ХЕМИСКИ АКТИВИРАНИ СИСТЕМИ СП КПНТРПЛИРАНП ПСЛПБПДУВАОЕ

CHEMICALLY-activated controlled drug delivery systems

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Konjugati so aktivna supstancija

HEMISKI AKTIVIRANI SISTEMI

1. BIORAZGRADLIVI POLIMERNI SISTEMI

- Degradacija in bulk (a)

- Degradacija na povrsinata (b)

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Sto pretstavuva degradacijata na polimer?

Polymers were synthesized from glycolic acid in 1920s

At that time, polymer degradation was viewed negatively as a process where properties and performance deteriorated with time.

Biodegradable Polymers: Chemical Degradation

Polimerna degradacija po pat na erozija

Surface erosion (poly(ortho)esters and polyanhydrides) Sample is eroded from the surface Mass loss is faster than the ingress

of water into the bulk

Bulk degradation (alifaticnipolyesters: PLA,PGA,PLGA, PCL) Degradation takes place

throughout the whole of thesample

Ingress of water is faster than therate of degradation

Biodegradabilni/erozivni sistemi

Sistemi so povrsinska degradacija

• Rastvoruvacot sporo difundira niz sistemot rastvarajki i osloboduvajki ja LS (difuzija),pritoa polimerot se razgraduva (degradira) po povrsinskiot sloj, so sto se namaluvaatdimenziite na sistemot.

• Osloboduvanjeto se vrsi so dvata mehanizmi i vo zavisnost od polimerot moze da epospora difuzijata od degradacijata po povrsinata.

Povrsinska erozijaZvezdickite I tockite pretstavuvaat rastvorena l.s. Il.s. dispergirana vo matriksot

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• Kaj sistemite koi se razgraduvaat so in bulk erozija, brzinata na penetracijata na voda vosistemot e pogolema od brzinata na degradacijata na polimernite lanci

• Celiot sistem brzo se navlaznuva vo dopir so voda I se javuva degradacija na polimernite lanciniz sistemot

• Poradi prisustvoto na vodata LS stanuva mobilna I difundira vo okolnata sredina

• Vokolku vo DDS ima visok na LS vo forma na kristali ili amorfni agregati, oslobodenata LS kese nadomesti od ovoj pul

• Formata I dimenziite na ovie sistemi ostanuvaat voglavno nepromeneti, dodekavnatresnata struktura stanuva poporozna radi degradacijata I osloboduvanjeto na LS,pritoa pri osloboduvanjeto opadja koncentracijata na LS vo sistemot (se zgolemuvaporoznosta I namaluva koncentracijata). So ponatamosna degradacija lancite stanuvaat sepomali, so toa polesno se dvizat, a so zgolemuvanjeto na mobilnosta na makromolekulite sezgolemuva I mobilnosta na LS.

Biodegradabilni/erozivni sistemi

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• Generalno, polimerite koi imaatreaktivni funkcionalni grupi nanivnite stranicni lanci degradiraat sopovrsinska erozija (polianhidridi)

• dodeka onie koi se so pomalkureaktivni grupi degradiraat in bulk(PLGA).

• Apsolutnata brzina na degradacija jaodreduva:– brzinata na erozija (povrsinska ili in

bulk)– brzinata na degradacija na

polimernite lanci– penetracijata na vodata.

• Brzinata na penetracija na voda vosistemot, a so toa vo odredeni slucaii mehanizmot na erozija, ke zavisi Iod geometrijata I dimenziite naDDS.

Biodegradabilni/erozivni sistemi

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Brzinata na hidrolitickata degradacijana polimerite zavisi od slednite

osobini:

• Hemiski sostav: brzinata na degradacija zavisi odvidot na vrskite prisutni vo polimerot. Generalno,brzinata na degradacija na razlicnite hem. vrski eAnhidridi>Estri> Amidi.

• Kristalnost: Polimerite sto imaat pogolemakristalnost pokazuvaat pospora degradacija.

• Hidrofilnost: Polimerite so golem br. na hidrofobnigr. pokazuvaat pospora degradacija vo odnos napolimeri koi se pohidrofilni po priroda.

HEMISKI KONTROLIRANI SISTEMI-Vokolku gi primenime biorazgradlivite polimeri vo implanti, -istite nema potreba da se otstranuvaat hirurski

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Mehanizmi na degradacija napolimerite

Mehanizam I- vodorastvorlivi polimeri cija rastvorlivost

e namalena so vkrsteno-povrzuvanjese razgraduvaat so degradacija navkrsteno-povrzanite lanci.

Mehanizam II- stranicnite hidrofobni grupi se

preveduvaat vo hidrofilni so hidroliza,jonizacija, protonacija I sl.

Mehanizam III- razgradba na glavniot lanec kaj

polimeri so labilni vrski

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Glavniot lanec; Vodor-rlivi niskomol. oligomeri ili monomeri

Stranicnite lanci, vodor-rlivivisoko mol. fragmenti

Moze i poveke mehanizmida se kombinirani!!!

Polimerot ne degradira I najcesto ostanuva so ista Mw

Vodorlilivi mol so mala Mw

Biodegradable Polymers

Najgolem broj odbiorazgradlivite polimerise polyestri

ester – kovalentnavrska so polarna priroda

I moze da se razrusi so hidroliza (C-O vrskatase raskinuva)

ESTER BOND

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GLIADEL® WAFER(polyanhydride wafer containing a chemotherapeutic agent Carmustine) for the treatment of malignant glioma

Concentration profiles of BCNU. x-axis is the distance from polymer/tissueinterface in mm. (a) 1 day (b) 3 day (c) 5 day (d) 7 day

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Implanti so biorazgradlivi polimeri vo terapijata- Gliadel

Primer za biorazgradliva forma so kontrolirano osloboduvanje• Gliadelot e polimeren disk koj sodrzi 1,2-bis(2-chloroethyl)-1-nitrosourea

(BCNU – Carmustine), za lokalno kontrolirano osloboduvanje na antikancerlekovita supstancija.

• Molekulata e mala i lipofilna sto ovozmozuva preod niz krvno mozocnatabariera no

• Sistemskiot tretman so BCNU e propraten so mnogu sporedni nesakaniefekti I istite se dozno zavisni (supresija na koskenata srcevina,pulmonarna fibroza), a pritoa poluvremeto na raspad e samo 15 min.

• Zaradi toa: Za vreme na operacijata na mozocnite tumori se insertiraatGliadel implanti vo prazninata na tumorot, BCNU se osloboduva nakontroliran nacin tokmu na mestoto na deluvanje, a implantite nemapotreba da se otstranuvaat bidejki primenetiot polimer e biorazgradlivpolyanhydride – poly[bis(p-carboxyphenoxy)propane-sebacic acid].

• Klinickite ispituvanja za efikasnosta (na prethodniot slajd) napraveni se1996, lekot e odobren e od strana na FDA).

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• LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as a intramuscular injection.

• LUPRON DEPOT is a gonadotropin releasing hormone (GnRH) agonist indicated for palliative treatment of advanced prostatic cancer.

• The prefilled dual-chamber syringe of LUPRON DEPOT 7.5 mg for 1-month administration contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid/glycolic acid copolymer.

HEMISKI KONTROLIRANI SISTEMI

2. KONJUGATI SO AKTIVNA SUPSTANCIJA

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JONOIZMENUVACKI REZINATI

(LEK - JONOIZMENIVACKI SMOLI KOMPLEKSI)

Pred da zapocneme so sovremenite sistemi nakratko ke gi prikazeme najstaritekompleksi no nekoi od niv seuste se na pazarot

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Joniizmenuvackismoli se nerastvorlivipolimeri koi imaatkiseli ili baznifunkcionalni gr. Imozat daizmenuvaat joni.

Osloboduvanjeto na l.s. moze da se

prolongira od 8-12 h a zavisi od pH i

koncentracijata na elektroliti vo GIT

(suspenzija, tabl., kaps., mikrokapsuli)

Vo GIT jonite difundiraat niz etilceluloznite membrani i

reagiraat so lek-smola kompleksot aktiviraj}i go osloboduvaweto na lekot

Dopolnitelno, mozno e polimerno oblozuvanje. Primer se tramadol-rezinakompleks na mikrokapsuli oblozeni so etil celuloza.

Polimerni terapevticiPolimerni lekovi

Polimer-protein kompleksi Polipleksi

Polimer-lek konjugati Polimerni miceli

Nature Rev. Drug Discov. (2003)Nature Rev. Cancer (2006)

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Prednosti na sovremenite hemiskikontrolirani sistemi bazirani na konjugati

• Podobreni terapevtski osobini (peptidi, proteini, mali molekuli I oligonukleotidi)

• Prodolzeno vreme na poluzivot• Zgolemena stabilnost, zastita od deaktivacija,

zacuvuvanje na aktivnosta pri cirkuliranjeto• Rastvorlivost vo voda• Namalena imunogenost I antigenost (pomalku

izrazen imunoloski odgovor)• Ednostavna administracija• Podobrena podnoslivost• Specificno targetiranje

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Struktura, mehanizamna dejstvo, efekti

- prednostiLek-polimer konjugati

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HEMISKI KONTROLIRANI SISTEMI – lek vrzan za polimer; lek-polimer kompleksi/konjugati

Se podgotvuvaat so konjugiranje na LS napolimeren lanec preku kovalentnovrzuvanjeSe vgraduva biorazgradliv spejser vokonjugatot so cel podobruvanje nastabilnosta I olesnuvanje na specificnoenzimsko ili hidroliticko osloboduvanje

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Polimeri za konjugacija so lek

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Structure of PK1 (HPMA copolymer doxorubicin).

Paul A. Vasey et al. Clin Cancer Res 1999;5:83-94

©1999 by American Association for Cancer Research

PK1 comprises doxorubicin covalently bound to N-(2-hydroxypropyl)methacrylamidecopolymer by a peptidyl linker. Following cellular uptake via pinocytosis, the linker is cleaved by lysosomal enzymes, allowing intratumoral drug release.

Schematic representation of the principle of macromolecular uptake by the EPR mechanism

and drug release intracellularly by cleavage of the peptidyl linker by lysosomal enzymes.

Paul A. Vasey et al. Clin Cancer Res 1999;5:83-94

©1999 by American Association for Cancer Research

• Normalno polimer-lek konjugatitepokazuvaat tumor targeting prekuEPR efektot (enhancedpermeability and retention effect).

• Hiperpermeabilnite angiogenskitumorni sadovi ovozmozuvaatizleguvanje na cirkulirackitemakromolekuli I lizozomi vointersticiumot kade se zadrzuvaatdolg vremenski period poradinedostig od limfaticnaintratumorna drenaza.

• So ova se postignuva visok stepenna tkn pasiven targeting.

• Konjugatite mozat da sodrzatligandi koi ke promoviraatreceptor-nasocen targeting(antitela, peptidi, saharidi) ilispecificen targeting.

Doxorubicin-HPMA konjugat (polimerot e N(2-hydroxypropyl) methacrylamideso biodegradabilen tetrapeptiden linker (P-GFLG-DOX), koj podlezi na enzimska

degradacija vo lizozomite.

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Konjugati so mali molekuli –najstariotso 5-ASA e Sulfosalazine

• SSZ (co drug odsulfapyridine I 5-ASA) is metabolized by intestinal bacteria to SP and 5-ASA (bacterial reductase and its azo bond cleavage)

• The majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces.

azo-prodrugs 5 ASA(e.g. sulfasalazine, olsalazine or balsalazide) 32

DDS so Pulsiracko osloboduvanjePulsiracki POLIMERNI SISTEMI

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PulsatileDelivery

SinglePulse

OsmoticallyRuptured

PolymerDissolution

PolymerMelting

MultiplePulse

Electrically-Stimulated

Ultrasonically-Controlled

Magnetically-Controlled

Temperature-Controlled

Ionic-StrengthDependent

pH-Sensitive

Pulsno osloboduvanje

• Postojat zaboluvanja kaj koi ne se potrebni konstantninivoa na LS tuku:– periodicno osloboduvanje na odredeni kolicestva na LS,

– odnosno osloboduvanje na LS posle odreden vremenskiperiod od aplikacijata (primena navecer a terapevstkiefekt nautro)

– ili osloboduvanje na LS posle odreden vremenski period (lag time) so cel LS da se oslobodi na odredeno mesto.

• Zaboluvanja kaj koi ne se potrebni konstantnikolicestva na LS: Astma, artritis, duodenalen ulcer, kardiovaskularni zaboluvanja, kancer

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Cirkaden ritam

Cirkaden ritam

Zosto sistemi so pulsiracko, hronobiolosko osloboduvanje

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Contd….

• Osven za zaboluvanja koi pokazuvaat dnevno-noken ritamvo nivnata patofiziologija (HRONOTERAPEVTICI),pulsirackoto osloboduvanje se primenuva i vo drugi celikako:– izbegnuvanje na metabolizmot na prv preod, na pr. kaj

proteini i peptidi,– Za lekovi naspram koi brzo se razviva tolerancija (salbutamol

sulphat)– Za targetiranje na delovi od GIT na pr. Colonot (budesonide)– Za vremenski programirano osloboduvanje na hormonski

preparati no i drugi LS– Za LS so kratko vreme na poluzivot (beta blokatori)

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Vidovi na sistemi so pulsnoosloboduvanje

• Sistemi so planirano osloboduvanje– Pulsni kapsuli

– Pulsni osmotski sistemi

– Erozivni i rastvorlivi pulsni sistemi

– Pulsni sistemi so rasprsnuvacki sloj

• Sistemi so inducirano osloboduvanje– Osloboduvanje inducirano so temperatura

– Hemiski inducirano osloboduvanje

– Osloboduvanje inducirano od nadvoresen stimul

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SISTEMI SO PLANIRANOOSLOBODUVANJE

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Enterosolventno oblozeni pulsni kapsuli

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– Pulsni kapsuli - Pulsincap- Babreckiot cep e izgraden od

polimeri koi- babrat kako hidrogelite;- enzimski kontrolirani erozivni

polimeri

- Pr za hidrogel polimer HPMC-hydroxylpropyl methylcellulosa,

- Pr za enzimski kontroliranierozivni polimeri se pektinot,agarot, citozanot i sl.

- Vo zavisnost od vidot idebelinata na cepot, LS seosloboduva na odredenomesto vo GIT, odnosno posleodredeno vreme.

Pulsni osmotski sistemi

Ima poveke izvedbi:

-Osmotski sistem so nerastvorlivcep

-Zelatinska kaps. oblozena so semipermeabilna membrana(celuloza acetat)

-So navleguvanje na vodata prekusemipermeabilnata membranaosmotski aktivnata supstancijago izbuktuva nerastvorliviot cep I ja osloboduva LS po odreden lag time.

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PORT SYSTEM

Erozivni i rastvorlivi pulsni sistemi

Osloboduvanjeto e kontrolirano so disolucijaI erozija na nadvoresniot sloj koj e apliciranna jadro koe ja sodrzi LS.

Osloboduvanjeto e po odreden lag time posto se osloboduva celata kolicina na LS.

1. ChronotropicR system

2. Time ClockR system

3. Povekeslojni tabletiR

ChronotropicR system

Vremeto na zakasnuvanje naosloboduvanjeto zavisi od debelinata naHPMC slojot kako I viskoznosta na ovaarastvorliva celluloza koja babri.

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ChronotropicR system

• Se sostoi od jadro koe ja sodrzi LS oblozeno so HPMC

K.Goracinova, 2012, Modificirano osloboduvanje, voved i sistemi

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Time ClockR system

Sistem sostaven od cvrsta dozirana forma oblozena so lipidnabariera (karnauba vosok i pcelin vosok) zaedno so PAM (Span 80)Po odreden lag time, proporcionalen so debelinata na filmot, obvivkata erodira ili se emulgira so tecnostite vo GIT, po stonastanuva osloboduvanje na LS.

Povekeslojni tableti

Sistem koj ja osloboduva LS vo dva pulsa.Troslojna tableta koja ima 2 sloja so LS odvoeni so gelirackipolimeren sloj.Edniot sloj so LS e oblozen so EC.

Pulsni sistemi so rasprsnuvackisloj/ruptura na membrana

• Rezervoar sistem oblozen so membrana (nadvoresenpolimeren sloj koj e nerastvorliv no e propustliv za vodataEC i e podlozen na mehanicka ruptura).

• Rupturata e rezultat na babrenje ili efervescentna reakcija.

49CMC, HPC, Na-skroben glikolat

Pulsni sistemi so rasprsnuvacki sloj

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SISTEMI SO STIMULIRANO(INDUCIRANO) OSLOBODUVANJE

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Osloboduvanje inducirano so

temperatura

Osloboduvanje inducirano so temperatura

• Za ovoj vid na osloboduvanje se koristattermosenzitivni polimeri

• Ovie polimeri babrat ili se kontrahiraat vozavisnost od temperaturata.

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Hemiski inducirani sistemi• Sistem koj ke osloboduva insulin vo zavisnost od conc. na glikozata vo

krvta• Pretstavuvaat pH zavisni sistemi (mikro, nanocestici izraboteni od pH

responsivni polimeri) koi sodrzat glukozo oksidaza• Ovoj enzim reagira so glikozata od krvta (sistemot e vo postojan kontakt

so okolnata sredina) I bidejki kako produkt na reakcijata e glukonskata k-na, vokolku nivoto na glikozata se zgolemi, se zgolemuva kiselosta nasistemot t.e. na mikrocesticata (moze da bide rezervoar sistem) so sto sepromenuva propustlivosta kon insulinot

• Koga ke se namali nivoto na glikozata vo krvta se namaluva I kiselosta vosistemot, a so toa I propustlivosta na membranata

• Smart pH responsive polymers: N, N- diethylaminoethyl methacrylate i2-hydroxypropyl methacrylate (DEA-HPMA)

• Vo ovie sistemi spadjaat i FDF so konvencionalni polimeri so pH zavisnoosloboduvanje ili osloboduvanje na odredena cel vo GIT (Eudragit E-100, Hydroxypropylmethylcellulose phthalate, Hydroxypropylmethylcelluloseacetate succinate), no isto taka tuka moze da se vbroi I citozanot kojodgovara na promeni vo pH na sredinata a I mikrobioloski se razgraduvaod mikroflorata zastapena vo kolonot, so svoite mikro, nano I makro FDF

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Hemiski induciran sistem

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Hemiski inducirani sistemi so pulsnoosloboduvanjeIli sistemi so samoregulacija

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The swelling ratio of their hydrogels depended on the glucose concentration. This is due to the fact that glucose results in the dissociation of the complex between pendant glucose of GEMA and Con. A and the crosslinking density in the hydrogels decreases.

Osloboduvanje inducirano odnadvoresen stimul

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Osloboduvanje inducirano od nadvoresen

stimul – magnetski stimulirani

• Magnetno stimulirani– Osloboduvanjeto od ovoj vid na polimerni sistemi e

stimulirano od dejstvoto na magnetno pole.– Fe3O4 cestici i insulin vokolku se dispergiraat vo alginatni

cestici koi ponatamu vkrsteno ke se povrze so poly(L-lysine)i/ili poly(ethylene imine) ke se dobie sistem od koj insulinotkontrolirano ke se osloboduva vo zavisnost od mehanickitesvojstva I karakteristikite na polimerniot sistem po aplikacijana magnetno pole.

– Polimerni cestici so magneten materijal koi sodrzatantikancer LS uspesno mozat da ja oslobodat LS tokmu votumorot posle izlozuvanje na magnetno pole. Podobruvanjena koncentriranjeto se izveduva so vrzuvanje na cesticite soligandi .

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Magnetically responsive microspheres for the pulsed delivery of insulin

Magnetically responsive microspheres for the pulsed delivery of insulin

O. Saslawskia, C. Weingartena, J.P. Benoita and P. Couvreur, a

aLaboratoire de Pharmacie Galénique et de Biopharmacie, UA CNRS 1218, Université de Paris XI, FranceRevised 19 February 1988.Available online 16 November 2002.

AbstractThis paper describes a new formulation for triggered delivery of insulin which consisted of magnetic particles dispersed in alginate spheres. When magnetic field was applied to that system, the release rate of insulin was about 50 times higher than in the absence of magnetic field. The influence of oscillating magnetic field was tested, in the same experimental conditions, on polyethylenimine cross-linked alginate spheres. In that case, the pulsed delivery of insulin occurednot immediately but during the period just after applying the magnetic field. The proposed magnetically responsive alginate spheres open new perspectives for the rhythmically delivery of peptides.

Life Sci. 1988;42(16):1521-8.

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• Miyazaki et al. koristele ultrazvuk za da go zgolemat osloboduvanjeto na5-FU za 27 pati od ethylenevinylacetat-en matrix

• Zarobuvanjeto na nano-jadra vo NIPAAm-co-AMM hidrogeli so posledovatelno izlozuvanje na IR zraci ke dovede do apsorpcija nazracite od strana na nano-jadrata koi gi pretvaraat vo toplotna En. Rastotna temperaturata vo hidrogelot ke go zgolemi osloboduvanjeto.

• Elektricno stimulirani sistemi – podgotveni se od polielektroliti, pa spored toa se pH zavisni i zavisni od elektricnoto pole, negoviotintenzitet i vremetraenje.Na pr. Vokolku pozitivno naelektrizirana LS inkorporirame vo negativnonaelektriziran gel, po aplikacijata na eletricno pole ke dojde do osloboduvanje na lS pod dejstvo na jonskata razmena na katodata, elektrostatskata sila, elektroosmozata vo gelot.

Osloboduvanje inducirano od nadvoresen

stimul – ultrasonicno stimulirani, foto

stimulirani, elektricno stimulirani

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Electrically controlled drug delivery system using polyelectrolyte gels

K. Sawahataa, M. Haraa, H. Yasunagaa and Y. Osadaa

aDepartment of Chemistry, Ibaraki University, Mito 310 JapanReceived 15 March 1990;accepted 9 July 1990.Available online 8 November 2002.

AbstractElectrically stimulated drug delivery systems using polyelectrolyte gel and microparticles are experimentally demonstrated. The principle of the systems is based on the chemomechanicalshrinking and swelling of polymer gels under an electric field. It was found that bioactive materials, such as pilocarpine hydrochloride, glucose and insulin, are successfully released from the gel by switching the electric field alternately on and off. The release mechanism of these compounds is briefly discussed.

Journal of Controlled ReleaseVolume 14, Issue 3, December 1990, Pages 253-262

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Modern development of pulsatile DDS

• Gastroretentive DDS (PLATFORMS-low densitymicrospheres with bioadhesive coatings,moderately swelling matrix systems,bioadhesives, superswelling hydrogel systems)

– Floating DDS (FDDS) – multiparticulate calcium

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Primeri na novi tehnologii:

• SODAS ® TEHNOLOGIJA - SpheroidalOral Drug Absorption System

– (AvinzaTM, Ritalin ®, Focalin ® XR)

• Elan SODAS®Technology is based onthe production of uniform sphericalbeads of 1-2mm in diametercontaining drug plus excipients andcoated with product specificcontrolled release polymers.

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Avinza is a once-daily morphine sulfate controlled-release formulation utilizing SODAS technology for the potential treatment of pain. This multiparticulate product is designed to provide a rapid onset of action together with a sustained therapeutic effect over 24 h.

Drugi primeri

• IPDAS ® TEHNOLOGIJA (Intestinal Protective Drug Absorption Syst.

• Tabletna tehnologija nameneta za LS koi go iritiraat GIT.

• Once an IPDAS® tablet is ingested, it rapidly disintegrates and disperses beadscontaining a drug in the stomach, which subsequently pass into theduodenum and along the gastrointestinal tract in a controlled and gradualmanner, independen to the feeding state. Release of active ingredient from themultiparticulates occurs through a process of diffusion through the polymericmembrane. Micromatrix of polymer/active ingredient formed in theextruded/spheronized multiparticulates.

• Naprelan®, which is marketed in the United States and Canada, employs theIPDAS® technology. This is innovative formulation of naproxen sodium.

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CODAS®, Chronotherapeutic Oral Drug Absorption System, is one of Elan Drug Technologies’ multiparticulate drug delivery systems. The extended-release, controlled-onset properties of the CODAS® technology is designed to allow a four-to-five hour delay of onset following administration of drug. This delay in release is introduced by the level of release controlling polymer applied to the drug loaded beads. The release controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes in contact with the polymer coat beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the drug.

Applying the CODAS® technology to Verapamil Hydrochloride, complimented the circadian pattern of hypertension and provided a controlled onset, extended release delivery system a rate of release essentially independent of pH, posture and food “sprinkle” dosing by opening the capsule and sprinkling the contents on food.

PrimeriCODAS® tehnologija

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Benefit to Patient

• controlled release of the drug, manipulated such that maximum blood levels of the antihypertensive are provided at appropriate times throughout the day

• night-time dosing as the drug beads disperse throughout the gastrointestinal tract

• maximum blood levels of drug achieved in the early morning, with bed-time dose, to offset the rapid surge in blood pressure

• therapeutic effect is maintained during wakening hours.

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PULSYS TECHNOLOGY• Sistem sostaven od peleti komprimirani vo

tableta so cel da se postigne ednas na den pulsno doziranje.

PRODAS® TECHNOLOGY

• which is unique in that it combines the benefits of tabletting technology within a capsule.

• It can be used to pre-program the release rate of a drug.

• PRODAS® technology, by incorporating minitabletswith different release rates, can display the characteristics of a number of different conventional dosage forms:

• delayed release component for site/regional release and/or food resistance

• sustained release component for additional controlled release/profile extension

3DP (Three-dimensional printing )technology

• Konstruiranje na specificni sloevikoristejki procesiranje na prasoki materjali koi vrzuvaat voda.

• Upotreba– linear drug delivery systems

(DDS), – colon-targeted DDS, – oral fast disintegrating DDS,– floating DDS, – time controlled, and pulse

release DDS– dosage form with multiphase

release properties and implantable DDS.