RESUMEN

Dimenhydrinate (DMH), used to alleviate motion sickness symptoms such as nausea, vomiting, dizziness, and vertigo, encounters limitations in oral pharmaceutical formulations due to its poor water solubility and bitter taste. Our research hypothesized that inclusion complexation with ß-cyclodextrin (ß-CD) might address these drawbacks while ensuring that the newly formed complexes exhibit no cytotoxic or genotoxic effects on peripheral blood mononuclear cells (PBMCs). Inclusion complexes were prepared using the kneading method and the solvent evaporation method. The phase solubility analysis, attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), and differential scanning calorimetry (DSC) were conducted to evaluate the complexation efficacy and stability constant of the new binary systems. The results demonstrated that both methods provided complete and efficient complexation. Cytogenotoxic analysis, including the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, alkaline comet assay, and cytokinesis-block micronucleus cytome (CBMN-cyt) assay, was conducted to assess the cytogenotoxic potential of DMH-ß-CD inclusion complexes, a topic previously unexamined. No cytotoxic or genotoxic effects were observed within the concentration range of 36.36 to 109.09 ng/mL. Cell viability of treated PBMCs exceeded 85% for all tested concentrations. No significant increases in DNA strand breaks were observed at any dose, and tail intensity of all complexes remained lower or up to 2.2% higher than the negative control. Parameters indicating genotoxic effects, as well as cytotoxic and cytostatic potential in the CBMN-cyt assay, did not significantly differ from untreated controls. These results suggest that inclusion complexation with ß-CD might be a safe and promising solution to overcome the limitations of poor solubility and unpleasant taste of DMH, potentially providing opportunities for new and improved oral pharmaceutical dosage forms.

RESUMEN

Four natural sweeteners (sucrose, xylitol, fructose, and isomalt) were selected to examine the influence of their qualities and amounts on the characteristics of orodispersible films. Sodium carboxymethylcellulose (2% w/w) was utilized as the film-forming polymer and 1% w/w glycerol as a plasticizer. Films were produced through the solvent casting method, rendering them suitable for convenient application in community or hospital pharmacy settings. The physicochemical and optical properties of the films were analyzed, and Fourier-transform infrared analysis was carried out. All films exhibited acceptable disintegration time, uniformity of mass, thickness, and optical characteristics, with significant dependence (p<0.05) on both sweetener type and quantity. Disintegration time varied based on the employed method, as well as the characteristics and amount of sweetener. Additionally, all films maintained pH values within the oral cavity range, suggesting no potential irritancy upon administration. Fourier-transform infrared analysis confirmed the formation of the film and demonstrated compatibility between its components.

Asunto(s)

RESUMEN

Although miRNA-27a has been identified as a promising candidate for miRNA mimic therapy of obesity, its application is limited due to enzymatic degradation and low membrane permeation. To overcome these problems, we developed cationic nanostructured lipid carriers (cNLCs) using high-pressure homogenization and used them as non-viral carriers for the anti-adipogenic miRNA-27a. Cargo-free octadecylamine-containing NLCs and miRNA/cNLC complexes were characterized regarding particle size, size distributions, zeta potential, pH values, particle topography and morphology, and entrapment efficacy. Furthermore, the cytotoxicity and cellular uptake of the miRNA/cNLC complex in the 3T3-L1 cell line were investigated. The investigation of the biological effect of miRNA-27a on adipocyte development and an estimation of the accumulated Oil-Red-O (ORO) dye in lipid droplets in mature adipocytes were assessed with light microscopy and absorbance measurements. The obtained data show that cNLCs represent a suitable DDS for miRNAs, as miRNA/cNLC particles are rapidly formed through non-covalent complexation due to electrostatic interactions between both components. The miRNA-27a/cNLC complex induced an anti-adipogenic effect on miRNA-27a by reducing lipid droplet accumulation in mature adipocytes, indicating that this approach might be used as a new therapeutic strategy for miRNA mimic replacement therapies in the prevention or treatment of obesity and obesity-related disorders.

RESUMEN

For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: -4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (-0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.

RESUMEN

OBJECTIVE: To examine the influence of vehicles on the stability of extemporaneous suspensions of proton pump inhibitors (PPIs), to single out the formulation most suitable for children, providing appropriate evidence and arguments. METHODS: A review was performed of data identified from Medline, Embase, Science Direct, as well as public digital archive PubMed, including reference texts, related to the field of stability testing of extemporaneous PPI suspensions. RESULTS: Fourteen selected formulations of extemporaneous suspensions are presented and discussed. Depending on the vehicle and its composition, which was analyzed and explained in detail, the suspensions had various beyond-use dates (BUDs). CONCLUSIONS: Selected vehicles and the process of preparation had great influence on the stability of extemporaneous PPI suspensions. The suspension with the longest BUD has been singled out, which is especially suitable for use in newborns. Because an explanation is provided for the influence of individual vehicle components on the stability of the mentioned suspensions, this can aid not only in the selection of an adequate formulation, but also in the development of new ones, which will be suited to individual patients.

RESUMEN

Microneedles (MNs) represent the concept of attractive, minimally invasive puncture devices of micron-sized dimensions that penetrate the skin painlessly and thus facilitate the transdermal administration of a wide range of active substances. MNs have been manufactured by a variety of production technologies, from a range of materials, but most of these manufacturing methods are time-consuming and expensive for screening new designs and making any modifications. Additive manufacturing (AM) has become one of the most revolutionary tools in the pharmaceutical field, with its unique ability to manufacture personalized dosage forms and patient-specific medical devices such as MNs. This review aims to summarize various 3D printing technologies that can produce MNs from digital models in a single step, including a survey on their benefits and drawbacks. In addition, this paper highlights current research in the field of 3D printed MN-assisted transdermal drug delivery systems and analyzes parameters affecting the mechanical properties of 3D printed MNs. The current regulatory framework associated with 3D printed MNs as well as different methods for the analysis and evaluation of 3D printed MN properties are outlined.

RESUMEN

The kinetics of passive transport of ketoprofen and metformin, as model substances for high and low permeability, respectively, across the artificial membrane under the influence of the pH of donor solution was investigated. There was an upward trend in the apparent permeation coefficient (P app) of ketoprofen with the decrease in pH to a value close to pKa. At the pH value below pKa the permeation coefficient had lower value, due to the higher retention of ketoprofen in the artificial membrane. Metformin is a low permeable compound, and the highest permeation values were recorded at pH 7.4. Two dissociation constants determine that metformin at physiological pH exists as a hydrophilic cationic molecule, i.e. predominantly in ionized form. At pH values below 2.8, metformin mainly exists in diprotonated form, and it was, thus, very poorly permeable. The highest retention, i.e. affinity of both ketoprofen and metformin to the membrane, was at the lowest pH values, which is explained by different mechanisms. At higher pH values of donor compartment the substances showed significantly less affinity to the membrane. The obtained values of apparent permeation coefficients at studied pH values showed good correlation with the obtained experimental values by other in vitro methods.

RESUMEN

Glaucoma is considered to be one of the biggest health problems in the world. It is the main cause of preventable blindness due to its asymptomatic nature in the early stages on the one hand and patients' non-adherence on the other. There are several approaches in glaucoma treatment, whereby this has to be individually designed for each patient. The first-line treatment is medication therapy. However, taking into account numerous disadvantages of conventional ophthalmic dosage forms, intensive work has been carried out on the development of novel drug delivery systems for glaucoma. This review aims to provide an overview of formulation solutions and strategies in the development of in situ gel systems, nanosystems, ocular inserts, contact lenses, collagen corneal shields, ocular implants, microneedles, and iontophoretic devices. The results of studies confirming the effectiveness of the aforementioned drug delivery systems were also briefly presented.

RESUMEN

Although transdermal drug delivery systems (DDS) offer numerous benefits for patients, including the avoidance of both gastric irritation and first-pass metabolism effect, as well as improved patient compliance, only a limited number of active pharmaceutical ingredients (APIs) can be delivered accordingly. Microneedles (MNs) represent one of the most promising concepts for effective transdermal drug delivery that penetrate the protective skin barrier in a minimally invasive and painless manner. The first MNs were produced in the 90s, and since then, this field has been continually evolving. Therefore, different manufacturing methods, not only for MNs but also MN molds, are introduced, which allows for the cost-effective production of MNs for drug and vaccine delivery and even diagnostic/monitoring purposes. The focus of this review is to give a brief overview of MN characteristics, material composition, as well as the production and commercial development of MN-based systems.

RESUMEN

In this study solid dispersions of carbamazepine in the hydrophilic Kollidon® VA64 polymer, adsorbed onto Neusilin® UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon® VA64 and Neusilin® UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin® UFL2. Proportion of Kollidon® VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30 min, whereby these parameters increase upon increasing in Kollidon® VA64 concentrations up to the middle values in the studied range of Kollidon® VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon® VA64 hydrophilic polymer and Neusilin® UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability.

RESUMEN

Propylene carbonate (PC) is a non-toxic solvent currently used in various pharmaceutical formulations. Consequently, a simple, cost-effective and most accurate analytical method for the quantification of this optical inert solvent is of major interest. Based on a consecutive three-step reaction 3,5-diacetyl-1,4-dihydro-2,6-lutidine was obtained from PC and used for quantification by either UV and fluorescent detection. Data were compared with results from LC-ESI-MS as a reference method. After using Mandel's test for linearity assessment of the calibration curves, linear fitting was used for LC-ESI-MS and spectrofluorimetry, while a polynomial 3rd order curve fitting was used for spectrophotometry. High intra- and inter-day precision as well as high accuracy were confirmed for all three analytical methods (spectrophotometry, spectrofluorimetry and LC-ESI-MS). The comparison of all three methods was assessed using correlation coefficients and Bland-Altman plots, both showing satisfying results with a high degree of agreement. The new method confirmed its applicability for PC quantification in two formulations, namely a PC-enriched cream and polyester microimplants. This new quantification method for PC is a reliable alternative to highly sophisticated chromatographic methods.

Asunto(s)

RESUMEN

Suspension stability can be theoretically estimated prior to the beginning of the formulating process based on the solid phase particle size, liquid phase density, and viscosity. Stokes equation can be used to predict suspension stability in order to save time and resources. The examples of these calculations for the assessment of suspension physical characteristics are given in this article. One parameter that cannot be theoretically estimated with precision is flocculation/deflocculation. Flocculation can be experimentally determined using the "jar test," and it is a critical parameter for the substances showing inclination toward caking. Suspensions will sediment in time; however, it is their key feature to be able to redisperse in order to preserve the efficacy and proper dosage. Bismuth subnitrate is practically insoluble in water, which makes it convenient for oral pharmaceutical suspensions, rather than the other pharmaceutical forms. Like the other bismuth compounds, it tends to cake in aqueous medium. In order to prevent formation of the solid sediment, controlled flocculation of the suspended bismuth subnitrate particles is recommended. The effect of the excipients (sodium citrate, Tween 20, propylene glycol, microcrystalline cellulose) on the transmittance of the prepared suspensions and the quantity and characteristics of the formed sediment were evaluated. Suspensions containing sodium citrate, as well as the formulations with sodium citrate and microcrystalline cellulose, based on their transmittance characteristics, were determined to be flocculating suspensions, regardless of the sodium citrate concentration used. The highest affinity towards formation of flocculating suspensions, with the highest transmittance value had microcrystalline cellulose with 15% (w/w) sodium citrate.

Asunto(s)

RESUMEN

Oral administration of indomethacin has been limited by its poor water solubility. Cyclodextrins have been recognized as potential candidates to overcome the poor solubility of indomethacin through the formation of inclusion complexes. The aim of our study was to compare the dissolution profiles of pure indomethacin and its mixtures with α- and γ-cyclodextrins The inclusion complexes of indomethacin with α- and γ-cyclodextrins were prepared by direct mixing in dissolution vessel. Fixed volumes of the dissolution medium were withdrawn at 0,5; 1 and 4 hours. Dissolution tests were performed on the USP Apparatus 2, rotating speed 100 rpm at 37±0.5 ° C, 500 ml, distilled water and 0,1 M HCl solution). Quantification of dissolved indomethacin was performed by UV/VIS spectrophotometric method at the absorption maximum around 320 nm. The results were expressed as relative dissolution rate (ratio between indomethacin dissolved from its physical mixtures with α- and γ-cyclodextrins and that dissolved the pure drug). Relative dissolution rates of indomethacin in combination with α- and γ-cyclodextrins at the end of testing were in the range of 91,66 to 337,14 % (for α- cyclodextrin) and in the range of 128,57 to 301,92 % (for γ-cyclodextrin). The complexation of indomethacin with α- and γ-cyclodextrins resulted in the enhancement of dissolution rate.

Asunto(s)

RESUMEN

Carbamazepine belongs to the class II biopharmaceutical classification system (BCS) which is characterized by a high per-oral dose, a low aqueous solubility and a high membrane permeability. The bioavailability of such a drug is limited by the dissolution rate. The present study deals with the formulations of immediate release tablets of poorly soluble carbamazepine. As model tablets for this investigation, two formulations (named "A" and "B" formulations) of carbamazepine tablets labeled to contain 200 mg were evaluated. The aim of this study was to establish possible differences in dissolution profile of these two formulations purchased from the local market. The increased crystallinity together with enlarged particle size, enhanced aggregation and decreased wettability of the drug, resulted in insufficient dissolution rate for formulation "B". From the dissolution point of view, this formulation was inferior to the formulation "A", due to the solubilization effect.

Asunto(s)

RESUMEN

The objective of this work was to compare several profiles of dissolution data for metoprolol controlled release tablet formulations in order to identify possible changes in dissolution profiles of whole and scored tablets. Adequate design of score lines (on one or both sides) as well as the technology of preparation of tablet mixtures ensure forming a score line of adequate thickness, shape, size, curvature. According to the obtained results, this type of extended release formulation is eligible for splitting and use in therapy either as a whole or scored tablets.

Asunto(s)

RESUMEN

Dissolution rate of two fluoroquinolone antibiotics (ciprofloxacin and moxifloxacin) was analysed in presence/absence of three antacid formulations. Disintegration time and neutralisation capacity of antacid tablets were also checked. Variation in disintegration time indicated the importance of this parameter, and allowed evaluation of the influence of postponed antacid-fluoroquinolone contact. The results obtained in this study showed decreased dissolution rate of fluoroquinolone antibiotics from tablets in simultaneous presence of antacids, regardless of their type and neutralisation capacity.

Asunto(s)

RESUMEN

Anthocyanins are effective antioxidants but they have also been proposed to have other biological activities independent of their antioxidant capacities that produce health benefits. Examples range from inhibition of cancer cell growth in vitro, induction of insulin production in isolated pancreatic cells, reduction of starch digestion through inhibition of a-glucosidase activity, suppression of inflammatory responses as well as protection against age-related declines in cognitive behavior and neuronal dysfunction in the central nervous system. However, to achieve any biological effect in a specific tissue or organ, anthocyanins must be bioavailable; i.e. effectively absorbed from the gastrointestinal tract (GIT) into the circulation and delivered to the appropriate location within the body. In this study, we assess the stability of anthocyanins from commercial Black currant (Ribes nigrum L.) juice using an in vitro digestion procedure that mimics the physiochemical and biochemical conditions encountered in the gastrointestinal tract (GIT). The main objective of this work was the evaluation of stability of anthocyanins during in vitro digestion in gastric and intestinal fluid regarding whether appropriate enzyme (pepsin or pancreatin) was added or not. Anthocyanins present in commercial black currant juice remain stable during in vitro digestion in gastric fluid regardless whether pepsin was added into the medium or not. Also, they remain stable during in vitro digestion in simulated intestinal fluid without pancreatin. The stability studies of anthocyanins in the intestinal fluid containing pancreatin indicated reduced stability, which also mainly contribute to slight reduction of total anthocyanins content (-1.83%) in commercial black currant juice.

Asunto(s)

RESUMEN

When considering single-dose preparations, it is fundamental that the patient receives in his individual dose an amount of drug close to that claimed on the label. Since drug content and content uniformity of single-dose preparations depend on a number of processes associated with their manufacture, it is obviously unrealistic to expect every unit of product to possess exactly the same amount of the active ingredient. For that reason, pharmacopeial standards and specifications have been established to provide limits for permissible variations in the amount of active ingredient of individual single-dose units. The aim of our study was to determine the applicability of content uniformity and dissolution variation test on ropinirole hydrochloride tablets. According to the results obtained, we may conclude that analyzed ropinirole hydrochloride tablets satisfied pharmacopeial requirements concerning content uniformity and dissolution testing. In this case RSD tended to increase with the decrease of the labeled strength. It is obvious from the R2 value, as well. On the other side, if consider larger number of lots, analyzed by different assay methods and various sample preparation procedures this correlation is less pronounced. This may be a consequence of different assay techniques applied, HPLC, UV-D1 or UV.

Asunto(s)

RESUMEN

Stability testing of an active substance or finished product provides information of the variation of drug substance or final product with time influenced by a variety of environmental factors such as temperature, humidity and light. Knowledge gained from stability studies enables understanding of the effects of the environment on the drugs. The aim of our study was to determine the stability of cefuroxime axetil oral suspension at different temperature storage conditions (stored at room /20 degrees C/ and refrigerated /5 degrees C/ conditions). Determination of cefuroxime (as cefuroxime axetil) was performed by dissolution testing. Fractions of the released cefuroxime axetil were compared using f2 value. After interpolating data for dissolution profiles at room and refrigerated conditions the following f2values were obtained: 62,56; 56,32 and 36,18 on 3rd, 6th and 10th day, respectively. These values indicate similarities in drug release from analyzed cefuroxime axetil oral suspension on 3rd, 6th day, and differences on 10th day. Based on our results, we may assume that cefuroxime axetil oral suspension preserves its stability for 10 days after reconstitution under room and refrigerated conditions. It is obvious, according to the f2 value obtained on the 10th day, that there is a difference between the released cefuroxime axetil from oral suspension at room (87,68%) and refrigerated (92,35%) conditions. Concentration changes can be caused by the mechanisms associated with drug release and hydrolytical decomposition of the sample and higher temperatures during longer period of storage.

Asunto(s)