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

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

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

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

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

Microencapsulation methods for plants biologically active compounds: A review

Biologically active compounds from plants have attracted great interest due to their affordability, effectiveness and low toxicity. Herbal extracts provide an infinite resource of raw materials for pharmaceutical, cosmetic and food industry. Unfortunately, use of the valuable natural compounds can be limited by their low bioavailability, volatilization of active compounds, sensitivity to the temperature, oxidation and UV light, in vivo instability, as well as unpleasant taste. One of the potential strategies to overcome these issues is microencapsulation of the biologically active ingredients. In this review, preparation, applications and limitations of the most popular techniques for microencapsulation, such as spray drying, fluid bed coating, encapsulation using supercritical fluids, freeze drying, ionic gelation, emulsification-solvent removal methods and formulation of liposomes, were discussed. Also, microparticles properties produced by presented microencapsulation methods were interpreted

Antidepresivi i anksiolitici - novine u formulaciji tableta

Development of new dosage forms with uncompromised efficacy, safety and stability and improved tolerability and dosage regimen that would result in better patient compliance is an imperative in modern pharmacotherapy. Patients" adherence to dosage regimen is of great importance, especially when prolonged treatment is an issue. Therefore, novelties in formulation development for antidepressants and anxiolytics are directed towards the modified/sustained or extended release drug products and orally disintegrating tablets. There is a number and variety of new technologies employed with this respect. In the present paper, an overview of the most important technologies applied in commercially available drug products within the group of antidepressants and anxiolytics is given

Diatoms - nature materials with great potential for bioapplications

Diatoms are widespread unicellular photosynthetic algae that produce unique highly ordered siliceous cell wall, called frustule. Micro- to nanoporous structure with high surface area that can be easily modified, high mechanical resistance, unique optical features (light focusing and luminescence) and biocompatibility make diatom frustule as a suitable raw material for the development of devices such as bio- and gas sensors, microfluidic particle sorting devices, supercapacitors, batteries, solar cells, electroluminescent devices and drug delivery systems. Their wide availability in the form of fossil remains (diatomite or diatomaceous earth) as well as easy cultivation in the artificial conditions further supports use of diatoms in many different fields of application. This review focused on the recent achievements in the diatom bioapplications such as drug delivery, biomolecules immobilization, bio- and gas sensing, since great progress was made in this field over the last several years

Karakteristike i potencijalna primena savremenih adsorbenata u formulaciji nosača lekovitih supstanci

In latest years, many natural and synthetic solid carriers attract increasing attention, due to theirs biocompatibility, acceptable ecological and toxicological properties, possible modification of physico-chemical properties, simple production, high stability and relatively low price. These carriers have similar chemical structure, mostly based on silicon-dioxide, magnesium aluminometasilicate and calcium phosphate, and differ from each other in structure porosity, specific surface area, size, volume and shape of pores, and possibility of surface functionalization. Ordered mesoporous materials like MCM - 41 and SBA - 15, as well as porous materials from Neusilin® and Sylysia® groups, represent the most common adsorbents evaluated in order to increase drug dissolution rate, and its bioavailability, and also in modifiedand targeted drug release formulations. Also, natural silica material, isolated from diatomites, diatom microshells, with its unique characteristics, represents relatively cheap solid carrier used in formulation of oral dosage forms and implants. Modern adsorbents are mostly used in formulations of solid dispersions with low water-soluble drugs, or as solid carriers for lipid formulations. In latest years, modern porous carriers are evaluated for possible surface functionalization in order to achieve prolonged or signal-initiated drug release.Poslednjih godina veliki broj adsorpcionih nosača prirodnog i sintetskog porekla privlači sve više pažnje zbog svoje biokompatibilnosti, prihvatljivih ekoloških i toksikoloških osobina, velike mogućnosti za modifikaciju fizičkohemijskih osobina, jednostavnog dobijanja, visoke stabilnosti i relativno niske cene. Ovi nosači su slične hemijske strukture, najčešće na bazi silicijum-dioksida, magnezijum-aluminometasilikata i kalcijum-fosfata, a međusobno se razlikuju po poroznosti struktura, specifičnoj površini, veličini, zapremini i obliku pora kao i mogućnosti funkcionalizacije površine. Uređeni mezoporozni materijali kao što su MCM - 41 i SBA - 15, kao i porozni materijali iz grupe Neusilin®-a i Sylysia®-a predstavljaju najčešće ispitivane adsorbente sa ciljem da povećaju brzinu rastvaranja lekovite supstance, a samim tim i biološku raspoloživost, ali se koriste i u formulaciji preparata sa modifikovanim ili ciljanim oslobađanjem lekovite supstance u određeno tkivo. Takođe prirodni silika materijal jedinstvenih karakteristika, izolovan iz dijatomita, dijatomitne mikrokapsule, predstavlja relativno jeftin adsorbent za formulaciju nosača za peroralnu primenu lekovite supstance kao i primenu u obliku implanta. Savremeni adsorbenti najčešće se koriste u izradi čvrstih disperzija sa nisko rastvorljivom lekovitom supstancom, ili kao adsorbenti za različite lipidne formulacije. Jedna od mogućnosti primene savremenih nosača koja se poslednjih godina ispituje jeste i funkcionalizacija površine poroznih materijala u cilju postizanja usporenog ili signalinicirajućeg oslobađanja lekovite supstance