Search

Purpose The aim of our research work was to develop dermally applicable, lidocaine hydrochloride (LID-HCl)-containing semisolid in situ film-forming systems (FFSs) using the Quality by Design (QbD) approach to increase drug permeation into the skin. Methods Silicones were used to improve the properties of formulations and to increase the permeation through the skin. The QbD approach was applied to ensure quality-based development. With initial risk assessment, the critical material attributes (CMAs) and the critical process parameters (CPPs) were identified to ensure the required critical quality attributes (CQAs). Results During the initial risk assessment, four high-risk CQAs, namely in vitro drug release, in vitro drug permeation, drying properties, and mechanical properties, and three medium-risk CQAs, namely pH, viscosity, and film appearance were identified and investigated. Moreover, four high-risk CMAs were also considered during the formulation: permeation enhancing excipients, drying excipients, film-forming excipients, and emollients. During the experiments, LID-HCl influenced these critical parameters highly, thereby reducing the drying time. The formulation containing 25% silicone showed the best mechanical properties (49 mN skin adhesion, 20.3% film flexibility, 1.27 N film burst strength), which could predict better patient adherence. In addition, in vitro permeation studies showed that formulation containing 50% silicone has the fastest permeation rate. The flux of diffused API was 6.763 µg/cm2/h, which is much higher compared to the silicone-free formulation (1.5734 µg/cm2/h), and it can already be observed in the lower part of the dermis in 0.5 hour. Conclusion Our results show that LID-HCl has great influence on the critical parameters of FFSs. The silicone content can improve the applicability of formulations and has a favorable effect on the permeation rate of LID-HCl into the skin.

Antiseptics – besides mechanical debridement – have an important role in the treatment of destructive periodontitis. Subgingivaldrug delivery systems containing chlorhexidine gluconate (CHX) may enhance or be a substitute to non-surgicaltherapy. In this article, we investigate a CHX-containing drug delivery system which is solid at room temperature but softensat body temperature. The examination was focused on the hardness, the drug diffusion profile and the antimicrobialeffectiveness of the formulation. Hardness was analyzed with a texture analyzer equipped with a spherical probe 5 mm indiameter. The investigation was carried out at 25 and 37 °C. The drug diffusion from formulations was investigated for oneweek in PBS solution. The antimicrobial effectiveness of the delivery systems was analyzed on 6 different anaerobic bacterialstrains. Results show that hardness of formulations at 25 °C is around 2000 mN which is suitable for handling andinsertion, whereas at 37 °C in PBS solution, hardness decreases greatly (to 800 mN) which contributes to the accommodationof the delivery systems to the shape of the periodontal pocket, the penetration of gingival crevicular fluid and thedrug diffusion from formulations. Results of the drug diffusion study indicate that 50% of the CHX diffused from the formulationsduring the one-week period and a concentration of 8 μg/mL were maintained in the acceptor phase after 24 hours.Formulations effectively inhibited the growth of anaerobic bacteria for at least one week and showed similar effectivenessto formulations containing amoxicillin or the combination of metronidazole and zinc hyaluronate. Our results suggest thatthis delivery system alone or in combination with mechanical debridement may be effective in the treatment of periodontitis.

The human skin is marked as a standard by the regulatory agencies in the permeation study of dermal formulations. Artificial membranes can substitute human skin to some extent. Academicians and pharmaceutical corporations are focusing their efforts on developing standardized protocols and safe, reliable options to substitute human skin for carrying out permeability studies. Our research aim was to study the applicability of new techniques in the case of different types of dermal formulations. The skin parallel artificial membrane permeability assay (PAMPA) method and Raman mapping were compared to the gold-standard Franz cell method. A hydrogel and two types of creams were investigated as the most generally used dermal preparations. The values of the diffused drug were closer to each other in PAMPA and Franz cell measurement. The diffused amount of drug showed the same order for the different formulations. These results correlate well with the results of Raman mapping. Our conclusions suggest that all early screening examinations can be performed with model tools such as skin PAMPA supplemented with methods like Raman mapping as a semi-quantitative method.

The aim of this study was to perform a preformulation study of dexamethasone (DXM)-loaded nanostructured lipid carriers (NLCs) for ocular use. Lipid screening was applied to find the most suitable solid and liquid lipids and surfactant for the NLC formulation. The visual observation was proved with XRD measurements for the establishment of the soluble state of DXM. Thermoanalytical measurements indicated that the most relevant depression of the crystallinity index could be ensured when using a 7:3 solid lipid:oil ratio. In order to optimize the NLC composition, a 23 full factorial experimental design was used. It was established that each independent factor (lipid, DXM, and surfactant concentration) had a significant effect on the particle size while in the case of entrapment efficiency, the DXM and surfactant concentrations were significant. Lower surfactant and lipid concentrations could be beneficial because the stability and the entrapment efficacy of NLCs were more favorable. The toxicity tests on human cornea cells indicated good ophthalmic tolerability of NLCs. The in vitro drug release study predicted a higher concentration of the solute DXM on the eye surface while the Raman mapping penetration study on the porcine cornea showed a high concentration of nanocarriers in the hydrophylic stroma layer.

Background: Despite being a highly prevalent disease and a possible contributor to adult tooth loss, periodontitis possesses no well-established therapy. The aim of the recent study was the development and evaluation of a mucoadhesive monophase lipid formulation for the sustained local delivery of amoxicillin, metronidazole, and/or zinc hyaluronate or gluconate. Methods: To investigate our formulations, differential scanning calorimetry, X-ray diffraction, swelling, erosion, mucoadhesivity, drug release, and antimicrobial measurements were performed. Results: Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results show that the loaded drugs are in a suspended form, the softening of the formulations starts at body temperature, but a part remains solid, providing sustained release. Swelling of the lipid compositions is affected by the hydrophilic components, their concentration, and the strength of the coherent lipid structure, while their erosion is impacted by the emulsification of melted lipid components. Conclusions: Results of drug release and antimicrobial effectiveness measurements show that a sustained release may be obtained. Amoxicillin had higher effectiveness against oral pathogens than metronidazole or zinc hyaluronate alone, but the combination of the two latter could provide similar effectiveness to amoxicillin. The applied mucoadhesive polymer may affect adhesivity, drug release through the swelling mechanism, and antimicrobial effect as well.

From aqueous NaOH/Ca(OH)2/NaAl(OH)4 mixtures, after allowing short reaction times we observed the precipitation of Ca(OH)2(s) at lower, and a mixture of Ca(OH)2(s) and a layered double hydroxide, hydrocalumite (HC) at higher aluminate concentrations. From the maximum aluminate concentration, at which the equilibrium solid phase is still portlandite (i.e., further increase in the aluminate concentration results in HC appearing in the precipitate beside the portlandite), the concentration based solubility products of two polymorphs of HC with the formula of [Ca2Al(OH)6]OH·nH2O (differing in n) has been estimated and was found to be log LHC=−11.4 at 25 °C and −12.1 at 75 °C, respectively (where LHC=[Ca2+]2[Al(OH)4−][OH−]3) and at constant ionic strength (I=1 M NaCl). To the best of our knowledge, this is the first published estimate for the solubility product of hydrocalumite. Additionally, from the composition obtained for NaOH/Ca(OH)2/NaAl(OH)4 mother liquors in equilibrium with Ca(OH)2(s), attempts were made to extract the formation constant of the ion pair CaAl(OH)4+. It was found, that the effects caused by the supposed formation of this solution species are too small to be reliably determined, which allowed an upper estimate for its formation constant, K, to be suggested in the temperature range of 25–75 °C (K

In the present study, we show that in hyperalkaline (pH > 13) aqueous solutions, Ca2+ forms a new, so far unknown complex species with the citrate ion, the structure of which is different from the well-known CaCit−(aq) species present in solutions of close to neutral pH. The solubility of Ca3Cit2(s) was found to increase significantly under hyperalkaline conditions. The decrease in the electric conductivity and the variations observed in the freezing point depression of such solutions also indicate complexation. From 1H NMR measurements, in this complex, the citrate ion is suggested to be in quadruply deprotonated form. From the variation of the 2JHH geminal proton coupling constant, two neighboring carboxylate groups are coordinated to the calcium ion in a monodentate mode (besides the alcoholate). The optimal structure of the complex with the composition of CaCitH−12−(aq) has also been calculated using DFT calculations, applying the Polarizable Continuum Model. Sodium ion-pairing was found to compete efficiently with this calcium complexation process, and in solutions with high Na-ion content, the equilibria are shifted towards the formation of NaCit2−(aq) and Na2Cit−(aq) ion pairs.

Purpose To design and stabilize Liraglutide loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) proper for oral administration. Methods PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. Results Spherical shaped NPs with homogeneous distribution, 188.95 nm particle size and 51.81% encapsulation efficiency were obtained. Liraglutide was successfully entrapped in the NPs while maintaining its native amorphous nature, and its structural integrity as well. Conclusion Lira-PLGA NPs with the required Critical Quality Attributes (CQAs) were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design (QbD) model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge. As the developed nanoparticles maintained the native structure of the active pharmaceutical ingredient (API), they are promising compositions for the further development for the oral delivery of Lira. Graphical Abstract Electronic supplementary material The online version of this article (10.1007/s11095-019-2620-9) contains supplementary material, which is available to authorized users.

Szilvia Berkó,1 Stella Zsikó,1 Gábor Deák,2 Attila Gácsi,1 Anita Kovács,1 Mária Budai-Szűcs,1 László Pajor,2 Zoltán Bajory,2 Erzsébet Csányi1 1Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Hungary; 2Department of Urology, University of Szeged, Szeged, Hungary Purpose: Papaverine hydrochloride (PaHCl) is an old, well-known drug with spasmolytic activity but it has therapeutic effect in erectile dysfunction, too. As an intracavernous injection, it is not used in urologic clinics today because the side effects of the injection are pain, scarring or priapism. Our aim was to develop and test a topical semi-solid preparation containing PaHCl that would provide an alternative administration option by eliminating the undesirable side effects of the injection.Materials and methods: Lyotropic liquid crystal (LLC) systems were formulated as a semi-solid preparation with different concentrations of PaHCl. The characterization of the LLC structure was performed by polarization microscopy using a Leica image analyzer and rheological measurements. The drug diffusion and penetration tests were performed with in vitro synthetic membrane and an ex vivo human epidermis, using Franz diffusion cell to test the skin penetration of PaHCl. Human skin was investigated by Raman microscope to visualize the Active Pharmaceutical Ingredient (API) in different skin layers.Results: The results of diffusion and penetration showed reverse concentration dependency. The in vitro and ex vivo studies correlated with each other and the results of Raman microscopy. The LLC structure influenced the penetration results, the lower viscosity and lamellar structure increased penetration through the skin.Conclusion: Based on our results, a PaHCl containing topically used LLC formulation may be a suitable and effective alternative to the injectable formulation. Keywords: nanocarrier, dermal penetration, impotence, Raman microscopy

Knowledge of the mechanism of action of skin penetration enhancers is essential to formulators for optimizing formulations and to maximize the efficacy of enhancers. To obtain information about the effects of penetration enhancers as a fast initial screening, investigations have been performed to identify possible correlations of the biological effectiveness of penetration enhancers with their interaction with a well-defined model system consisting of skin mimic lipid bilayers, as determined by calcein release experiments using stratum corneum lipid liposomes (SCLLs). We aimed to investigate the enhancing effects of different concentrations of two chemical penetration enhancers, Kolliphor RH40 and Transcutol on SCLLs. The results obtained by SCLL-based techniques were compared with conventional ex vivo penetration studies in case of Kolliphor RH40 to evaluate the potential of SCLLs as an alternative tool for screening various types and concentrations of penetration enhancers. As a result, calcein leakage assay performed with SCLL was considered to be a good model for the skin penetration enhancing effect. This method could be used as a time-saving and sensitive alternative in vitro screening technique in the early stage of the development of dermal formulations.

The solubility of calcium hydroxide and the aqueous speciation of Ca(II) in alkaline medium at various temperatures and background electrolyte concentrations were characterized by solubility measurements applying ICP-OES and potentiometric detection methods. Contrary to suggestions from previous literature, the (dissolved) Ca(OH)2(aq) was found to be the dominant solution species above pH ∼ 13, although the well-known CaOH+(aq) is also formed to a much smaller extent. The solubility product, as well as the formation constants for the species CaOH+ and Ca(OH)2 were found to be (8.8 ± 0.2) × 10−5 M3, (1.5 ± 0.1) M−1 and (4.7 ± 0.1) M−2, respectively, at 25 °C, at 1 M ionic strength and expressed in terms of concentrations. The most important implication of this model is that the total concentration of the dissolved calcium(II) cannot be decreased below ca. 2 × 10−4 M at any base concentration, even if this is increased to the solubility limit of the caustic. This statement was further validated via precipitation titrations. The standard enthalpies and entropies of the reactions were also calculated from temperature-dependent solubility measurements.

The application of local anesthetics, usually administered by subcutaneous injection, is common in the course of diagnostic, therapeutic, and cosmetic dermatology procedures. The effective dermal delivery of lidocaine could offer a solution to many adverse effects caused by needle insertion, such as pain, local reactions or toxicity, and additionally, it avoids the disruption of anatomical landmarks. Therefore, novel dermal formulations of local anesthetics are needed to overcome the barrier function of the skin and provide sufficient and prolonged anesthesia. In our study, we aimed to investigate and compare the penetration profiles of four different lidocaine containing formulations (hydrogel, oleogel, lyotropic liquid crystal and nanostructured lipid carrier) by Raman microscopic mapping of the drug. The application of Raman spectroscopy provided information about the spatial distribution of lidocaine in the skin ex vivo. The penetration of lidocaine from lyotropic liquid crystal and nanostructured carrier reached deeper skin layers and a higher amount of the drug was diffused into the skin, compared with hydrogel and oleogel. This study confirmed that nanostructured carriers can improve skin penetration properties of lidocaine and proved the applicability of Raman spectroscopy in the research of dermatological preparations ex vivo as a nondestructive, relatively easy and fast technique.

The aim of our research work was to develop dermally applicable, semisolid film-forming systems (FFSs) containing silicones, which form a film on the skin in situ, with suitable mechanical properties for skin application. FFSs were developed and investigated by means of the Quality by Design (QbD) methodology. With this QbD approach, the initial risk assessment defines the critical quality attributes (CQAs), the critical material attributes (CMAs) and the critical process parameters (CPPs) to ensure the required quality. Different semisolid systems were formed with or without silicones. During the initial risk assessment, three CQAs, namely skin adhesion, film flexibility and burst strength, were found to be critical attributes, while film appearance, film integrity and the drying time of the semisolid system, were found to be medium attributes. These parameters were investigated. The initial risk assessment also showed that there are three high CMAs: the type of silicones, film-forming excipients, drying excipients, and that there was one medium CMA: viscosity-enhancing excipients. Based on our results, the silicone content had a great effect on the film-forming systems. Different silicones affected the mechanical properties of the films in varying ways, decreased the drying time and showed promising results regarding the drying mechanism.

The complex formation reaction between the L-tartrate (Tar2−) and calcium ions taking place in neutral and in hyperalkaline (pH > 13) aqueous solutions has been investigated. It was demonstrated that upon NaOH addition the solubility of the CaTar(s) precipitate significantly increases. Conductometric and freezing point depression measurements further confirmed that in this process water soluble species are formed as a result of a reaction between the CaTar(s) and the hydroxide ion (or, conversely, between Ca(OH)2(s) and the Tar2− ion). 13C NMR spectroscopic measurements yielded the value of pK3 = 15.4 ± 0.2 for the proton dissociation of one of the alcoholic OH groups of Tar2− (at 25.0 °C and 4 M Na(Cl) ionic strength). Upon addition of calcium ions to an alkaline Tar2− solution, the 1H NMR signal gradually broadened and the 13C-satellite peaks split to two components, which also indicate complexation. From H2/Pt potentiometric titrations performed with solutions in the 13.6 ≤ pH ≤ 14.4 range, it was observed, that this complex formation is accompanied by a hydroxide ion consuming process. The titration curves can be best described via assuming the formation of the CaTarH−1−(aq) (lgβ11−1 = −11.2 ± 0.1) and CaTarH−22−(aq) (lgβ11−2 = –25.3 ± 0.1) complexes. In hyperalkaline solutions, these two species account for more than 90–99% of the calcium ions present and the contribution of the other reasonable and well-established calcium-containing solution species is rather small. The possible structures of the above complexes have been modeled via ab initio calculations. The stoichiometries are consistent both with species containing coordinated alcoholate group(s) and with mixed Ca(II)-hydroxo-tartrato complexes. From the data available at present, both types of structures can be considered as chemically reasonable.

The solubility of Ca(OH)2 in aqueous NaOH solutions up to 12.50 M at 25°C has been determined. The solubility data obtained for NaOH concentrations lower than 3 M was compared with those published in the literature. The solubility of Ca(OH)2 steadily decreases with the increasing NaOH concentration. The solubility data obtained at a constant ionic strength (I = 1 M Na(Cl,OH)) enabled the determination of the conditional solubility product of Ca(OH)2(s) (lgLCa(OH)2 = − 4.10 ± 0.02). Formation of the hydroxo complex CaOH+(aq) was invoked to describe the variation of [Ca2+]T with [OH−]T. Its conditional stability constant was found to be lgKCaOH+ = 0.97 ± 0.02. The experimental protocol employed was proven to be suitable for accurate solubility determinations in rapidly equilibrating systems comprising of highly concentrated, alkaline solutions and containing analytes in the ppm range.

A set of flame-hydrolytic TiO2 samples was synthesized. Via systematically increasing the precursor (TiCl4) feeding rate to the flame, nanocrystalline TiO2 specimens with practically identical bulk structural properties (that is: particle size, anatase-to-rutile ratio, specific surface area) were obtained. However, it has been observed that with increasing precursor feed rate, the fraction of the polyhedral particles increased in the products at the expense of the spherical ones. In our previous work, we argued, that faceted particles are superior to spherical ones in phenol decomposition. In this work, the photocatalytic activities of these samples were determined in the gas phase using methanol and acetaldehyde as model compounds and they were compared with those obtained for an aqueous solution containing phenol. The photocatalytic activities were found to vary in parallel in the case of phenol and methanol: they increased with the precursor feed rate (and also with the frequency of the faceted nanocrystals) for both. However, for acetaldehyde, the photocatalytic activity did not change systematically within this series of experiments, and roughly remained constant. Our results indicate that the surface quality of TiO2 is of primary importance in the selectivity of photocatalytic reactions.