U radu su formulisane i ispitane i formulisane različiti čvrsti samodispergujući sistemi kao
potencijalni nosači za teško rastvorljivu model lekovitu supstancu karbamazepin (CBZ).
Ispitivani su: čvrsti samomikroemulgujući sistem (eng. Solid Self-microemulsifying drug
delivery system, skr. SSMEDDS), čvrsta samomulgujuća fosfolipidna suspenzija (eng. Solid
Self-emulsifying phospholipid suspension, skr. SSEPS) kao i samoemulgujuće pelete.
Samomikroemulgujući sistem (eng. Self-microemulsifying drug delivery system - SMEDDS)
je fomulisan korišćenjem surfaktanta (Polisorbat 80 (S)), kosurfaktanta (PEG – 40
hidrogenizovano ricinusovo ulje (C)) i uljane faze (trigliceridi srednje dužine lanca (O)).
Prilikom izrade SSMEDDS sistema korišćena su četiri različita adsorbensa velike specifične
aktivne površine, pri čemu su dva bila tipa magnezijum-aluminometasilikata (Neusilin® UFL2 i
Neusilin® FL2) i dva tipa silicijum-dioksida (Sylysia® 320 i Sylysia® 350). Ispitana je
mikroemulziona oblast sistem...a pri odnosu surfaktanta i kosurfaktanta (Km) 1:1 i SMEDDS
formulacija sa surfaktant-kosurfaktant/ulje odnosom (eng. surfactant-cosurfactant/oil ratio -
SC/O) 8/2 je izabrana za dalja istraživanja. Kapacitet solubilizacije odabrane SMEDDS
formulacije za CBZ iznosio je 33771 ± 41 μg/ml. Reološka merenja SMEDDS formulacije sa i
bez CBZ, pri sadržaju vode od 10 do 60 % (m/m), su pokazala da nakon razblaženja sa vodom
CBZ ima znatan uticaj na reološko ponašanje ispitivanih sistema. Fotonska korelaciona
spektroskopija je pokazala sposobnost formulacije da, nakon razblaženja sa vodom, formira kapi
čiji prečnik odgovara mikroemulzijama. SSMEDDS formulacije su znatno poboljšale brzinu
rastvaranja CBZ, pri čemu je pokazano da vrsta adsorbensa znatno utiče na brzinu rastvaranja.
Kod formulacija sa adsorbensom tipa magnezijum-aluminometasilikata brzina rastvaranja CBZ
opada sa porastom specifične aktivne površine, usled zadržavanja dela tečne SMEDDS unutar
pora sistema i njegovom postepenom izlaganju spoljašnjem medijumu. SSMEDDS formulacije
sa adorbensima na bazi silicijum-dioksida nisu pokazale značajnu razliku u odnosu na
odgovarajuće fizičke smeše. Prisustvo amorfnog oblika CBZ u fizičkim smešama je razlog
primećene velike brzine rastvaranja. Takođe je formulisana samoemulgujuća fosfolipidna
suspenzija (eng. Self-emulsifying phospholipid suspension, skr. SEPS) korišćenjem PEG-8
kaprilno/kaprinski gliceridi (S)/(lecitin/propilen-glikol) (C)/trigliceridi srednje dužine lanca (O)
samoemulgujućeg sistema kao disperznog medijuma. Km odnos 3:2 je ispitan i SC/O odnos 8:2
je uzet za dalja istraživanja. Fotonska korelaciona spektroskopija je pokazala sposobnost
supernatanta SEPS da nakon razblaženja sa vodom formira kapi prečnika koji odgovara
emulzijama. Dijatomitne mikrokapsule, koje predstavljaju fosilizovane skelete fotosintetičlih algi
za kompleksnom trodimenzionalnom (3D) strukturom, porozne strukture, koje se sastoje od
amorfnog silika materijala i koje se dobijaju prečišćavanjem dijatomejske zemlje, su korišćene
kao adsorbensi za SEPS prilikom formulisanja SSEPS. Različiti čvrsti uzorci SSEPS su
pripremljeni korišćenjem dve metode: adsorpcija disperzije CBZ u SEDDS na dijatomitne
mikrokapsule blagim mešanjem u tarioniku sa pistilom (Metoda A); disperzijom dijatomitnih
mikrokapsula u etanolnom rastvoru CBZ i SEDDS, nakon čega je etanol uparen (Metoda B).
Brzina rastvaranja CBZ iz izrađenih SSEPS formulacija je bila znatno veća u poređenju sa čistim
CBZ, ali i fizičkom smešom i odgovarajućom čvrstom disperzijom dobijenom uparavanjem
etanolnog rastvora CBZ iz disperzije dijatomitnih mikrokapsula. Brzina rastvaranja CBZ iz
SSEPS formulacije pripremljene metodom B je veća u poređenju sa brzinom rastvaranja CBZ iz
SSEPS pripremljene metodom A. Razlog za ovo je verovatno parcijalna adsorpcija SSEPS
formulacije pripremljene metodom B unutar pora dijatomitnih mikrokapsula...
The purpose of this study was to investigate different solid self-dispersing formulations as
potential drug delivery system for poorly soluble carbamazepine (CBZ). Solid selfmicroemulsifying
drug delivery system (SSMEDDS), solid self-emulsifying phospholipid
suspension (SSEPS) and self-emulsifying pellet formulations were investigated. Selfmicroemulsifying
drug delivery system (SMEDDS) was formulated using the surfactant
polyoxyethylene 20 sorbitan monooleate (S), the cosurfactant PEG-40 hydrogenated castor oil
(C) and the oil caprylic/capric triglycerides (O). Four different adsorbents with high specific
surface area were used: Neusilin® UFL2, Neusilin® FL2 (magnesium aluminometasilicate),
Sylysia® 320 and Sylysia® 350 (porous silica). Microemulsion area at the surfactant to cosurfactant
ratio (Km) 1:1 was evaluated and for further investigation SMEDDS with SC/O ratio
8:2 was selected. Solubilization capacity of selected SMEDDS for CBZ was 33771 ± 41 μg/ml.
Rheological measurements of... unloaded and CBZ-loaded SMEDDS system at water content
varied from 10 to 60 % (w/w) were conducted. It has been found that CBZ has great influence on
rheological behaviour of investigated system upon water dilution. Photon correlation
spectroscopy has shown ability of CBZ-loaded SMEDDS system to produce microemulsion
droplet size. SSMEDDS improved release rate of CBZ, but type of adsorbent significantly
affects release rate of CBZ. For SSMEDDS with different magnesium aluminometasilicate
adsorbents, release rate of CBZ decreased with increasing specific surface area due to
entrapment of liquid SMEDDS inside the pores and its gradual exposure to dissolution medium.
With porous silica adsorbents no difference in release rate was found in comparison to physical
mixtures. In physical mixtures presence of amorphous CBZ led to high dissolution rate. Self –
emulsifying phospholipid suspension (SEPS) was formulated using caprylocaproyl macrogol-8
glycerides (S)/ (lecithin/ propylene glycol) (Cs)/ caprylic/capric triglyceride (O) self-emulsifying
system. Km 3:2 was evaluated and for further investigation SEDDS with SCs/O ratio 8:2 was
selected. Photon correlation spectroscopy has shown ability of SEPS supernatant to produce
emulsion droplet size Diatoms, which represent fossilized skeletons of photosynthetic algae with
complex 3 – dimensional (3D), porous structure consisting of amorphous silica, obtained by
purification of diatomaceous earth, was used as solid carrier. Different solid samples of CBZ
suspension in SEDDS, called solid self – emulsifying phospholipid suspension (SSEPS), were
prepared using two methods: adsorption of CBZ dispersion in SEDDS by gentle mixing with
diatoms in mortar with pestle (Method A) or dispersion of diatoms in ethanol solution of CBZ
and SEDDS components, followed by ethanol evaporation (Method B). Release rate of CBZ
from SSEPS was significantly higher in comparison to pure drug, physical mixture of diatoms
and CBZ as well as solid dispersion of pure CBZ and diatoms obtained by ethanol evaporation.
The dissolution of CBZ from SSEPS sample prepared using method B was faster than from the
sample prepared by the method A. Higher dissolution for sample prepared by the method B can
be attributed to the partial adsorption (deeper localization) of liquid material inside the pores of
diatoms. Upon storage of the samples under accelerated conditions (40°C and 70% RH) for 10
weeks no significant changes in CBZ crystallinity and dissolution was in case of SSEPS,
contrary to solid dispersion with increased crystallinity, indicating that diatoms with adsorbed
liquid CBZ – loaded SEPS can maintain initial CBZ characteristics. Self-emulsifying pellets
were formulated by layering SEPS formulation on the surface of sugar pellets, 710- 825 μm i
size, using fluid-bed coater and ethanol/water 9/1 dispersion medium. Optimized amounts of
colloidal silica (anti-tacky agent) as well as hidroxypropilmethylcellulose (as binder) were used...
