Dissolution rate Dotaz Zobrazit nápovědu
- Publikační typ
- abstrakt z konference MeSH
Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.
Transferring an existing marketed pharmaceutical product from batch to continuous manufacturing (CM) without changes in regulatory registration is a challenging task in the pharmaceutical industry. Continuous manufacturing can provide an increased production rate and better equipment utilisation while retaining key quality attributes of the final product. Continuous manufacturing necessitates the monitoring of critical quality attributes in real time by appropriate process analytical tools such as near infra-red (NIR) probes. The present work reports a successful transfer of an existing drug product from batch to continuous manufacturing process without changing the formulation. A key step was continuous powder blending, whose design and operating parameters including weir type, agitation rate, dynamic hold-up and residence time were systematically investigated with respect to process repeatability. A NIR-based multivariate data model for in-line composition monitoring has been developed and validated against an existing quality control method for measuring tablet content uniformity. A continuous manufacturing long-run with a throughput of 30 kg/h (approx. 128,000 tablets per hour), uninterrupted for 320 min, has been performed to test and validate the multivariate data model as well as the batch to continuous process transfer. The final disintegration and dissolution properties of tablets manufactured by the continuous process were found to be equivalent to those manufactured by the original batch process.
- MeSH
- blízká infračervená spektroskopie metody MeSH
- farmaceutická chemie metody MeSH
- farmaceutická technologie * metody MeSH
- pomocné látky chemie MeSH
- prášky, zásypy, pudry chemie MeSH
- příprava léků metody MeSH
- řízení kvality MeSH
- rozpustnost MeSH
- tablety * MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články 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
- antiflogistika terapeutické užití MeSH
- dexamethason MeSH
- doxorubicin chemie MeSH
- leukocyty mononukleární * MeSH
- lidé MeSH
- myši MeSH
- nanomedicína MeSH
- nosiče léků chemie MeSH
- polymery chemie MeSH
- revmatické nemoci * MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.
- MeSH
- klinické křížové studie MeSH
- lidé MeSH
- omeprazol * chemie MeSH
- terapeutická ekvivalence MeSH
- tobolky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
Treating oral diseases remains challenging as API is quickly washed out of the application site by saliva turnover and mouth movements. In situ gels are a class of application forms that present sol-gel transition's ability as a response to stimuli. Their tunable properties are provided using smart polymers responsible for stimuli sensitivity, often providing mucoadhesivity. In this study, antimicrobial in situ gels of thermosensitive and pH-sensitive polymers loaded with silver nanoparticles were prepared and evaluated. The nanoparticles were prepared by green synthesis using Agrimonia eupatoria L. extract. According to the data analysis, the in situ gel with the most promising profile contained 15 % of Pluronic® F-127, 0.25 % of methylcellulose, and 0.1 % of Noveon® AA-1. Pluronic® F-127 and methylcellulose significantly increased the viscosity of in situ gels at 37 °C and shear rates similar to speaking and swallowing. At 20 °C, a behavior close to a Newtonian fluid was observed while being easily injectable (injection force 13.455 ± 1.973 N). The viscosity of the formulation increased with temperature and reached 2962.77 ± 63.37 mPa·s (37 °C). A temperature increase led to increased adhesiveness and rigidity of the formulation. The critical sol-gel transition temperature at physiological pH was 32.65 ± 0.35 °C. 96.77 ± 3.26 % of Ag NPs were released by erosion and dissolution of the gel after 40 min. The determination of MIC showed effect against E. coli and S. aureus (0.0625 mM and 0.5000 mM, respectively). The relative inhibition zone diameter of the in situ gel was 73.32 ± 11.06 % compared to gentamicin sulfate. This work discusses the optimization of the formulation of novel antibacterial in situ gel for oromucosal delivery, analyses the impact of the concentration of excipients on the dependent variables, and suggests appropriate evaluation of the formulation in terms of its indication. This study offers a promising dosage form for local treatment of oral diseases.
Spray drying is commonly used for producing amorphous solid dispersions to improve drug solubility. The development of such formulations typically relies on comprehensive excipient and composition screening, which requires the preparation of many spray-dried powder samples. This is both labour-intensive and time-consuming when carried out manually. In the present work, the formulation screening task was automated by coupling a laboratory spray dryer operated in a semi-continuous mode with custom-made add-ons, allowing for rapid, computer-controlled production of formulation samples with systematically varying composition. The practical use of the spray drying robot in formulation development was demonstrated on a case study of poorly water-soluble model drugs simvastatin and ezetimibe. Six different polymers and several drug:polymer ratios were screened for the enhancement of dissolution properties. From a pool of 28 spray-dried samples, ternary compositions containing Eudragit L100-55 were identified as the most suitable ones for further processing and characterisation. The ability to populate the formulation design space rapidly and automatically made it possible to construct maps of physico-chemical properties such as glass transition temperature or dissolution rate. The spray drying robot thus enables the acceleration of early formulation development and a deeper understanding of composition-property relationships for multi-component spray dried powders.
- MeSH
- polymery chemie MeSH
- příprava léků MeSH
- robotika * MeSH
- rozpustnost MeSH
- sprejové sušení * MeSH
- Publikační typ
- časopisecké články MeSH
Orally dispersible films (ODFs) prepared by an electrospinning are a novel type of pharmaceutical formulation. This dosage form has the potential to be beneficial for small children and the elderly, who can have problems with administration of classical tablets due to the increased risk of choking and difficulty with swallowing. Due to the highly porous nanofiber morphology, the ODFs examined in this study achieve rapid disintegration into drug microparticles when in contact with saliva. The suspension is then easier to swallow. In this study, we focus on the impact of film composition (polymer matrix composition) on the properties of electrospun membranes. In particular, we prepared ODFs composed of a mixture of PEG 100 000 with HPMC E5 and PVP k90 with HPMC E5. We found significant differences in the structure of electrospinned membranes, where samples containing PEG 100 000 and HPMC E5 exhibited much narrower distribution of fibers. Furthermore, nanofibers containing PVP k90 exhibit a faster disintegration rate, while dissolution of the drug was faster in the case of PEG 100 000 containing ODFs. The improvement was caused by both the structure and composition of the membranes.
- MeSH
- dítě MeSH
- lékové transportní systémy * MeSH
- lidé MeSH
- polymery * chemie MeSH
- příprava léků MeSH
- rozpustnost MeSH
- senioři MeSH
- tablety MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
The performance of a pharmaceutical formulation, such as the drug (API) release rate, is significantly influenced by the properties of the materials used, the composition of the final product and the tablet compression process parameters. However, in some cases, the knowledge of these input parameters does not necessarily provide a reliable description or prediction of tablet performance. Therefore, the knowledge of tablet microstructure is desirable to understand such formulations. Commonly used analytical techniques, such as X-ray tomography and intrusion mercury porosimetry, are not widely used in pharmaceutical companies due to their price and/or toxicity, and therefore, efforts are made to develop a tool for fast and easy microstructure description. In this work, we have developed an image-based method for microstructure description and applied it to a model system consisting of ibuprofen and CaHPO4∙2H2O (API and excipient with different deformability). The obtained parameter, the quadratic mean of the equivalent diameter of the non-deformable, brittle excipient CaHPO4∙2H2O, was correlated with tablet composition, compression pressure and API release rate. The obtained results demonstrate the possibility of describing the tablet dissolution performance in the presented model system based on the microstructural parameter, providing a possible model system for compressed solid dosage forms in which a plastic component is present and specific API release is required.
- MeSH
- biologické modely * MeSH
- ibuprofen chemie MeSH
- pomocné látky * chemie MeSH
- příprava léků MeSH
- tablety chemie MeSH
- Publikační typ
- časopisecké články MeSH
Biocontrol fungi are widely used to promote plant growth and pest control. Four fungi were isolated from Cremastra appendiculata tubers and screened for plant growth-promoting and antagonistic effects. Based on the morphological characterization and ITS, 18S rRNA and 28S rRNA gene sequencing analysis, the fungi were identified to be related to Colletotrichum gloeosporioides (DJL-6), Trichoderma tomentosum (DJL-9), Colletotrichum godetiae (DJL-10) and Talaromyces amestolkiae (DJL-15). The growth inhibition tests showed that the four isolates had different inhibitory effects on Colletotrichum fructicola, Alternaria alternata and Alternaria longipes, among which DJL-9 showed the highest inhibitory activity. Their culture filtrates (especially that of DJL-15) can also inhibit pathogens. Four isolates were positive for the production of indole-3-acid (IAA) and β-1,3-glucanase and possessed proteolytic activity but were negative for the production of iron siderophore complexes. The four fungi showed strong nitrogen fixation and potassium dissolution abilities. In addition to DJL-9 being able to solubilize phosphate, DJL-10 was able to produce chitinase and cellulase. Pot experiments indicated that the four fungi increased the germination rate of C. appendiculata and soybean seeds and increased soybean radicle growth and plant biomass. Among them, DJL-6 had a better growth-promoting effect. Therefore, we successfully screened the biocontrol potential of endophytes from C. appendiculata, with a focus on preventing fungal diseases and promoting plant growth, and selected strains that could provide nutrients and hormones for plant growth.
- MeSH
- endofyty MeSH
- fosfáty MeSH
- houby * MeSH
- nemoci rostlin mikrobiologie MeSH
- semena rostlinná MeSH
- vývoj rostlin * MeSH
- Publikační typ
- časopisecké články MeSH
