Kniga na apstrakti book of abstrcts

Spray-dried chitosan-Ca-alginate microparticles 
as GIT drug delivery systems
Katerina Goracinova
Institute of Pharmaceutical technology, Faculty of Pharmacy, Ss. Cyril and Methodius University, 
Vodnjanska 17, Skopje 1000, Macedonia
Microparticles based on biocompatible and biodegradable natural polymers, such as chitosan and alginate,
paid much attention in the last decade in the field of development of novel drug delivery systems for local treatment
of colon diseases by per oral route, like IBD and colon cancer. Delivery of such systems to the site of action, or in
other words treatment of local disease of the colon by such systems, not only reduces the dose to be administered,
but also reduces the incidence of possible adverse effects associated with these drugs.
Chitosan-Ca-alginate MP`s loaded with BDS (low molecular weight and hydrophobic drug) and 5-FU (low
molecular weight and hydrophilic drug) were prepared using one step spray-drying process (Buchi 290, Mini Spray
Dryer, Swiss) [1]. 
In order to achieve localisation and prolonged residence time in the colon, matrices should have optimal par-
ticle size, between 4-15 
µm [2-8]. Carrier systems in that size range are able to attach more efficiently to the mucus
layer and accumulate in the inflamed region without the need for macrophage uptake [3, 4]. 
Spray-drying technique allowed formation of spherical particles with relatively smooth surface, high pro-
duction yield, mean diameter <10
µm and unimodal narrow size distribution, positive surface charge and high encap-
sulation efficiency.
Mucoadhesiveness of the polymers depends on the flexibility of polymer backbone structure and its polar
functional groups, which is however reduced during the cross linking procedure used in order to prepare micropar-
ticulated carriers with controlled drug release [7, 8]. So, care should be taken for preserving mucoadhesiveness and
obtaining desired biopharmaceutical properties during formulation and preparation of the microparticles. Because,
disadvantage of the mucoadhesive colloidal drug carrier systems is adherence to the substrate by non-specific inter-
actions i.e. polymers cannot distinguish between the adherence to intestinal mucus or to the surfaces of other gut
parts or contents, coating of chitosan and alginate based microparticles by polymer with pH dependent properties
such as Eudragit is desired. At this point, we might obtain direct targeting of the microparticles to the colon region
whereby increased drug control release will be present. 
By Eudragit coating of BDS loaded MP`s or incorporation of enteric coated 5-FU into MP`s, sustained drug
release at acidic media was achieved and improved dissolution at pH 6.8 and 7.40 was observed.
When compared drug release from Eudragit coated formulations to uncoated, it can be clearly seen that Eudragit
coating has successfully sustained the release of BDS in acidic media and pH 6.8 which is due to pH dependent solu-
bility of Eudragit
®
S 100. In addition, these findings might be associated not only with physical coating of microparti-
cles with Eudragit, but also with possibility of certain interactions between chitosan and Eudragit [9]. During the coat-
ing procedure (spray drying) one might suspect that redistribution of drug substance (BDS) in the hydrophilic matrix
will be triggered by Eudragit solvent (acetone) what might influence the drug release rate at pH 7.4, the pH where the
Eudragit coating is solluble. So, at pH 7.4, BDS was released faster from coated beads than the uncoated ones.
Coating of the 5-FU with H55, efficiently retained the drug inside the particles, maintaining ~80% of the
initial drug loaded after 2 h at pH 2.0. A comparatively fast release was observed at pH 6.8 and 7.4 due to the swelling
of the particles and pH-dependent solubility of H55. In these microparticles, initial swelling and buffer gaining inside
the beads leads to matrix rehydration and dissolution of H55, afterwards the drug delivery during the time of the dis-
solution study was controlled from chitosan-Ca-alginate matrix.
The efficacy of the prepared formulations was evaluated after experimentally induced colitis in rats (for BDS
loaded MP`s) and uptake studies in Caco-2 cell lines (for 5-FU loaded MP`s).
Macedonian pharmaceutical bulletin 53 (1,2) 38 (2007)
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Pharmaceutical aspects of positron emission tomography (PET)
implemetation
Emilija Janevik-Ivanovska
Institute of Pathophysiology and Nuclear Medicine, Faculty of Medicine,
Vodnjanska 17, Skopje, Republic of Macedonia
Positron Emission Tomography (PET) is one of the most rapidly expanding areas of medical diagnosis. PET
is a powerful, proven, diagnostic, molecular imaging modality that displays the biological basis of function in the
organs and systems of the human body and exploits the unique decay physics of positron-emitting isotopes to pro-
duces a three dimensional image or map of functional processes in the body. 
Unlike X-rays or a CT scan, which show only structural details within the body, PET excels at determining
organ function, because functional change often predates structural change in tissues, such as tissue metabolism and
physiologic functions.
The aim of this paper is to present the basic principles of PET and all arguments (technical, technological,
material, human, economic, financial and environmental) supporting the PET implementation in our country, includ-
ing installation of cyclotron for radionuclide production and establishment of radiopharmacy for synthesis and pro-
duction of PET radiopharmaceuticals.
The radiopharmaceuticals that are used in PET studies are chosen specifically to have a desired biological
activity, depending on the metabolic activity of the organ under study, and are introduced to the subject by injection
or inhalation. The most commonly used radionuclides are compounds that constitute, or are consumed by, the liv-
ing body such as carbon, nitrogen and oxygen. They are isotopes of biologically significant chemical elements that
exist in all living tissues of the body and in almost all nutrients. 
The most commonly used PET radiopharmaceutical in oncology imaging is fluorine-18 coupled with fluo-
rodeoxyglucose (FDG). FDG has a metabolism related to glucose metabolism. It has been considered potentially
useful in cancer imaging, since tumor cells show increased metabolism of glucose. Oxygen-15, which has a two-
minute half-life, can be used to study brain blood flow and brain oxygen metabolism. The radionuclide 13N, is used
in myocardial perfusion. PET scans to differentiate viable myocardium from infracted tissue in patients that are sus-
pected to have hibernating or stunned myocardium. The isotope 11C is used as a radiotracer in PET scans to study
normal/abnormal brain functions. It is one of the methods in localizing areas of the brain affected by epileptic seizures.
PET is widely used in Pharmacology and Neuropsychology in pre-clinical and clinical trials to study psy-
chiatric and cognitive disorders along with developing new radiolabel drugs.
The importance of the role of pharmacists in PET has been increasing as the use of PET radiopharmaceuti-
cals in clinical application, to contribute to the operation of a PET center, perhaps one of the most important factors
influencing the increased role of pharmacists in PET is their expertise and experience in the drug regulatory process
The real benefits of PET implementation is:
- PET has significantly impacted patient care and has proven to be a very cost-effective way to diagnose
stage, restage and monitor diseases, especially in oncology.
- PET will contribute to develop and expend new diagnostic procedures in the country and potentially in the
neighbor countries in the region and to establish production of short-lived radioisotopes for PET investigation need-
ed for our country and region.
Macedonian pharmaceutical bulletin 53 (1,2) 39-40 (2007)
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Implementacija na pozitronska emisiona tomografija 
– farmacevtski aspekt
Emilija Janevi}-Ivanovska
Institut za patofiziologija i nuklearna medicina, Medicinski fakultet, 
Vodwanska 17, Skopje, Republika Makedonija
Pozitronskata emisiona tomografija (PET) pretstavuva nuklearno medicinska vizuelizaciona
tehnika koja gi prika`uva biolo{kite osnovi na funkcioniraweto na organite i sistemite od ~ovekoviot
organizam i koristej}i gi pozitron-emitira~kite radioizotopi dava trodimenzionalna slika na
funkcionalnite i metabolnite procesi vo teloto.
Za razlika od H-zracite i kompjuteriziranata tomografija, koi gi prika`uvaat samo struktur-
nite detali i promeni, PET ja odreduva i funkcijata na organite, kako i tkivniot metabolizam.
Celta na ovoj trud e da se prika`at osnovnite principi na pozitronskata emisiona tomografija
i site argumenti (tehni~ki, tehnolo{ki, materijalni, humani, ekonomski, finansiski i dr.) koi ja
podr`uvaat implementacijata na PET vo na{ata zemja, vklu~uvaj}i ja tuka i instalacijata na ciklotron
i proizvodstvoto na kratko`ive~ki izotopi, kako i etablirawe na radiofarmacevtska laboratorija za
sinteza i produkcija na PET radiofarmacevtici.
Radiofarmacevticite koi se koristat vo PET studiite se visoko specifi~ni i treba da posedu-
vaat biolo{ka aktivnost zavisno od metabolnata aktivnost na organot koj se ispituva i se apliciraat na
pacientite po pat na inekcija ili inhalacija. Naj~esto upotrebuvani radionuklidi se onie na osnovnite
hemiski elementi od koi e izgradeno ~ove~koto telo kako {to se izotopite na jaglerod, azot i kislorod. 
Naj~esto koristen PET radiofarmacevtik, posebno vo onkologijata e fluor-18 vrzan za fluo-
rodeoksiglikoza (FDG). FDG ima metabolizam skoro identi~en na onoj na glikozata, pa od tie pri~ini e
naj~esto koristen za vizuelizacija na maligni zaboluvawa, od pri~ina {to tumorskite kletki imaat zgole-
men metabolizam na glikoza vo sporedba so normalnite. Kislorodot-15 se koristi za srceva perfuzija kaj
pacienti koi se suspektni za hiberniran ili kolabiran miokard. Jaglerod-11 se upotrebuva za ispituvawe
na normalna ili abnormalna mozo~na funkcija, posebno za vizuelizacija i lokalizacija na mozo~ni regii
koi se zafateni od epilepti~en atak.
Ulogata na farmacevtite vo PET e zna~itelno zgolemena so zgolemuvaweto na klini~kite
aplikacii na PET radiofarmacevticite. Eden od najva`nite faktori koi ja potenciraat ulogata na far-
macevtite vo PET centrite e nivnata stru~nost i kompetentnost vo postapkite vrzani za sproveduvawe
na regulativata koja se odnesuva na upotrebata na PET radiofarmacevtici.
Glavnite i najbitni pridobivki za implemetacijata na pozitronskata emisiona tomografija se:
- podobruvawe na dijagnostikata i sledeweto na terpapijata, posebno kaj pacienti od onkologijata,
hematologijata, kardiologijata i nevrologijata {to pretstavuva kvalitetiven skok vo gri`ata za zdravjeto
- razvoj na novi dijagnosti~ki proceduri vo zemjata i regionot, posebno preku etablirawe na
uslovite za proizvodstvo na kratko-`ive~ki radioaktivni izotopi i radiofarmacevtici. 
Macedonian pharmaceutical bulletin 53 (1,2) 39-40 (2007)
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FOURTH CONGRESS OF PHARMACY OF MACEDONIA WITH INTERNATIONAL PARTICIPATION

Formulation of Immediate Release Metronidazole Tablets
Meri Davceva, Katerina Goracinova
Institute of Pharmaceutical Technology, Faculty of Pharmacy, 
University „Ss Cyril and Methodious“, Vodnjanska 17, 1000 Skopje, Macedonia
Purpose: The purpose of this research was to prepare formulation containing metronidazole, BCS Class I API
and to identify the most appropriate diluent for tablet manufacturing, to compare wet granulation (WG) and direct com-
pression (DC) methods in terms of physical parameters (angle of repose, rate of flow, bulk and tapped density, com-
pressibility index and moisture content) and tablet performance (hardness, friability, dissolution and disintegration time).
Methodology: Both manufacturing processes, wet granulation and direct compression were used. Wet gran-
ulation was carried out with binder solution and with vehiculum. 5 % of polvinylpyrollidone (PVP) was used as a
binding agent, 0.5 % of calcium stearate and 0.5 % of natrium lauryl sulfate as lubricants. To evaluate the effect of
the diluent, three of the most common diluents (lactose, MCC and dicalcium phosphate) were used in the formula-
tions. Crospovidone was included in selected formulation to evaluate the role of the disintegrant. All prepared gran-
ulations and mixtures for DC were studied for: angle of repose, rate of flow, bulk and tapped density, compressibil-
ity index and moisture content. Also tablet parameters (hardness, friability, disintegration and dissolution time) were
evaluated for the prepared formulations.
Results: In general tablets manufactured with WG- with a binder solution, show low mechanical strength, with
lamination when determining friability and insufficient strength, which probably results from unequal binder distribu-
tion. Formulations prepared by WG- granulated by vehiculum only, resulted in tablets with higher mechanical strength,
density and excellent friability values. All DC formulations have appropriate mechanical strength, density and friabil-
ity. It can be clearly seen that in formulations containing a disintegrant, the tablet disintegration time is reduced from
minutes to seconds. But also the disintegrant has impact on tablet strength and friability. The nature of the diluent affects
both the disintegration and the dissolution. However, its influence is minor in comparison to the effect of the disinte-
grant. MCC is the only exception since it acts not only as a diluent, but also as a binder and disintegrant.
Conclusion: The results show that when DC was used with MCC as a diluent tablets with superior quality
both in terms of its physical characteristics and in terms of tablet disintegration and dissolution were produced. The
DC, MCC formulation is a promising one and can be further optimized.
Macedonian pharmaceutical bulletin 53 (1,2) 41-42 (2007)
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Formulacija na metronidazol tableti so brzo osloboduvawe
Meri Dav~eva
1
, Katerina Gora~inova
2
1
AD Alkaloid, bul.A.Makedonski br.12, Skopje, R. Makedonija
2
Institut za farmacevtska tehnologija, Farmacevtski fakultet, 
Univerzitet Sv. Kiril i Metodij, Vodwanska 17,Skopje,Makedonija
Cel: Da se formulira tableta so brzo osloboduvawe, so model lekovita supstancia -metronidazol,
koja pripa|a na prvata grupa na supstancii spored biofarmacevtskiot klasifikacionen sistem. Da se
izbere najefikasniot polnitel i proizvoden proces za priprema na metronidazol tabletite.
Metodi: Dvata proizvodni procesi vla`na granulacija (VG) i direktna kompresija (DC) bea
upotrebeni. VG be{e izveduvana so rastvor na vrzivno sredstvo, no i samo so vehikulum. Vo site formulacii
u~estvuvaat: povidon (Kollidon K-25) kako vrzuva~ vo koncentracija od 5%, kalcium stearat i natrium lau-
ril sulfat kako lubrikanti podednakvo zastapeni so po 0,5% poedine~no. So cel da se sogleda ulogata na
polnitelot, upotrebivme tri naj~esto koristeni polniteli vo prvite 4 formulacii: laktoza, mikrokristal-
na celuloza (MCC) i dikalcium fosfat vo koncentracija od 34%, vo procesot vla`na granulacija, so rastvor
na vrzivno sredstvo. Za da se prou~i ulogata na dezintegransot-krospovidon (Kollidon CL) go vklu~ivme vo
slednite 4 formulacii vo koncentracija od 3%, za smetka na polnitelot. MCC i dikalcium fosfat kako
polniteli bea vklu~eni vo formulaciite pripremeni so VG so vehikulum. MCC kako polnitel be{e i vo
formulaciite pripremeni so direktna kompresija. Site pripremeni granulati i suvi smesi od formulaci-
ite bea ispituvani na nasipen agol, brzina na protekuvawe, nasipna gustina, gustina po tapkawe, indeks na
kompresibilnost i vlaga. Parametri za procenuvawe na tabletite bea: cvrstinata, frijabilnosta i
mehani~kata jakost na tabletite, koi se merewa za mehani~kata jakost na tabletite, no i vremeto na dezin-
tegracija i disolucija, indikatori za svojstvata za osloboduvawe na aktivnata supstancija.
Rezultati: Generalno gledano so primena na VG dobivme izvonredno dobro proto~ni granulati,
sporedeno so suvite smesi za DC, koi imaa zadovolitelni vrednosti. Tabletite dobieni so VG - so rastvor
na vrzivno sredstvo, poka`uvaat mala mehani~ka jakost, so pojava na listawe pri odreduvawe na friabil-
nosta i nezadovolitelna cvrstina, koe najverojatno se dol`i na nevoedna~ena distribucija na vrzivnoto
sredstvo. Toj problem e nadminat, dobiena e povoedna~ena raspredelba na vrzuva~ot, kaj formulaciite
dobieni so VG- so vehikulum, koe rezultira{e vo tableti so pogolema mehani~ka jakost, cvrstina i odli~ni
vrednosti na frijabilnost. Generalno gledano, site formulacii dobieni so DC, imaat zadovolitelna
mehani~ka jakost, cvrstina i frijabilnost. Jasno se zabele`uva ulogata na dezintegransot kaj site formu-
lacii kade e vklu~en, namaluvawe na vremeto na raspa|awe od minuti do sekundi, no i negovoto vlijanie
vrz cvrstinata i friabilnosta na tabletite. Prirodata na polnitelot ima uloga vrz dezintegracijata a
so toa i vrz disolucijata, no toa vlijanie e malo vo odnos na vlijanieto na dezintegransot, so isklu~ok na
MCC, koja pokraj uloga na polnitel ima svojstvo i na vrzuva~ i dezintegrans. Superiornosta na disoluci-
ite na formulaciite dobieni so DC vo odnos na VG e o~igledna.
Zaklu~ok: Rezultatite uka`uvaat deka DC e poefikasen proizvoden proces za izrabotka na metron-
idazol tableti. MCC e superioren polnitel vo odnos i na mehani~kite svojstva, no i vo odnos na dezinte-
gracijata i disolucijata na tabletite. Kako formulacija koja mo`e da bide predmet na ponatamo{na opti-
mizacija, ja izbravme formulacijata so DC.
Macedonian pharmaceutical bulletin 53 (1,2) 41-42 (2007)
PP - 1
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Dissolution profile of 5-ASA loaded in chitosan-Ca-alginate 
microparticles; influence of formulation variables
K. Mladenovska
1
, O. Cruaud
2
, R. S. Raicki
1
, M. G. Dodov
1
, M. S. Crcarevska
1
, 
E. I. Janevic
3
, Z. Kavrakovski
1
, K. Goracinova
1
1
Faculty of Pharmacy and 
3
Faculty of Medicine, University “Ss. Cyril and Methodious”, Skopje, Macedonia;
2
Faculty of Pharmacy, Universite d’Angers, Angers, France
Novel chitosan-Ca-alginate microparticulated drug carrier system was prepared, which can effectively deliv-
er 5-ASA to the colon after oral administration. The objective of the work was to investigate the influence of the for-
mulation variables on 5-ASA release under different pHs and enzymatic and salt content simulating in vivo condi-
tions. For this objective, a spray-drying technique was applied to 5-ASA/sodium alginate aqueous dispersion to obtain
spherical particles having a mean diameter less than 10 
µm. The microparticles formed were hardened using solution
of calcium chloride and chitosan to obtain stable microsystem. Three types of sodium alginate with similar Mw and
different viscosity and guluronic to manuronic acid ratio and two types of chitosan with different Mw and same deacety-
lation degree >85% were used. The cross-linking procedure and polyelectrolyte complexation were carried out at con-
centration limits of alginate (1 and 3% w/w), chitosan (0.1 and 0.5% w/w) and calcium chloride (0.5 and 5% w/w) and
limits in pH of the cross-linking medium (3.5 and 4.5). For multiple-response optimization, mixed 2 and 3 level frac-
tional factorial design was used. Nemrod, a window based program, was used for generating the experimental design,
modelling of response surfaces and evaluation of quality of fit of the model. The matrix of the plan included 14 batch-
es. To compare the drug release, the experiment was performed in pH 1.2 (fasted stomach) and pH 6.8 (mid jejunum).
To simulate passage through stomach and small intestine, all series were additionally tested with a pH gradient method
including pH range from 1.2 to 7.5 and enzymatic method where phosphate buffer saline pH 6.8 was replaced by a
suspension of 10% w/w rat cecal content in bicarbonate buffer pH 7 under CO
2
to maintain an anaerobic environment. 
In general, particles with zeta potential between -33.8 and 10.3 mV, size between 5 and 14 
µm, calcium con-
tent between 2.5 and 5.5 % and actual drug content up to 8.72% (for theoretical content 14%) and 16.59% (for the-
oretical content 33%) were obtained. SEM pointed to acceptable spherical morphology, but also flattened, disk-
shaped particles. By imaging with CLSM, the chitosan was localised dominantly in the particle wall, while for
alginate, homogeneous distribution throughout the particle was observed. The thermograms and X-ray diffractograms
of loaded microparticles were almost identical to those of empty ones, indicating molecularly dispersed drug with-
in the particles.
Data analysis pointed to dominant influence of the concentration of CaCl2 on 5-ASA release in pH 1.2 dur-
ing 2 h, which is considered as average resident time in the stomach and until complete drug release. During 2 h, high-
er drug release rate was observed in series prepared of alginate rich in M units and relatively higher viscosity. Higher
Ca
2+
content in the gelling medium resulted in slower drug release. When analysing drug release in pH 6.8, slower
drug release occurred when higher Mw chitosan was used. Statistical analysis of 5-ASA release when pH gradient
method was used pointed to the active influence of the CaCl
2
concentration and interaction calcium chloride/alginate
type. By increasing Ca
2+
in the gelling medium, slower drug release occurred irrespective of the alginate type used
for particle preparation. Slowest drug release occurred in the series prepared from alginate rich in G units due to the
higher mechanical resistance and stability towards monovalent cations.
In general, at pH 1.2, alginate is protonated into the insoluble form of alginic acid displaying swelling prop-
erties that explain the low amount released. The release is hindered by chitosan also; its positively charged groups
strongly interact with alginate and 5-ASA reducing swelling and release. The rates of 5-ASA release in pH 6.8 were
similar and in some instances lower than those in pH 1.2. The colonic salt and enzymatic action modified the release-
determining factors, probably by increasing the internal matrix pH, porosity and degradation rate. Linear square-root
time kinetics suggests release governed by drug dissolution and diffusion. The diffusional exponents according to
the general exponential release equation indicated anomalous (non-Fickian) mechanism in 5-ASA release controlled
by polymer relaxation, erosion and degradation.
Macedonian pharmaceutical bulletin 53 (1,2) 43-44 (2007)
PP - 2
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