Quality assessment of total parenteral nutrition admixtures by the use of fractional factorial design

Background/Aim. Parenteral nutrition as a specific aspect of providing nutritients still remains a permanent topic of both theoretical and experimental research. Total parenteral nutrition (TPN) admixtures have complex contents making difficult to maintain their stability. The most critical parameter is the diameter of a lipid droplet, i.e. droplet size distribution. It is recommended that droplet size should not be more than

Integrisani biofarmaceutski pristup u razvoju i karakterizaciji lekova: opšti koncept i primena

The importance of biopharmaceutical considerations in pharmaceutical development and drug characterization has been well recognized both by pharmaceutical industry and regulatory authorities as a tool to establish predictive relationships between drug product quality attributes (in vitro data) and its clinical performance (in vivo data). In the present paper, contemporary biopharmaceutics toolkit including in vivo predictive dissolution testing, Biopharmaceutics Classification System, physiologically based pharmacokinetic and biopharmaceutics modeling and simulation, in vitro-in vivo correlation and biowaiver, are reviewed with regards to relevant general principles and applicability. The recently introduced innovative strategy for patient-centric drug development using an integrated systems approach grounded in fundamental biopharmaceutics concepts, clinical insights and therapeutic drug delivery targets, described as Biopharmaceutics Risk Assessment Roadmap (BioRAM) is also presented. Further development in the field will benefit from joint efforts and exchange of knowledge and experiences between pharmaceutical industry and regulatory authorities for the common goal to accelerate development of effective and safe drug products designed in accordance with patients’ needs and expectations.Značaj biofarmaceutskih razmatranja u razvoju i karakterizaciji lekova s ciljem uspostavljanja korelacije i mogućnosti predviđanja odnosa između in vitropodataka, odnosno karakteristika kvaliteta leka i njegovog in vivoponašanja/kliničkog učinka, prepoznata je kako od strane farmaceutske industrije, tako i od strane odgovarajućih regulatornih tela. U radu je dat pregled savremenih biofarmaceutskih alata,uključujući prediktivno ispitivanje brzine rastvaranja lekovite supstance iz farmaceutskog oblika leka, Biofarmaceutski sistem klasifikacije, fiziološki zasnovano farmakokinetičko i biofarmaceutsko modelovanje i simulacije, in vitro-in vivokorelaciju i mogućnost izostavljanja in vivostudija bioekvivalencije (engl. biowaiver) iz aspekta opštih principa i mogućnosti primene u razvoju i karakterizaciji lekova.Predstavljena je i nedavno osmišljena inovativna strategija za razvoj leka usmerena ka pacijentu, uz primenu integrisanog sistemskog pristupa zasnovanog na osnovnim biofarmaceutskim konceptima, uvidu u kliničku situaciju i definisanim terapijskim ciljevima označena kao Plan aktivnosti za procenu biofarmaceutskog rizika (engl. Biopharmaceutics Risk Assessment Roadmap, BioRAM). Očekuje se da će daljem razvoju u ovoj oblasti najviše doprineti združene aktivnosti i razmena znanja i iskustava između farmaceutskih kompanija i regulatornih agencija sa zajedničkim ciljem da se ubrza razvoj efikasnih i bezbednihlekova dizajniranih u skladu sa potrebama i očekivanjima pacijenata

ANALIZA BRUTO DOMAĆEG PROIZVODA OD 2000. DO 2007. GODINE PRIMJENOM STATISTIČKIH METODA

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Izazovi četvrte industrijske revolucije: primena digitalnih tehnologija u farmaceutskoj industriji

The fourth industrial revolution brought with it the development and application of advanced, digital technologies, in all segments of the pharmaceutical industry: from the discovery of new active substances to post-marketing monitoring of the drug. New, virtual technologies are: artificial intelligence, quantum computing, blockchain, telecommunications, Internet of Things, augmented, virtual and mixed reality. Many research and development centers in the pharmaceutical industry use artificial intelligence technologies in the discovery of new active substances, in silico modeling of drug release and absorption, optimization of drug formulation composition and production process and simulation of clinical trials. Blockchain technology is beginning to be used in drug distribution and makes it easier to reliably track pharmaceutical products at every step of the supply chain. In this way, the possibility of distributing counterfeit medicines can be reduced to a minimum. Virtual reality is used for drug discovery and design, enabling 3D visualization of drug molecular structures. In R&D laboratories, it is used in the planning of experiments; it can also be used in pharmaceutical education. In Mixed Reality, elements from the real and virtual worlds coexist, allowing users to "enter" the combined world of real and digital and move through it using state-of-the-art tools and sensors. There are a number of challenges that need to be overcome in order to accelerate the use of new and revolutionary virtual technologies, but the benefits of applying these technologies and the opportunities they provide in the advancement of the pharmaceutical industry are promising.Četvrta industrijska revolucija je donela sa sobom razvoj i primenu naprednih, digitalnih tehnologija, u svim segmentima razvoja i rada farmaceutske industrije: od otkrića novih aktivnih supstanci do postmarkentinškog praćenja leka. Nove, virtuelne tehnologije su: veštačka inteligencija, kvantno računarstvo, blockchain, telekomunikacije, internet stvari, proširena, virtuelna i mešovita stvarnost. U mnogim centrima istraživanja i razvoja u farmaceutskoj industriji se koriste tehnologije veštačke inteligencije u otkriću novih aktivnih supstanci, za in silico modelovanje oslobađanja i resorpcije leka, optimizaciju sastava formulacije leka i procesa proizvodnje i simulacije kliničkih ispitivanja. Blockchain tehnologija počinje da se koristi u distribuciji lekova i olakšava pouzdano praćenje farmaceutskih proizvoda na svakom koraku lanca snabdevanja. Na ovaj način se može smanjiti na minimum mogućnost distribucije falsifikovanih lekova i obezbediti bezbednost distributivnog lanca. Virtuelna stvarnost se primenjuje za otkrivanje i dizajn lekova, omogućavajući 3D vizualizaciju molekularnih struktura lekova. U laboratorijama se primenjuje u planiranju eksperimenata; može se koristiti i u okviru farmaceutskog obrazovanja, za obuku studenata. U Mešovitoj stvarnosti, elementi iz stvarnog i virtuelnog sveta koegzistiraju, omogućavajući korisnicima da “uđu” u kombinovani svet realnog i digitalnog i da se kreću kroz njega koristeći najsavremenije alate i senzore. U farmaceutskoj industriji, Microsoft HoloLens je korišćen kao primer mešovite stvarnosti, koja će se koristiti u različitim oblastima: od sinteze i razvoja lekova, analitičkih procedura, proizvodnje, inspekcije, pa do pakovanja i čuvanja lekova. Postoji niz izazova koje treba prevazići kako bi se ubrzala upotreba novih i revolucionarnih virtuelnih tehnologija, ali su prednosti primene ovih tehnologija i mogućnosti koje pružaju u napretku farmaceutske industrije velike.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Application of mixture experimental design in formulation and characterization of solid selfnanoemulsifying drug delivery systems containing carbamazepine [Primena dizajna smeše u formulaciji i karakterizaciji čvrstih samo-nanoemulgujućih terapijskih sist

One of the problems with orally used drugs is their poor solubility, which can be overcome by creating solid self-nanoemulsifying drug delivery systems (SNEDDS). The aim is to choose the appropriate SNEDDS using mixture design and adsorption of SNEDDS on a solid carrier to improve the dissolution rate of carbamazepine. Self-emulsifying drug delivery systems (SEDDS) consisting of oil phase (caprilic-capric triglycerides), a surfactant (Polisorbat 80 and Labrasol (R) (1: 1)) and cosurfactant (Transcutol (R) HP) are formed by applying mixture design. 16 formulations were formulated, where the proportion of lipids, surfactant and cosurfactant were varied (input parameters) in the following ranges: 10-30%, 40-60%, 30-50%, respectively. After dilution of SEDDS with water (90% water), the droplet size and polydispersity index (PdI) of the obtained emulsions (output parameters) were measured using photon correlation spectroscopy. After processing data, appropriate mathematical models that describe the dependence of input and output parameters were selected. The optimized SNEDDS was adsorbed on the carbamazepine and solid carrier physical mixture, containing 20% carbamazepine. Neusilin (R) UFl2, Neusilin (R) FL2, Sylysia (R) 320 and diatomite were used as the carriers. The ratio of SNEDDS: carrier was 1: 1 or 2: 1. Dissolution testing was carried out in the rotation paddles apparatus. Characterization of solid SNEDDS was performed using the hot stage microscopy (HSM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectrophotometry with Fourier transformation (FT-IR), scanning electron microscopy (SEM) and X-ray diffraction (PXRD). Selected SNEDDS consisting of lipids (21.12%), surfactant (42.24%) and cosurfactant (36.64%) had a droplet size 157.02 +/- 34.09 nm and PdI 0.184 +/- 0.021. Drug release profiles showed that in all formulations dissolution rate increased (the fastest drug release was observed in formulations with Sylysia (R) 320). It can be concluded that in all formulations carbamazepine is present in the thermodynamically most stable polymorphic form III. Formulation of solid SNEDDS can significantly increase dissolution rate of carbamazepine, with conservation of the polymorphic form III CBZ and potentially increased bioavailability

Insight into the formation of glimepiride nanocrystals by wet media milling

Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Di erent stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by di erential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray di raction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals

Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading

Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers

Stabilnost lekova - industrijski aspect

Stability testing is carried out in several phases of new product development. The effect of various external factors on possible formulations, compatibility of active pharmaceutical ingredient, excipients and primary packaging material, is examined in early phases of development. Possible pathways of degradation are defined, and degradation rate is estimated by subjecting the products to different, extreme conditions. The results obtained during this phase of testing are used for defining the testing parameters in formal stability studies. Numerous guidelines, which define the testing parameters, are used in this phase of testing. The principal elements which are defined include testing conditions and testing frequency. An accelerated stability testing is carried out over a period of 6 months, whereby a product is exposed to the temperature exceeding the expected warehousing temperature, while a long-term stability testing is performed under the predicting storage conditions, and the length of testing corresponds to the envisaged shelf life. Photostability testing is carried out within a stress testing, and in certain cases, in use stability testing is carried out, whereby storage conditions and the period within which a product must be used after the first opening, i.e. reconstitution, are defined. Testing results are also used for establishing the final specifications of the quality of medicinal products, particularly from the aspect of degradation products (impurities). Various statistical methods and mathematical models, such as artificial neural networks, are used in results processing for the purpose of estimating the stability in a shorter period of time.Ispitivanje stabilnosti realizuje se u više faza razvoja novog proizvoda. U ranim fazama razvoja ispituju se uticaji različitih spoljašnjih faktora (temperatura, vlaga, svetlost, kiseonik, mikroorganizmi) na potencijalne formulacije, kompatibilnost lekovite supstance, pomoćnih supstanci i kontaktne ambalaže. Kondicioniranjem proizvoda u različitim, ekstremnim uslovima, definišu se mogući putevi degradacije i predviđa brzina degradacije. Rezultati koji se dobiju u toku ove faze ispitivanja koriste se za definisanje parametara ispitivanja u formalnim studijama stabilnosti. U ovoj fazi ispitivanja, primenjuju se brojne smernice kojima se definišu parametri koji će se ispitivati. Osnovni elementi koji se definišu jesu uslovi ispitivanja i frekvenca ispitivanja. Ubrzano ispitivanje stabilnosti sprovodi se u trajanju od 6 meseci, pri čemu se proizvod izlaže temperaturi višoj od očekivane temperature skladištenja; dugotrajno ispitivanje se izvodi pod očekivanim uslovima čuvanja, a dužina ispitivanja se poklapa sa predviđenim rokom trajanja. U okviru stres ispitivanja se vrši i ispitivanje fotostabilnosti, a u pojedinim slučajevima, vrši se ispitivanje in use stabilnosti, pri čemu se definišu uslovi čuvanja i rok u kome se proizvod mora upotrebiti nakon prvog otvaranja, odnosno rekonstitucije. Rezultati ispitivanja koriste se i za postavljanje konačnih specifikacija kvaliteta lekova, posebno sa aspekta degradacionih proizvoda (nečistoća). U obradi rezultata koriste se različite statističke metode i matematički modeli, kao što su veštačke neuronske mreže, u cilju predviđanja stabilnosti u kraćem vremenskom roku

Numerical Modeling of Particle Dynamics Inside a Dry Powder Inhaler

The development of novel dry powders for dry powder inhalers (DPIs) requires the in vitro assessment of DPI aerodynamic performance. As a potential complementary method, in silico numerical simulations can provide additional information about the mechanisms that guide the particles and their behavior inside DPIs. The aim of this study was to apply computational fluid dynamics (CFDs) coupled with a discrete phase model (DPM) to describe the forces and particle trajectories inside the RS01® as a model DPI device. The methodology included standard fluid flow equations but also additional equations for the particle sticking mechanism, as well as particle behavior after contacting the DPI wall surface, including the particle detachment process. The results show that the coefficient of restitution between the particle and the impact surface does not have a high impact on the results, meaning that all tested combinations gave similar output efficiencies and particle behaviors. No sliding or rolling mechanisms were observed for the particle detachment process, meaning that simple bouncing off or deposition particle behavior is present inside DPIs. The developed methodology can serve as a basis for the additional understanding of the particles’ behavior inside DPIs, which is not possible using only in vitro experiments; this implies the possibility of increasing the efficiency of DPIs