a distributor.