Dose dumping of modified-release solid oral dosage forms.

The presented review article is a compilation of several foreign reviews and experimental papers, as well as several authority guidelines, which deal with the phenomenon of dose dumping of solid dosage forms with modified drug release. The aim of the publication is to present this often-neglected issue to a wider domestic audience. The work deals with two basic types of dose dumping, i.e., alcohol-induced dose dumping and food-induced dose dumping. It contains basic factors affecting this phenomenon as well as possible formulation solutions that can be used to eliminate it. Last but not least, the current requirements of the authorities are also mentioned, especially for testing newly introduced products with the presumed potential risk of dose dumping.

Use of droplet-based microfluidic techniques in the preparation of microparticles.

Microparticles are widely used in myriad fields such as pharmaceuticals, foods, cosmetics, and other industrial fields. Compared with traditional methods for synthesizing microparticles, microfluidic techniques provide very powerful platforms for creating highly controllable emulsion droplets as templates for fabricating uniform microparticles with advanced structures and functions. Microfluidic techniques can generate emulsion droplets with precisely controlled size, shape, and composition. A more precise preparation process brings an effective tool to control the release profile of the drug and introduces an easily accessible reproducibility. The paper gives information about basic droplet-based set-ups and examples of attainable microparticle types preparable by this method.

Use of droplet-based microfluidic techniques in the preparation of microparticles.

Microparticles are widely used in myriad fields such as pharmaceuticals, foods, cosmetics, and other industrial fields. Compared with traditional methods for synthesizing microparticles, microfluidic techniques provide very powerful platforms for creating highly controllable emulsion droplets as templates for fabricating uniform microparticles with advanced structures and functions. Microfluidic techniques can generate emulsion droplets with precisely controlled size, shape, and composition. A more precise preparation process brings an effective tool to control the release profile of the drug and introduces an easily accessible reproducibility. The paper gives information about basic droplet-based set-ups and examples of attainable microparticle types preparable by this method.

Preformulation design of PLGA particulate system for multi-day drug delivery of the antidepressant mirtazapine.

In this experimental study, the biodegradable polylactide-co-glycolide (PLGA) microparticles (MP) loaded with the insoluble antidepressant mirtazapine were prepared by the simple o/w solvent evaporation method. The formation involved intrinsic variables, such as the content of polymer (700, 900 or 1200 mg), dichloromethane (5 or 10 ml) and/or drug (200 or 400 or 600 mg), and the volume of the aqueous emulsion phase (400, 600 or 800 ml). The influence of these parameters on the size and morphology of microparticles, encapsulation efficiency, and drug release behavior was observed. All MP were successfully prepared, and their size ranged between 165.34 ± 42.88 and 360.17 ± 121.59 μm. MP exhibited prolonged drug release (days), and some profiles had multiphasic character. It was found that the samples prepared with a  higher initial amount of PLGA were bigger with prolonged lag time up to 34.3 hours. On the other hand, higher drug concentrations reduced the lag time. The external phase volume reduction and multiplication of dichloromethane amount prolonged the mirtazapine release and decreased the encapsulation efficiency. These observations were further confirmed by multivariate data analysis.

Matrix Vaginal Rings for Female Dogs-Effect of Altering Dimensions on Mechanical Properties and Dissolution Characteristics, and In vivo Safety Study.

The vaginal rings research is almost exclusively focused on rings for human medicine, although the dosage form offers improvement of therapeutic effect in other mammals as well. This contribution studied an effect of varying dimension parameters (diameter 20, 30 or 40 mm; height 3, 4 or 5 mm; width of annulus 5, 7.5 or 10 mm) on mechanical properties and dissolution behaviour of silicone vaginal rings with constant drug amount, intended for use in dogs. Results showed that altering dimensions influenced mechanical properties (compressive force, tensile strength and resistance of removal thread), in vitro drug release and water uptake. The removal thread resistance was increasing with increasing height and width. Compression force was higher for the rings with smaller diameter. The total drug release was increasing with decreasing height and rising diameter, surface area and water uptake during dissolution test. The initial dissolution rate was slower for the rings with higher width. As the best candidate for use in model dog subjects, the ring with 30 mm diameter, 3 mm height and 7.5 mm width was found. These drug-free vaginal rings were further tested in in vivo safety study. The results did not show any major deviation from the physiological conditions. Graphical abstract.

Interaction Pathways and Structure-Chemical Transformations of Alginate Gels in Physiological Environments.

The remarkably diverse affinity of alginate (ALG) macromolecules for polyvalent metal ions makes cross-linked alginate gels an outstanding biomaterial. Surprisingly, however, very little is known about their interactions and structural transformations in physiological environments. To bridge this gap, we prepared a set of ALG gels cross-linked by various ions and monitored their structural changes at different media simulating gastric and intestinal fluids and cellular environments. For these studies, we used multinuclear solid-state NMR (ss-NMR) spectroscopy, which revealed a range of competitive ion-exchange and interconversion reactions, the rate of which strongly depended on the nature of the cross-linking metal ions. Depending on the environment, ALG chains adopted different forms, such as acidic (hydro)gels stabilized by strong hydrogen bonds, and/or weakly cross-linked Na/H-gels. Simultaneously, the exchanged polyvalent ions extensively interacted with the environment even forming in some cases insoluble phosphate microdomains directly deposited in the ALG bead matrix. The extent of the transformations and incorporation of secondary phases into the alginate beads followed the size and electronegativity of the cross-linking ions. Overall, the applied combination of various macroscopic and biological tests with multinuclear ss-NMR revealed a complex pathway of alginate beads transformations in physiological environments.

The development of a silicone vaginal ring with a prostaglandin analogue for potential use in the treatment of canine reproductive disorders.

In veterinary medicine, vaginal rings (VRs) are rarely used. However, there are diseases of female dogs' reproductive system which represent a suitable possibility for their usage. An example of such a disease is canine pyometra which can be treated by lipophilic prostaglandin drugs, unfortunately with harmful side effects after systemic administration. The aim of the study was to prove that the matrix VR based on silicone and channel-forming substance can be successfully used as a carrier for a three-day delivery of prostaglandin E2 (PGE2). Based on an in-vitro release study, an optimum channel-forming substance and its concentration were selected. The results were implemented during the construction of VR from the medical grade silicone DDU-4840 with PGE2 (5 mg). Glucose anhydrous in the 30% concentration was chosen as the most functional channel-forming substance due to synergism of osmotic activity and solubility. The DDU-VR containing PGE2 and 30% of glucose anhydrous exhibited excellent mechanical characteristics and ensured 29% drug release through water-filled channels in first-order kinetic manner. This is eight times higher than a sample without glucose where molecular diffusion through the silicone matrix was dominating the release mechanism. Moreover, drug-free VRs were tested for mechanical resistance and the design of removal thread.

Honoring the 80th Anniversary of the World War II outbrake.

This article, prepared on the occasion of the 80th anniversary of the World War II outbreak, serves to remind the war generation of pharmacists and their sacrifices through several selected personalities. In several short medallions it recalls the lives of heroes Tadeusz Pankiewicz and Laure Gatet, the German tanker Otto Carius and it mentions several other personalities. From the post-war generation it presents Jean-Claude Pressac as the author of the evidence elaboration on the Holocaust.

New approach for detoxification of patients dependent on benzodiazepines and Z-drugs for reduction of psychogenic complications.

Benzodiazepines (BZDs) and Z-drugs are strongly addictive substances, acting on identical GABA receptors. Detoxification should be long-term and gradual, usually by tapering a long-acting BZD (diazepam) but no suitable commercial pharmaceutic product exists with the necessary low drug content. This review describes the specific pharmacological aspects and comparisons of individual BZDs in relation to their effects and addictiveness. The success of the treatment relates to the patients comfort during this process. Patients are typically afraid of switching to a more suitable long-acting BZD (diazepam), and become stressed during the tapering and anxious from withdrawal symptoms. These obstacles could be overcome through individualized detoxification according to already published withdrawal schedules based on the administration of very precise diazepam doses in a long-term gradual tapering with possible addition of adjuvant drugs. Dose reduction does not change external appearance of the dosage form, and the patient could be treated until the placebo phase. Individually prepared pharmaceutics with different and precise diazepam contents can be used for comfortable detoxification and also may eliminate psychogenic stress during switching, tapering, and the withdrawal period.

(Meth)acrylate copolymers of Eudragit® type in oral tablet technology.

This review focuses on the characterization of (meth)acrylate copolymers - Eudragit®, describing their thermal treatment behaviour, possible interactions between cationic and anionic polymers, incompatibilities related to Eudragits® and their use in the pharmaceutical technology of oral tablets. In summary, Eudragit® copolymers are divided into soluble ones, insoluble ones and a combination of these two types. The combination of soluble and insoluble poly(meth)acrylate gave a new type of polymer, Eudragit® FL. In oral tablet technology, Eudragits® are widely used in matrix tablets, either alone or in combination, where they mainly provide sustained drug release. To a lesser extent, Eudragits® are used in gastroretentive systems. Moreover, Eudragits® are also of great importance in coated tablets technology, where these enteric polymers provide specific drug targeting to certain parts of the digestive tract, mainly to the small intestine or colon. Important systems such as CODESTM and MMX® technology are mentioned. Last but not least an overview table of currently available oral medicinal products on the Czech market, where at least one of the Eudragits® was used as a film-forming agent, is included.

Influence of formulation and process parameters on the properties of Cu2+/alginate particles prepared by external ionic gelation evaluated by principal component analysis.

Currently, the method of external ionic gelation for the preparation of alginate particles is successfully used not only in the field of pharmacy and medicine, but also especially in the field of biotechnology. Therefore, the preparation of alginate particles and their subsequent evaluation using principal component analysis was the key task of our experiment. To optimize this method, we focused on the evaluation of the effect of formulation (the polymer concentration, the hardening solution concentration) and process parameters (the outer diameter of the injection needle) on the properties of the resulting beads (yield, sphericity factor, equivalent diameter and swelling capacity at pH 6). Using multivariate data analysis, the major influence on the resulting properties of the prepared particles was confirmed only in sodium alginate concentration. Obtained results verified the reliable and safe potential of the external ionic gelation for preparation alginate-based particulate dosage forms.

The size-reduced Eudragit® RS microparticles prepared by solvent evaporation method - monitoring the effect of selected variables on tested parameters.

Size-reduced microparticles were successfully obtained by solvent evaporation method. Different parameters were applied in each sample and their influence on microparticles was evaluated. As a model drug the insoluble ibuprofen was selected for the encapsulation process with Eudragit® RS. The obtained microparticles were inspected by optical microscopy and scanning electron microscopy. The effect of aqueous phase volume (600, 400, 200 ml) and the concentration of polyvinyl alcohol (PVA; 1.0% and 0.1%) were studied. It was evaluated how those variations and also size can affect microparticle characteristics such as encapsulation efficiency, drug loading, burst effect and microparticle morphology. It was observed that the sample prepared with 600 ml aqueous phase and 1% concentration of polyvinyl alcohol gave the most favorable results.Key words: microparticles solvent evaporation sustained drug release Eudragit RS®.

Structure and Dynamics of Alginate Gels Cross-Linked by Polyvalent Ions Probed via Solid State NMR Spectroscopy.

Alginate gels are an outstanding biomaterial widely applicable in tissue engineering, medicine, and pharmacy for cell transplantation, wound healing and efficient bioactive agent delivery, respectively. This contribution provides new and comprehensive insight into the atomic-resolution structure and dynamics of polyvalent ion-cross-linked alginate gels in microbead formulations. By applying various advanced solid-state NMR (ssNMR) spectroscopy techniques, we verified the homogeneous distribution of the cross-linking ions in the alginate gels and the high degree of ion exchange. We also established that the two-component character of the alginate gels arises from the concentration fluctuations of residual water molecules that are preferentially localized along polymer chains containing abundant mannuronic acid (M) residues. These hydrated M-rich blocks tend to self-aggregate into subnanometer domains. The resulting coexistence of two types of alginate chains differing in segmental dynamics was revealed by 1H-13C dipolar profile analysis, which indicated that the average fluctuation angles of the stiff and mobile alginate segments were about 5-9° or 30°, respectively. Next, the 13C CP/MAS NMR spectra indicated that the alginate polymer microstructure was strongly dependent on the type of cross-linking ion. The polymer chain regularity was determined to systematically decrease as the cross-linking ion radius decreased. Consistent with the 1H-1H correlation spectra, regular structures were found for the gels cross-linked by relatively large alkaline earth cations (Ba2+, Sr2+, or Ca2+), whereas the alginate chains cross-linked by bivalent transition metal ions (Zn2+) and trivalent metal cations (Al3+) exhibited significant irregularities. Notably, however, the observed disordering of the alginate chains was exclusively attributed to the M residues, whereas the structurally well-defined gels all contained guluronic acid (G) residues. Therefore, a key role of the units in M-rich blocks as mediators promoting the self-assembly of alginate chains was experimentally confirmed. Finally, combining 2D 27Al 3Q/MAS NMR spectroscopy with density functional theory (DFT) calculations provided previously unreported insight into the structure of the Al3+ cross-linking centers. Notably, even with a low residual amount of water, these cross-linking units adopt exclusively 6-fold octahedral coordination and exhibit significant motion, which considerably reduces quadrupolar coupling constants. Thus, the experimental strategy presented in this study provides a new perspective on cross-linked alginate structure and dynamics for which high-quality diffraction data at the atomic resolution level are inherently unavailable.

Optimization of Dissolution Compartments in a Biorelevant Dissolution Apparatus Golem v2, Supported by Multivariate Analysis.

Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for an updated version of the biorelevant dissolution apparatus-Golem v2. We designed eight compartments of uniform size but different inner geometry. The dissolution performance of the compartments was tested using immediate release caffeine tablets and evaluated by standard statistical methods and principal component analysis. Based on two phases of dissolution testing (using 250 and 100 mL of dissolution medium), we selected two compartment types yielding the highest measurement reproducibility. We also confirmed a statistically ssignificant effect of agitation rate and dissolution volume on the extent of drug dissolved and measurement reproducibility.

The influence of thermal treatment and type of insoluble poly(meth)acrylates on dissolution behavior of very soluble drug from hypromellose matrix tablets evaluated by multivariate data analysis.

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit®. Multivariate data analysis showed that the addition of Eudragit® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

Influence of pH Modulation on Dynamic Behavior of Gel Layer and Release of Weakly Basic Drug from HPMC/Wax Matrices, Controlled by Acidic Modifiers Evaluated by Multivariate Data Analysis.

The solubility of weakly basic drugs in passage through gastrointestinal tract leads to their pH-dependent release from extended release formulations and to lower drug absorption and bioavailability. The aim of this study was to modulate the micro-environmental pH of hypromellose/montanglycol wax matrices and to observe its influence on the release of weakly basic drug verapamil hydrochloride (VH) with a pH-dependent solubility with respect to gel layer formation and its dynamics. For this study, malic and succinic acids differing in their solubility and pKa were selected as pH modifiers. The dissolution studies were performed by the method of changing pH. Within the same conditions, pH, thickness, and penetration force of the gel layer were measured as well. From the PCA sub-model, it is evident that a higher acid concentration ensured lower gel pH and conditions for higher drug solubility, thus creating larger gel layer with smaller rigidity, resulting in higher VH release during the dissolution test. Incorporation of stronger and more soluble malic acid (100 mg/tablet) created the most acidic and the thickest gel layer through which a total of 74% of VH was released. Despite having lower strength and solubility, matrices containing succinic acid (100 mg/tablet) released a comparable 71% of VH in a manner close to zero-order kinetics. The thinner and less rigid gel layers of the succinic acid matrices allowed an even slightly faster VH release at pH 6.8 than from matrices containing malic acid. Thus acid solubility is more parametrically significant than acid pKa for drug release at pH 6.8.

Long-term controlled release of PLGA microparticles containing antidepressant mirtazapine.

The aim of the study was to prepare PLGA microparticles for prolonged release of mirtazapine by o/w solvent evaporation method and to evaluate effects of PVA concentration and organic solvent choice on microparticles characteristics (encapsulation efficiency, drug loading, burst effect, microparticle morphology). Also in vitro drug release tests were performed and the results were correlated with kinetic model equations to approximate drug release mechanism. It was found that dichloromethane provided microparticles with better qualities (encapsulation efficiency 64.2%, yield 79.7%). Interaction between organic solvent effect and effect of PVA concentration was revealed. The prepared samples released the drug for 5 days with kinetics very close to that of zero order (R(2 )= 0.9549 - 0.9816). According to the correlations, the drug was probably released by a combination of diffusion and surface erosion, enhanced by polymer swelling and chain relaxation.

[Possibilities of influencing the drug content and encapsulation efficiency of chitosan microspheres prepared by ionic gelation process]. / Moznosti ovlivnení obsahu léciva a enkapsulacní úcinnosti chitosanových mikrosfér pripravených procesem iontové gelace.

UNLABELLED: This study aimed to prepare high molecular weight chitosan blank and drug-loaded microparticles using 5-aminosalicylic acid (5-ASA) as the model active substance by an external ionic gelation. Formulation and process variables included the chitosan concentration and presence of drug in the polymer solution, and/or in hardening solution during the microparticles preparation. The effect of different preparation conditions on the properties of the microparticles was observed with a view to increase drug content in microparticles. For both types of microparticles (with and without the drug), it was found that their sphericity and equivalent diameter increased with increasing chitosan concentration. The drug content of drug-loaded microparticles was the highest in the case of the sample prepared from 1.75% chitosan dispersion, when the drug was present both in the chitosan dispersion and the hardening solution. Maximum six times higher drug content was achieved by change of the placement of 5-ASA during preparation (1.25% chitosan concentration). KEYWORDS: microparticles external ionotropic gelation chitosan 5-ASA encapsulation efficiency.

[Impact of formulation and process parameters on the properties of chitosan-based microspheres prepared by external ionic gelation]. / Vliv formulacních a procesních promenných na vlastnosti chitosanových mikrosfér pripravených vnejsí iontovou gelací

The aim of this experimental study was to optimize a preparation of microspheres from high viscosity chitosan by external ion gelation and to evaluate selected aspects of their preparation. For drug-free microparticles, the concentration of chitosan dispersions was chosen as a formulation variable; the position of instrument for a dispersion extrusion (horizontal vs. vertical) was evaluated as a process variable. On the basis of sphericity and equivalent diameter results, three different concentrations of chitosan dispersions were used for 5-aminosalicylic acid (5-ASA) encapsulation with the extrusion instrument in horizontal position, which was considered as the optimal. In consequent drug-loaded microparticle preparation, the influence of the concentration of chitosan dispersions and composition of hardening solution (10% sodium tripolyphosphate (TPP) vs. 10% TPP containing drug) was evaluated. In prepared 5-ASA microspheres it was found that the equivalent diameter increased with increasing chitosan concentration. In the case of sphericity, significant differences were not found. Samples prepared with the drug in both chitosan dispersion and hardening solution had a higher drug content, a smaller equivalent diameter and they showed a faster in vitro drug release in comparison with the samples prepared with the drug in chitosan dispersion only.

Influence of formulation and process parameters on the characteristics of PLGA-based microparticles with controlled drug release.

PLGA microparticles for sustained release of ibuprofen as the model drug were prepared by the O/W solvent evaporation method under altering stirring speed (600, 1000 rpm), emulsifier concentration (PVA concentration 0.1%, 1%) and organic solvent selection (dichloromethane, ethyl acetate). The obtained results confirmed the effect of selected formulation and process parameters on the properties of prepared PLGA-based microparticles. An influence on encapsulation efficiency, yield, morphological properties, mean size and drug release was observed. Increased stirring speed within the solvent evaporation process resulted in a decrease of encapsulation efficiency, yield and mean size but the incorporated drug was released faster. Increased PVA concentration in the external emulsion phase brought the same results except the ibuprofen release rate. Microparticles prepared with dichloromethane as the organic solvent exhibited higher sphericity, a more regular shape with a smooth surface, and thus dichloromethane was considered to be a more suitable organic solvent in comparison with ethyl acetate for this purpose.