Nanos zdravilnih učinkovin na biokompatibilne podlage z metodo 2D tiskanja za izdelavo farmacevtskih oblik, prilagojenih bolnikom

Pomen personaliziranega načina zdravljenja se iz leta v leto povečuje, saj je zavedanje, da ljudje nismo popolnoma enaki in da vsak organizem potrebuje sebi lastno terapijo, vedno večje. Poznavanje genetike in njenega vpliva na izvor in potek nekaterih bolezni pomen personaliziranega zdravljenja še povečuje. Zato se trenutne raziskave v farmacevtski stroki vedno bolj nagibajo k razvoju in optimizaciji zdravil, ki bi omogočala tak način zdravljenja. V ta namen je dandanes vedno več raziskovalcev, usmerjenih v razvoj nanosa zdravilnih učinkovin (ZU) na podlage z metodo 2D tiskanja, ki zaradi svoje priročnosti, možnosti široke uporabe in enostavnega prilagajanja odmerkov iz dneva v dan pridobiva na vrednosti. Princip tiskanja poteka na enak način kot tiskanje besedilnih dokumentov, le da črnila zamenjamo z disperzijo ZU, medtem ko namesto listov papirja uporabimo različne biološko kompatibilne podlage, ki skupaj z natisnjeno zdravilno učinkovino služijo kot per oralna farmacevtska oblika. Pri tiskanju ZU lahko uporabimo različne vrste tiskalnikov, pri čemer pa vsak izmed njih za uspešno tiskanje zahteva izpolnitev določenih specifikacijskih zahtev. Prednosti, ki jih nanos ZU z metodo 2D tiskanja prinaša, so poleg hitre izdelave personalizirane farmacevtske oblike (FO) z natančnim odmerjanjem tudi hkratno tiskanje in s tem združevanje več ZU hkrati v eno samo FO. Kljub vsemu omenjenemu pa na tem področju še vedno obstaja veliko izzivov, s katerimi se bo potrebno spopasti, preden bo tak način izdelave in odmerjanja zdravil dosegel trg in bil na voljo pacientom

Influence of fused deposition modelling printing parameters on tablet disintegration times: a design of experiments study

Despite the importance of process parameters in the printing of solid dosage forms using fused deposition modelling (FDM) technology, the field is still poorly explored. A design of experiment study was conducted to understand the complete set of process parameters of a custom developed FDM 3D printer and their influence on tablet disintegration time. Nine settings in the Simplify 3D printing process design software were evaluated with further experimental investigation conducted on the influence of infill percentage, infill pattern, nozzle diameter, and layer height. The percentage of infill was identified as the most impactful parameter, as increasing it parabolically affected the increase of disintegration time. Furthermore, a larger nozzle diameter prolonged tablet disintegration, since thicker extruded strands are generated through wider nozzles during the printing process. Three infill patterns were selected for in-depth analysis, demonstrating the clear importance of the geometry of the internal structure to resist mechanical stress during the disintegration test. Lastly, layer height did not influence the disintegration time. A statistical model with accurate fit (R2 = 0.928) and predictability (Q2 = 0.847) was created. In addition, only the infill pattern and layer height influenced both the uniformity of mass and uniformity of the disintegration time, which demonstrates the robustness of the printing process

Uporaba metodologije odgovornih površin za študij in situ granulacije s talinami v zvrtinčenih plasteh

The objective of this work was to investigate the influence of selected individual variables (binder content, inlet air temperature, and product endpoint temperature) of in situ fluid bed melt granulation on the granule particle size distribution and percentage of dissolved carvedilol using a three-factor, five-level circumscribed central composite design. Increased binder content had the effect of increasing the granule particle size and drug dissolution rate. The effect of inlet air temperature and product endpoint temperature was found to be more pronounced in case of granule particle size parameters. Within the studied intervals, the optimal quantity of binder as well as optimal process parameters were identified and validated using response surface methodology. Utilizing these optimal process and formulation parameters, successful scaling up of the fluid bed melt granulation process was carried out. Granule characteristics obtained at pilot scale are comparable to those obtained at laboratory scale.V raziskovalnem delu smo z uporabo tri-faktorskega pet-nivojskega središčnega mešanega eksperimentalnega načrta proučevali vpliv izbranih procesnih spremenljivk (delež veziva, temperatura vhodnega zraka in končna temperatura produkta) in situ granulacije s talinami na porazdelitev velikosti izdelanih granul in na delež raztopljenega karvedilola. Ugotovili smo, da povečana količina veziva v formulaciji kaže učinek povečanja velikosti izdelanih granul kakor tudi hitrosti raztapljanja karvedilola. Prav tako smo ugotovili, da temperatura vhodnega zraka in končna temperatura produkta izkazujeta izrazit vpliv na parametre velikosti granul. Z metodo odgovornih površin smo znotraj proučevanih intervalov določili in validirali optimalno količino veziva in optimalne procesne parametre. Z uporabo optimalnih formulacijskih in procesnih parametrov smo tehnologijo in situ granulacije s talinami uspešno prenesli iz laboratorijskega v večje (pilotno) merilo, pri čemer smo zagotovili primerljivost proučevanih lastnosti granulata

Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets

During the past few years, the studies of bi- and multi-layered tablets increased due to the consumption of several different drugs per day by a patient and requests for appropriate patient compliance. The demographic shift toward older population increases the use of combination therapy as polypharmacy. Hydrochlorothiazide (HCTZ), as a model drug, is most commonly used in the treatment of hypertension, congestive heart failure and as a diuretic. The aim of the present study is to investigate the effect of the local environment on dissolution and stability behaviour of HCTZ in fixed multi-layered tablet combinations, which are commonly used in polypharmacy. For this purpose, three different systems were introduced: (i) two conventional tablets (HCTZ and pH modifying placebo), (ii) 2-layer tablets (HCTZ, pH modifying placebo) and (iii) 3-layer tablets (HCTZ, barrier and pH modifying placebo). Disintegration of tablets, dissolution of HCTZ from tablets and HCTZ related substances were monitored for all systems. Results showed that there was a significant difference between dissolution profiles of the conventional two-tablet system (HCTZ tablet and pH modifying tablet) and the 2-layer and 3-layer tablets, which include the pH modifying layer. In the case of the conventional two-tablet system, 85 % of HCTZ was dissolved in less than 15 minutes. The dissolution profiles of HCTZ from 2-layered and 3-layered tablets showed a decrease in the dissolution rate. In addition, during the stability studies, it has been confirmed that the typical degradation product of HCTZ is formed, impurity B (4-amino-6-chloro-1,3-benzenedisulfonamide), which implies formation of formaldehyde as hydrolytic impurity not reported in the Ph. Eur. (16). Both impurities are particularly raised in 2-layered tablets with alkaline and neutral placebo layers. Stability of HCTZ was improved in the case of the 3-layer tablet, where the intermediate separation layer of glycerol monostearate was present. It is presumed that the HCTZ dissolution rate was decreased due to formation of non-soluble substances as a result of HCTZ degradation in the presence of alkaline layer

Development of Simvastatin-Loaded Particles Using Spray Drying Method for Ex Tempore Preparation of Cartridges for 2D Printing Technology

In this work, a spray drying method was developed to produce drug/polymer (simvastatin/polycaprolactone) microparticles that have the potential to be used as a pre-formulation for ex tempore preparation of 2D printing cartridges. An experimental model was designed with the process parameters set to predict the smallest particle size required for successful 2D printing. Three different types of particles (lactose, nanocellulose/lactose, calcium silicate) were produced, and the average size of the dry particles varied depending on the sampling location (cyclone, collection vessel). The encapsulation efficiency of simvastatin was highest with nanocellulose/lactose from the collection vessel. The one-month stability of simvastatin in the particles showed low content, but the addition of ascorbic acid as an antioxidant increased the chemical stability of the drug. Interestingly, the addition of antioxidants decreased the stability of simvastatin in the calcium silicate particles from the collection vessel. Dispersion of the particles in three different propylene glycol and water mixtures (10/90, 50/50, and 90/10% (v/v)), representing a printable ink medium with three different viscosity and surface tension properties, showed that nanocellulose/lactose was the most suitable antiadhesive in terms of dispersed particle size (˂1 µm). After one month of storage, the dispersed particles remained in the same size range without undesirable particle agglomeration

The potential of macroporous silica—nanocrystalline cellulose combination for formulating dry emulsion systems with improved flow properties

The objective of this study was to explore the possible use of a new combination of two excipients, i.e., nanocrystalline cellulose (NCC) and macroporous silica (MS), as matrix materials for the compounding of dry emulsion systems and the effects these two excipients have on the characteristics of dry emulsion powders produced by the spray drying process. A previously developed liquid O/W nanoemulsion, comprised of simvastatin, 1-oleoyl-rac-glycerol, Miglyol 812 and Tween 20, was employed. In order to comprehend the effects that these two matrix formers have on the spray drying process and on dry emulsion powder characteristics, alone and in combination, a DoE (Design of Experiment) approach was used. The physicochemical properties of dry emulsion samples were characterised by atomic force microscopy, scanning electron microscopy, mercury intrusion porosimetry, energy-dispersive X-ray spectroscopy and laser diffraction analysis. Additionally, total release and dissolution experiments were performed to assess drug release from multiple formulations. It was found that the macroporous silica matrix drastically improved flow properties of dry emulsion powdershowever, it partially trapped the oil—drug mixture inside the pores and hindered complete release. NCC showed its potential to reduce oil entrapment in MS, but because of its rod-shaped particles deposited on the MS surface, powder flowability was deteriorated

Comparison of the robustness of pellet film coating with and without in-process coating thickness evaluation

The robustness of the pellet coating process with and without the use of an in-process coating thickness analyzer (PATVIS APA) was investigated. Pellets containing model drug were coated with a prolonged release film coating, using different process conditions. In the first set of experiments film coating was performed as process repetitions with unintentional variation of process parameters, and in the second set, controlled changes (inlet air humidity, gap between distribution plate and Wurster partition, starting pellet load) were made. Within the first set of experiments, the coating process endpoint was determined either via gravimetric consumption of coating dispersion or by means of in-line coating thickness monitoring. The release profiles of the pellets were analyzed and the density of coating calculated. Both methods of the process endpoint determination can be relatively robust in batch processing, if key factors influencing drug release profile are under control. PATVIS APA was shown to be a useful tool to better understand the coating process and can be helpful if coating process interruptions are encountered. Water content was shown to be the key factor influencing the drug profile, presumably by influencing the structure and thickness of the coating applied