Long-acting injectable formulations represent a rapidly emerging category of drug delivery systems that offer several advantages compared to orally administered medicines. Rather than having to frequently swallow tablets, the medication is administered to the patient by intramuscular or subcutaneous injection of a nanoparticle suspension that forms a local depot from which the drug is steadily released over a period of several weeks or months. The benefits of this approach include improved medication compliance, reduced fluctuations of drug plasma level, or the suppression of gastrointestinal tract irritation. The mechanism of drug release from injectable depot systems is complex, and there is a lack of models that would enable quantitative parametrisation of the process. In this work, an experimental and computational study of drug release from a long-acting injectable depot system is reported. A population balance model of prodrug dissolution from asuspension with specific particle size distribution has been coupled with the kinetics of prodrug hydrolysis to its parent drug and validated using in vitro experimental data obtained from an accelerated reactive dissolution test. Using the developed model, it is possible to predict the sensitivity of drug release profiles to the initial concentration and particle size distribution of the prodrug suspension, and subsequently simulate various drug dosing scenarios. Parametric analysis of the system has identified the boundaries of reaction- and dissolution-limited drug release regimes, and the conditions for the existence of a quasi-steady state. This knowledge is crucial for the rational design of drug formulations in terms of particle size distribution, concentration and intended duration of drug release.
- MeSH
- Antipsychotic Agents * MeSH
- Injections, Intramuscular MeSH
- Delayed-Action Preparations MeSH
- Humans MeSH
- Prodrugs * MeSH
- Solubility MeSH
- Suspensions MeSH
- Drug Liberation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Due to the additional particle coalescence in the coating, changes in the dissolution profile occur over time in the formulations coated by aqueous ethylcellulose latex. Dry thermal treatment (DT) of the coating can be used as a prevention of this process. Alternatively, it is advisable to take advantage of the synergistic effect of high humidity during wet treatment (WT), which substantially accelerates the film formation. This can be a problem for time-controlled systems, which are based on the coating rupture due to the penetration of water into the core causing the increase in the system volume. This process can begin already during the WT, which may affect the coating adversely. The submitted work was focused on the stability testing of two pellet core compositions: pellets containing swelling superdisintegrant sodium carboxymethyl starch (CMS) and pellets containing osmotically active polyethylene glycol (PEG). Another objective was to identify the treatment/storage condition effects on the pellet dissolution profiles. These pellets are intended to prevent hypoglycemia for patients with diabetes mellitus and therefore, besides the excipients, pellet cores contain 75% or 80% of glucose. The pellet coating is formed by ethylcellulose-based latex, which provides the required lag time (120-360 min). The sample stability was evaluated depending on the pellet core composition (PEG, CMS) for two types of final pellet coating treatment (DT or WT). Scanning electron microscopy and Raman microspectroscopy revealed the penetration of glucose and polyethylene glycol from the core to the PEG pellet surface after WT. For the CMS sample, significant pellet swelling after WT (under the conditions of elevated humidity) was statistically confirmed by the means of stereomicroscopic data evaluation. Therefore, the acceleration of dissolution rate during the stress tests is caused by the soluble substance penetration through the coating in the case of PEG pellets or by dosage form volume increase in the case of CMS pellets. The observed mechanisms can be generally anticipated during the stability testing of the ethylcellulose coated dosage forms. The aforementioned processes do not occur after DT and the pellets are stable in the environment without increased humidity.
- MeSH
- Cellulose analogs & derivatives chemistry MeSH
- Chemistry, Pharmaceutical MeSH
- Glucose chemistry pharmacology MeSH
- Hypoglycemia prevention & control MeSH
- Drug Implants chemistry MeSH
- Delayed-Action Preparations MeSH
- Polyethylene Glycols chemistry MeSH
- Excipients chemistry MeSH
- Surface Properties MeSH
- Drug Compounding methods MeSH
- Solubility MeSH
- Starch analogs & derivatives chemistry MeSH
- Drug Stability MeSH
- Drug Liberation MeSH
- Particle Size MeSH
- Hot Temperature MeSH
- Publication type
- Journal Article MeSH
The rapid dissolution of copper oxide (CuO) nanoparticles (NPs) with release of ions is thought to be one of the main factors modulating their toxicity. Here we assessed the cytotoxicity of a panel of CuO NPs (12 nm ± 4 nm) with different surface modifications, i.e., anionic sodium citrate (CIT) and sodium ascorbate (ASC), neutral polyvinylpyrrolidone (PVP), and cationic polyethylenimine (PEI), versus the pristine (uncoated) NPs, using a murine macrophage cell line (RAW264.7). Cytotoxicity, reactive oxygen species (ROS) production, and cellular uptake were assessed. The cytotoxicity results were analyzed by the benchmark dose (BMD) method and the NPs were ranked based on BMD20values. The PEI-coated NPs were found to be the most cytotoxic. Despite the different properties of the coating agents, NP dissolution in cell medium was only marginally affected by surface modification. Furthermore, CuCl2(used as an ion control) elicited significantly less cytotoxicity when compared to the CuO NPs. We also observed that the antioxidant, N-acetylcysteine, failed to protect against the cytotoxicity of the uncoated CuO NPs. Indeed, the toxicity of the surface-modified CuO NPs was not directly linked to particle dissolution and subsequent Cu burden in cells, nor to cellular ROS production, although CuO-ASC NPs, which were found to be the least cytotoxic, yielded lower levels of ROS in comparison to pristine NPs. Hierarchical cluster analysis suggested, instead, that the toxicity in the current in vitro model could be explained by synergistic interactions between the NPs, their dissolution, and the toxicity of the coating agents.
- MeSH
- Antioxidants MeSH
- Cell Death drug effects MeSH
- Cell Line MeSH
- Metal Nanoparticles chemistry toxicity MeSH
- Macrophages metabolism MeSH
- Copper chemistry pharmacokinetics toxicity MeSH
- Mice MeSH
- Surface Properties MeSH
- Reactive Oxygen Species metabolism MeSH
- Solubility MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Vonkajšie faktory životného prostredia, fajčenie a stres podnecujú v našom organizme tvorbu veľmi reaktívnych voľných častíc – radikálov. V prípade nedostatku vhodných obranných mechanizmov v organizme, tieto reaktívne častice vytvárajú v tele prostredie pre vznik zápalových chorôb. Ľudské telo má vlastné obranné mechanizmy chrániace organizmus pred voľnými radikálmi. Z tohto hľadiska nadobúdajú zvýšený význam najmä antioxidanty, čo sú látky schopné neutralizovať voľné radikály. Jedným z kľúčových antioxidantov je práve nutričný prvok selén, význam ktorého už bol potvrdený množstvom rôznych štúdií 1). Cieľom práce bolo vypracovať a optimalizovať pracovné podmienky pri identifikácii a stanovení selénu v krvnej plazme u pacientov trpiacich na zápalové kožné ochorenie, ktorým je atopická dermatitída. Stanovené hodnoty selénu u pacientov s uvedeným ochorením boli porovnané s hodnotami selénu, ktoré boli stanovené u skupiny zdravých jedincov. Cieľom práce bolo taktiež vyhodnotiť súvis medzi zníženou hladinou selénu v organizme a atopickou dermatitídou ako aj sledovať vplyv užívania prípravku s obsahom selénu na priebeh ochorenia. Merací postup bol verifikovaný porovnaním výsledkov obsahu selénu získaných novšou elektrochemickou analytickou metódou – galvanostatickou rozpúšťacou chronopotenciometriou (SCP) s výsledkami získanými komparačnou metódou – atomovou absorpčnou spektrometriou s generovaním hydridov (HGAAS).
In the human organism, the external factors of the environment, smoking and stress provoke the production of very reactive free particles – radicals. In the case of deficiency of suitable protective mechanisms in the organism, these reactive particles produce the conditions for the development of inflammatory diseases in the body. The human body possesses protective mechanisms of its own to defend the organisms against free radicals. From this viewpoint, particularly antioxidants, i.e. substances capable to neutralize free radicals, are of increased importance. One of the antioxidants of key importance is the nutritional element selenium, the importance of which has already been confirmed in a number of different studies 1). The present paper aimed to elaborate and optimize the working conditions in the identification and determination of selenium in blood plasma in patients suffering from atopic dermatitis, an inflammatory skin disease. The selenium values found in patients suffering from the above-mentioned disease were compared with the selenium values determined in a group of healthy subjects. The paper also aimed to evaluate the connection between a decreased selenium level and the organism and atopic dermatitis as well as to examine the influence of the administration of a preparation containing selenium upon the course of the disease. The procedure of measurement was verified by comparing the results of selenium content obtained by a more recent electrochemical analytical method – galvanostatic solution chronopotentiometry (SCP) – with the results obtained by a comparative method – hydrid generation atomic absorption spectrophotometry (HGAAS).
Hypoglycaemic episodes represent serious and frequent complications of type 1 and 2 diabetes. Theoretically, the risk of hypoglycaemic states can be affected by a dosage form based on a food supplement containing a delayed release formulation of glucose. The release of glucose should compensate for balance the peak effect of an antidiabetic treatment. In clinical practice, a diet with fibre and grains is recommended and patients are broadly educated in the topic of low and high glycaemic indexes to achieve the same effect. However, a precisely-timed release of carbohydrates can favourably target expected hypoglycaemia and concurrently decrease carbohydrate content. To study the possibility of preparing the dosage form with controlled-release carbohydrates, a dosage form of pellets containing four osmotically active substances coated by a membrane created of ethylcellulose was prepared. These pellets can be administered in a mixture with liquid or semisolid food. The resulting dissolution profiles for selected compositions showed that delayed release can be achieved for 120, 240 and 360min in vitro, representing an ideal delay for clinical purposes.
- MeSH
- Child MeSH
- Glucose chemistry MeSH
- Hypoglycemia prevention & control MeSH
- Drug Delivery Systems * MeSH
- Delayed-Action Preparations chemistry MeSH
- Humans MeSH
- Solubility MeSH
- Drug Liberation MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The application of polymer-based drug delivery systems is advantageous for improved pharmacokinetics, controlled drug release, and decreased side effects of therapeutics for inflammatory disease. Herein, we describe the synthesis and characterization of linear N-(2-hydroxypropyl)methacrylamide-based polymer conjugates designed for controlled release of the anti-inflammatory drug dexamethasone through pH-sensitive bonds. The tailored release rates were achieved by modifying DEX with four oxo-acids introducing reactive oxo groups to the DEX derivatives. Refinement of reaction conditions yielded four well-defined polymer conjugates with varied release profiles which were more pronounced at the lower pH in cell lysosomes. In vitro evaluations in murine peritoneal macrophages, human synovial fibroblasts, and human peripheral blood mononuclear cells demonstrated that neither drug derivatization nor polymer conjugation affected cytotoxicity or anti-inflammatory properties. Subsequent in vivo tests using a murine arthritis model validated the superior anti-inflammatory efficacy of the prepared DEX-bearing conjugates with lower release rates. These nanomedicines showed much higher therapeutic activity compared to the faster release systems or DEX itself.
- MeSH
- Anti-Inflammatory Agents therapeutic use MeSH
- Dexamethasone MeSH
- Doxorubicin chemistry MeSH
- Leukocytes, Mononuclear * MeSH
- Humans MeSH
- Mice MeSH
- Nanomedicine MeSH
- Drug Carriers chemistry MeSH
- Polymers chemistry MeSH
- Rheumatic Diseases * MeSH
- Drug Liberation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Patients tend to prevent hypoglycemia by excessive saccharide intake leading to poorer glycemic control with potentially fatal consequences. This problem could be resolved by means of pellets with glucose release delayed by 120-360 min as a compensation of the antidiabetic drug peak effect. No glucose is released before; hence there is no risk of hyperglycemia and secondary complications. The pellets contain glucose in combination with an osmotically active ingredient and are coated with an ethylcellulose dispersion, which forms an insoluble semipermeable membrane and ensures delayed release. The release of glucose was assessed using dissolution and high-performance liquid chromatography. Dissolution profiles indicated the possibility of achieving the requested lag time using a combination of adequate compositions and coating concentrations. Lag times of 60, 240 and 360 min were achieved. The sample containing carboxymethyl starch was found to be most suitable for the intent of this work.
- MeSH
- Cellulose analogs & derivatives chemistry MeSH
- Glucose administration & dosage chemistry MeSH
- Hypoglycemia blood prevention & control MeSH
- Kinetics MeSH
- Blood Glucose metabolism drug effects MeSH
- Delayed-Action Preparations MeSH
- Humans MeSH
- Membranes, Artificial MeSH
- Excipients chemistry MeSH
- Surface Properties MeSH
- Drug Compounding MeSH
- Solubility MeSH
- Starch chemistry MeSH
- Chromatography, High Pressure Liquid MeSH
- Check Tag
- Humans MeSH
Although ellipticine (Elli) is an efficient anticancer agent, it exerts several adverse effects. One approach to decrease the adverse effects of drugs is their encapsulation inside a suitable nanocarrier, allowing targeted delivery to tumour tissue whereas avoiding healthy cells. We constructed a nanocarrier from apoferritin (Apo) bearing ellipticine, ApoElli, and subsequently characterized. The nanocarrier exhibits a narrow size distribution suggesting its suitability for entrapping the hydrophobic ellipticine molecule. Ellipticine was released from ApoElli into the water environment under pH 6.5, but only less than 20% was released at pH 7.4. The interaction of ApoElli with microsomal membrane particles containing cytochrome P450 (CYP) biotransformation enzymes accelerated the release of ellipticine from this nanocarrier making it possible to be transferred into this membrane system even at pH 7.4 and facilitating CYP-mediated metabolism. Reactive metabolites were formed not only from free ellipticine, but also from ApoElli, and both generated covalent DNA adducts. ApoElli was toxic in UKF-NB-4 neuroblastoma cells, but showed significantly lower cytotoxicity in non-malignant fibroblast HDFn cells. Ellipticine either free or released from ApoElli was concentrated in the nuclei of neuroblastoma cells, concentrations of which being significantly higher in nuclei of UKF-NB-4 than in HDFn cells. In HDFn the higher amounts of ellipticine were sequestrated in lysosomes. The extent of ApoElli entering the nuclei in UKF-NB-4 cells was lower than that of free ellipticine and correlated with the formation of ellipticine-derived DNA adducts. Our study indicates that the ApoElli form of ellipticine seems to be a promising tool for neuroblastoma treatment.
- MeSH
- DNA Adducts genetics metabolism MeSH
- Apoferritins chemistry pharmacology MeSH
- Cytochrome P-450 CYP3A metabolism MeSH
- Ellipticines chemistry pharmacology MeSH
- Phosphorylation MeSH
- Histones metabolism MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Nanoparticles * MeSH
- Neuroblastoma drug therapy enzymology genetics pathology MeSH
- Drug Carriers * MeSH
- Drug Compounding MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Drug Liberation MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Kyselina ursodeoxycholová jakožto sekundární žlučová kyselina je po řadu desetiletí úspěšně využívána u patologických stavů postihujících žlučové cesty. Kromě disoluce žlučových kamenů se uplatňuje u chronických onemocnění jater či u reaktivní gastritidy navozené refluxem žluči. V následujícím textu je pojednán její terapeutický potenciál na pozadí pleiotropního mechanismu účinku.
Ursodeoxycholic acid, as a secondary bile acid, has been used successfully for many decades in pathological conditions affecting the bile ducts. In addition to the dissolution of gallstones, it is used in chronic liver diseases or in reactive gastritis induced by bile reflux. In the following text, its therapeutic potential against the background of its pleiotropic mechanism of action is discussed.
- MeSH
- Liver Cirrhosis, Biliary drug therapy MeSH
- Cholagogues and Choleretics administration & dosage pharmacology therapeutic use MeSH
- Cystic Fibrosis drug therapy MeSH
- Gastritis drug therapy MeSH
- Gastrointestinal Diseases * drug therapy MeSH
- Ursodeoxycholic Acid * administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Non-alcoholic Fatty Liver Disease drug therapy MeSH
- Cholangitis, Sclerosing drug therapy MeSH
- Check Tag
- Humans MeSH
The international standard ISO 23317:2014 for the in vitro testing of inorganic biomaterials in simulated body fluid (SBF) uses TRIS buffer to maintain neutral pH. In our previous papers, we investigated the interaction of a glass-ceramic scaffold with TRIS and HEPES buffers. Both of them speeded up glass-ceramic dissolution and hydroxyapatite (HAp) precipitation, thereby demonstrating their unsuitability for the in vitro testing of highly reactive biomaterials. In this article, we tested MOPS buffer (3-[N-morpholino] propanesulfonic acid), another amino acid from the group of "Goods buffers". A highly reactive glass-ceramic scaffold (derived from Bioglass®) was exposed to SBF under static-dynamic conditions for 13/15 days. The kinetics and morphology of the newly precipitated HAp were studied using two different concentrations of (PO4 )3- ions in SBF. The pH value and the SiIV , Ca2+ , and (PO4 )3- concentrations in the SBF leachate samples were measured every day (AAS, spectrophotometry). The glass-ceramic scaffold was monitored by SEM/EDS, XRD, WD-XRF, and BET before and after 1, 3, 7, 11, and 13/15 days of exposure. As in the case of TRIS and HEPES, the preferential dissolution of the glass-ceramic crystalline phase (Combeite) was observed, but less intensively. The lower concentration of (PO4 )3- ions slowed down the kinetics of HAp precipitation, thereby causing the disintegration of the scaffold structure. This phenomenon shows that the HAp phase was predominately generated by the presence of (PO4 )3- ions in the SBF, not in the glass-ceramic material. Irrespective of this, MOPS buffer is not suitable for the maintenance of pH in SBF.
