With an increasing focus on sustainable technologies in the pharmaceutical industry, milling provides a solvent-free approach to improve drug dissolution. Milling of drugs with an excipient offers additional opportunities to achieve supersaturation kinetics. Therefore, this work aims to present insights of co-milling fenofibrate and apremilast, two good glass formers with low and high glass transition temperatures (Tgs) respectively. Drugs were co-milled with croscarmellose sodium for various process durations followed by thermal analysis, investigation of crystallinity, surface area and dissolution. The dissolution enhancement of the low-Tg glass former fenofibrate highly correlated with the process-induced increase in surface area of co-milled systems (R2 = 0.96). In contrast, the high-Tg glass former apremilast lost its crystalline order gradually after ≥ 10 min of co-milling, and favourable supersaturation kinetics during biorelevant dissolution testing were observed. Interestingly, the melting point of co-milled apremilast decreased and linearly correlated with the highest measured drug concentration (cmax) during in vitro dissolution (onset temperature R2 = 0.98; peak temperature R2 = 0.96). The melting point depression remained stable after 90 days for apremilast, whereas fenofibrate co-milled for 20 min or more showed an increase in melting point upon storage. This study demonstrated that co-milling with croscarmellose sodium is ideally suited to good glass formers with a high Tg. The melting point depression is thereby proposed as an easily accessible critical quality attribute to estimate likely dissolution performance of drugs in dry co-milled formulations.
- MeSH
- Aspirin chemistry analogs & derivatives MeSH
- Fenofibrate * chemistry MeSH
- Excipients chemistry MeSH
- Drug Compounding methods MeSH
- Solubility MeSH
- Glass * chemistry MeSH
- Thalidomide analogs & derivatives MeSH
- Transition Temperature MeSH
- Drug Liberation MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
Background/Objectives: Omeprazole undergoes degradation in acidic conditions, which makes it unstable in low pHs found in the gastric environment. The vast majority of already marketed omeprazole formulations use enteric polymer coatings to protect the drug from exposure to acidic pH in the stomach, allowing for drug release in the small intestine where the pH is higher. This study aimed to explore the technical aspects of using stomach acid neutralizers as an alternative to polymeric coatings for omeprazole. Methods: After evaluating various neutralizers, magnesium oxide and sodium bicarbonate were chosen to be incorporated into capsules containing omeprazole, which then underwent in vitro dissolution testing to assess their ability to maintain optimal pH levels and ensure appropriate dissolution kinetics. Hygroscopicity and chemical stability of the selected formulation were tested to prove pharmaceutical quality of the product. An in vivo pharmacokinetic study was conducted to demonstrate the efficacy of the omeprazole-sodium bicarbonate formulation in providing faster absorption in humans. Results: Sodium bicarbonate was selected as the most suitable antacid for ensuring omeprazole stabilization. Its quantity was optimized to effectively neutralize stomach acid, facilitating the rapid release and absorption of omeprazole. In vitro studies demonstrated the ability of the formulation to neutralize gastric acid within five minutes. In vivo studies indicated that maximum concentrations of omeprazole were achieved within half an hour. The product met the requirements of pharmaceutical quality. Conclusions: An easily manufacturable, fast-absorbing oral formulation was developed as an alternative to enteric-coated omeprazole.
- Publication type
- Journal Article MeSH
Free radical polymerization technique was used to formulate Poloxamer-188 based hydrogels for controlled delivery. A total of seven formulations were formulated with varying concentrations of polymer, monomer ad cross linker. In order to assess the structural properties of the formulated hydrogels, Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric analysis (TGA), Differential Scanning Calorimetry (DSC), Scanning electron microscopy (SEM), and X-ray diffraction (XRD) were carried out. To assess the effect of pH on the release of the drug from the polymeric system, drug release studies were carried in pH 1.2 and 7.4 and it was found that release of the drug was significant in pH 7.4 as compared to that of pH 1.2 which confirmed the pH responsiveness of the system. Different kinetic models were also applied to the drug release to evaluate the mechanism of the drug release from the system. To determine the safety and biocompatibility of the system, toxicity study was also carried out for which healthy rabbits were selected and formulated hydrogels were orally administered to the rabbits. The results obtained suggested that the formulated poloxamer-188 hydrogels are biocompatible with biological system and have the potential to serve as controlled drug delivery vehicles.
- MeSH
- Acrylic Resins * chemistry MeSH
- Calorimetry, Differential Scanning MeSH
- X-Ray Diffraction MeSH
- Hydrogels * chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Rabbits MeSH
- Drug Delivery Systems MeSH
- Delayed-Action Preparations chemistry pharmacokinetics MeSH
- Microscopy, Electron, Scanning MeSH
- Drug Carriers chemistry MeSH
- Poloxamer * chemistry MeSH
- Spectroscopy, Fourier Transform Infrared MeSH
- Thermogravimetry MeSH
- Timolol * administration & dosage pharmacokinetics chemistry MeSH
- Drug Liberation MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Sildenafil citrate has low oral bioavailability, systemic adverse effects, and a relatively delayed action. These issues may be addressed through direct transdermal delivery to the penis. This study aims to investigate the microemulsion formulation of the drug for effective transdermal delivery. Sildenafil citrate was formulated as a microemulsion using clove oil, dimethyl sulphoxide, phosphate buffer (pH 7), propylene glycol, Tween®80, and distilled water. Different proportions of these components were used to create six formulations of the microemulsion (F1-F6), which were then characterised by their physical appearance and clarity, pH, viscosity, conductivity, percent transmission, and droplet size. Furthermore, the stability, content analysis, in-vitro drug release, and transdermal permeation of sildenafil citrate from the generated drug-loaded microemulsions were studied. All prepared formulas contained nano-sized oil droplets (less than 20 nm), and the pH values were within the range of skin pH; however, two formulas were not transparent. Additionally, all formulations were thermodynamically stable, passing freeze-thaw, heating-cooling, and centrifugation tests. Next, the formulas demonstrated zero-order release kinetics, indicating that they can provide a sustained release profile for sildenafil citrate. Finally, the microemulsion formulation exhibited a 2.8-fold enhancement in skin permeation compared with that of the sildenafil citrate suspension. The prepared microemulsions demonstrated beneficial physical properties and skin permeation profiles that are promising for the local administration of sildenafil citrate.
- Keywords
- mikroemulze,
- MeSH
- Administration, Cutaneous * MeSH
- Emulsions MeSH
- Clove Oil MeSH
- Rats MeSH
- Dosage Forms MeSH
- Models, Animal MeSH
- Permeability MeSH
- Drug Compounding methods MeSH
- Sildenafil Citrate * administration & dosage pharmacokinetics pharmacology MeSH
- Drug Stability MeSH
- Suspensions MeSH
- Drug Liberation MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Clinical Study MeSH
Polysaccharides like hyaluronan (HA) and chondroitin sulfate (CS) are native of the brain's extracellular matrix crucial for myelination and brain maturation. Despite extensive research on HA and CS as drug delivery systems (DDS), their high water solubility limits their application as drug carriers. This study introduces an injectable DDS using aldehyde-modified hyaluronic acid (HAOX) hydrogel containing polyelectrolyte complexes (PEC) formed with calcium, gelatin, and either CS or aldehyde-modified CS (CSOX) to deliver minocycline for Multiple Sclerosis therapy. PECs with CSOX enable covalent crosslinking to HAOX, creating immobilized PECs (HAOX_PECOX), while those with CS remain unbound (HAOX_PECS). The in situ forming DDS can be administered via a 20 G needle, with rapid gelation preventing premature leakage. The system integrates into an implanted device for minocycline release through either Fickian or anomalous diffusion, depending on PEC immobilization. HAOX_PECOX reduced burst release by 88 %, with a duration of 127 h for 50 % release. The DDS exhibited an elastic modulus of 3800 Pa and a low swelling ratio (0-1 %), enabling precise control of minocycline release kinetics. Released minocycline reduced IL-6 secretion in the Whole Blood Monocytes Activation Test, suggesting that DDS formation may not alter the biological activity of the loaded drug.
- MeSH
- Aldehydes chemistry MeSH
- Chondroitin Sulfates * chemistry MeSH
- Hydrogels * chemistry pharmacology MeSH
- Interleukin-6 metabolism MeSH
- Hyaluronic Acid * chemistry MeSH
- Drug Delivery Systems methods MeSH
- Humans MeSH
- Minocycline * chemistry pharmacology administration & dosage MeSH
- Drug Carriers * chemistry MeSH
- Polyelectrolytes * chemistry MeSH
- Drug Liberation MeSH
- Gelatin * chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article 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
The polymeric cytisine-enriched fibers based on poly(3-hydroxybutyrate) were obtained using electrospinning method. The biocompatibility study, advanced thermal analysis and release of cytisine from the poly(3-hydroxybutyrate) fibers were carried out. The nanofibers' morphology was evaluated by scanning electron microscopy. The formation and description of phases during the thermal processes of fibers by the advanced thermal analysis were examined. The new quantitative thermal analysis of polymeric fibers with cytisine phases based on vibrational, solid and liquid heat capacities was presented. The apparent heat capacity of fibers was measured using the standard differential scanning calorimetry. The quantitative analysis allowed for the study of the glass transition and melting/crystallization process. The mobile amorphous fraction, degree of crystallinity and rigid amorphous fraction were determined depending on the thermal history of semicrystalline polymeric fibers. Furthermore, the cytisine dissolution behaviour was studied. It was observed that the kinetic of the release from polymeric nanofiber is delayed than for the marketed product. The immunosafety of the tested polymeric nanofibers with cytisine was confirmed by the Food and Drug Agency Guidance as well as the European Medicines Agency. The polymeric matrix with cytisine seems to be a promising candidate for the prolonged release formulation.
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
Aqueous solutions of some polymers exhibit a lower critical solution temperature (LCST); that is, they form phase-separated aggregates when heated above a threshold temperature. Such polymers found many promising (bio)medical applications, including in situ thermogelling with controlled drug release, polymer-supported radiotherapy (brachytherapy), immunotherapy, and wound dressing, among others. Yet, despite the extensive research on medicinal applications of thermoresponsive polymers, their biodistribution and fate after administration remained unknown. Thus, herein, they studied the pharmacokinetics of four different thermoresponsive polyacrylamides after intramuscular administration in mice. In vivo, these thermoresponsive polymers formed depots that subsequently dissolved with a two-phase kinetics (depot maturation, slow redissolution) with half-lives 2 weeks to 5 months, as depot vitrification prolonged their half-lives. Additionally, the decrease of TCP of a polymer solution increased the density of the intramuscular depot. Moreover, they detected secondary polymer depots in the kidneys and liver; these secondary depots also followed two-phase kinetics (depot maturation and slow dissolution), with half-lives 8 to 38 days (kidneys) and 15 to 22 days (liver). Overall, these findings may be used to tailor the properties of thermoresponsive polymers to meet the demands of their medicinal applications. Their methods may become a benchmark for future studies of polymer biodistribution.
- MeSH
- Mice MeSH
- Polymers * MeSH
- Temperature MeSH
- Tissue Distribution MeSH
- Drug Liberation MeSH
- Water * MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Meloxicam (MLX) is a poorly soluble drug exhibiting strong hydrophobicity. This combination of properties makes dissolution enhancement by particle size reduction ineffective; therefore, combined formulation approaches are required. Various approaches were investigated in this study, including milling, solid dispersions, and self-emulsified lipid formulations. Whereas milling studies of MLX and its co-milling with various polymers have been reported in recent literature, this study is focused on investigating the dissolution kinetics of particulate formulations obtained by co-milling MLX with sodium lauryl sulfate (SLS) in a planetary ball mill with 5-25 wt.% SLS content. The effects of milling time and milling ball size were also investigated. No significant reduction in drug crystallinity was observed under the investigated milling conditions according to XRD data. For the dissolution study, we used an open-loop USP4 dissolution apparatus, and recorded dissolution profiles were fitted according to the Weibull model. The Weibull parameters and a novel criterion-surface utilization factor-were used to evaluate and discuss the drug release from the perspective of drug particle surface changes throughout the dissolution process. The most effective co-milling results were achieved using smaller balls (2 mm), with a co-milling time of up to 15 min SLS content of up to 15 wt.% to increase the dissolution rate by approximately 100 times relative to the physical mixture reference. The results suggest that for hydrophobic drugs, particle performance during dissolution is very sensitive to surface properties and not only to particle size. Co-milling with SLS prepares the surface for faster drug release than that achieved with direct mixing.
- Publication type
- Journal Article MeSH
