magistrska naloga
Marko Janković (Avtor), Mirjana Gašperlin (Mentor), Katarina Bolko (Komentor)

Povzetek

Peroralna aplikacija je zaradi številnih prednosti še vedno prva izbira vnosa zdravila v človeški sistem. Za dosego terapevtskega učinka nekega zdravila je pomembna dobra biološka uporabnost (BU), na katero vplivata dve najpomembnejši lastnosti zdravilne učinkovine (ZU), to sta topnost in permeabilnost. Slaba topnost omejuje doseganje primerne BU pri skoraj polovici na novo odkritih ZU. Eden izmed novejših pristopov izboljšanja topnosti je vgrajevanje ZU v na lipidih osnovane sisteme, med katere spadajo tudi samo(mikro)emulgirajoči sistemi (S(M)ES). Z vgradnjo ZU v te sisteme omogočimo njeno dostavo v že raztopljenem stanju in se tako v večji meri izognemo omejujočemu procesu raztapljanja. Po aplikaciji omenjenih sistemov pride v tankem črevesju do encimske razgradnje komponent sistema in sproščanja ZU v medij gastrointestinalnega trakta (GIT). In vivo obnašanje teh sistemov skušamo napovedati s pomočjo in vitro testov, kot je in vitro lipoliza. V sklopu magistrske naloge smo vrednotili vpliv in vitro lipolize S(M)ES na sproščanje modelne slabo topne ZU naproksen. Naproksen je šibka kislina (pKa ~ 4,15), zato je po vnosu v želodec večinoma v neionizirani obliki. Zaradi neželenih učinkov in slabše topnosti v želodcu se naproksen pogosto dostavlja v gastrorezistentnih oblikah. V tem primeru se sprošča šele v tankem črevesju, kar smo simulirali z in vitro lipolizo. Pri višjem pH v tankem črevesju je topnost naproksena sicer boljša, a je zaradi ionizacije nekoliko slabše permeabilen. Iz tega stališča je njegova vgradnja v S(M)ES smiselna, saj površinsko aktivne snovi, ki jih le-ta vsebuje, izboljšajo tudi permeabilnost. Pripravili smo 4 kvantitativno različne formulacije, ki so ustrezale smernicam S(M)ES - na lipidih osnovanih sistemov tipa III. Za sestavo formulacij smo uporabili naslednje sestavine: Capmul MCM EP, ricinusovo olje, Kolliphor RH 40, Kolliphor HS 15, Kolliphor EL, PEG 400, Miglyol 812, gliceril monooleat in Gelucire 44/14. V formulacije smo vgradili naproksen do nasičene topnosti. In vitro lipolizo formulacij smo spremLjali pri različnih pogojih, ki posnemajo pogoje na tešče, pogoje po jedi, dodatek 250 mL vode ter opazovali njihov vpliv na sproščanje naproksena. Ugotovili smo, da je naproksen najbolj topen v neionskih emulgatorjih in sotopilih ter najmanj v oljih, kar je potrebno upoštevati pri nadaljnjih stopnjah razvoja formulacije. Topnost naproksena v prebavnih medijih GIT je močno odvisna od pH vrednosti, zato sama sestava na lipidih osnovanih sistemov tipa III nima večjega vpliva na sproščanje te ZU. Iz porabe NaOH pri izvedbi in vitro lipolize s pH-stat metodo smo določili njen obseg pri posamezni formulaciji in prišli do ugotovitve, da sproščanje in posledično absorpcija nista pogojena s prebavo S(M)ES-ov tipa III. Z rezultati fotonske korelacijske spektroskopije smo pokazali, da pri redčenju S(M)ES z vodno fazo ni zadostna vizuelna ocena za določanje nastanka mikroemulzije. Z izvedbo in vitro lipolize smo pokazali, da kljub boljši topnosti naproksena v tem pH pride do izgube solubilizacijske kapacitete S(M)ES. Zmanjšanje solubilizacijske kapacitete ni bilo odvisno od in vitro prebave, niti ne od deleža oljne faze v S(M)ES ali velikosti kapljic po dispergiranju formulacij. Z dodatkom 250 mL vode k S(M)ES pride do še večje izgube solubilizacijske kapacitete. V prihodnjih raziskavah bi zaradi večje napovedne moči in vitro testov bilo smiselno vključiti tudi simulacijo pogojev v želodcu, saj bi se tako bolj približali in vivo pogojem. Prav tako bi bilo smiselno določiti vpliv in vitro lipolize S(M)ES-ov na sproščanje ZU pri različnih vsebnostih ZU v S(M)ES-ih.

Ključne besede

samo(mikro) emulgirajoči sistem;in vitro lipoliza;pH-stat metoda;pankreasna lipaza;naproksen;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.09 - Magistrsko delo
Organizacija: UL FFA - Fakulteta za farmacijo
Založnik: [M. Janković]
UDK: 544.351.3:615.2(043.3)1
COBISS: 4650097 Povezava se bo odprla v novem oknu
Št. ogledov: 402
Št. prenosov: 75
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Angleški jezik
Sekundarni naslov: ǂThe ǂeffect of in vitro lipolysis of self (micro)emulsifying systems on naproxen release
Sekundarni povzetek: Because of its many advantages oral drug delivery still remains the preferred route of drug administration. To achieve therapeutic effect good bioavailability is crucial. It is determined by the drugs solubility and its permeability. Almost half of newly discovered active pharmaceutical ingredients exhibit low solubility in water, which limits the bioavailability. Recently much attention has been focused on lipid based drug delivery systems, especialy self microemulsifying drug delivery systems. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is that the drug is delivered in a disolved state and thus avoiding the limiting step. After administration of lipid based drug delivery systems enzymatic digestion takes place in the small intestine of the gastrointestinal tract. Simultaneously with the digestion of the lipid components the drug is released into the gastrointestinal medium. In vitro evaluation of lipid-based drug delivery systems is an important step to help predict in vivo performance. As a part of my master's thesis, we evaluated the effect of in vitro lipolysis of self (micro)emulsifying drug delivery systems on naproxen release. Naproxen is a weak acid (pKa ~ 4,15), which means it's mostly in the non-ionised form in the acidic environment of the stomach. Because of adverse effects and low solubility in the stomach environment, naproxen is often incorporated into gastro-resistant pharmaceutical form. In the mentioned case the release of naproxen occurs only after passing through the small intestine of the gastrointestinal tract. With the help of pH-stat method and in vitro lipolysis, we simulated the conditions in which naproxen was released. At higher pH values in the small intestine the solubility of naproxen improves, at the same time permeability decreases on the account of higher percentage of ionised naproxen. From this point of view, the incorporation of naproxen into self (micro)emulsifying systems seems reasonable, since surfactants also improve permeability. We prepared four different type III on lipids based formulations. The formulations consisted of: Capmul MCM EP, castor oil, Kolliphor RH 40, Kolliphor HS 15, Kolliphor EL, PEG 400, Miglyol 812, glyceryl monooleate and Gelucire 44/14. All four formulations contained naproxen at 100 % saturated solubility. We performed in vitro lipolysis at different conditions simulating fasted state, fed state, addition of 250 mL of water and observed the effect on naproxen release. Naproxen exhibited the highest solubility in non-ionic surfactants and the lowest solubility in oils, this has to be taken into account when we decide which components we use in our formulations. Naproxen solubility in gastrointestinal media is highly dependent on the pH value. From the amount of NaOH used with the pH-stat method we determined the extent of the in vitro lipolysis for each formulation. The gathered data indicates that release of naproxen from self (micro)emulsifying systems is not dependent on digestion type III lipid based drug delivery systems. With the help of foton correlation spectroscopy we showed that after dilution of self (micro)emulsifying systems in water, visual evaluation is not a sufficient method to determinate whether a microemulsion forms or not. In conclusion in vitro lipolysis showed that despite good solubility in the chosen pH a part of the incorporated naproxen always precipitates because loss of solubility capacity of the self (micro)emulsifying systems occurs. The loss of solubility capacity of the system is not dependent on digestion, procentage of the oil phase or the oil droplet size after dispersion of the formulation in the media. With addition of water the loss of solubility capacity is even more extensive. In future researches it would be reasonable to also include the gastric part of in vitro lipolysis and thus enhance the predictive power of the used pH-stat method. Also testing formulations with different amounts of incorporated naproxen would be a reasonable step.
Sekundarne ključne besede: Topnost;
Vrsta dela (COBISS): Magistrsko delo/naloga
Komentar na gradivo: Univ. Ljubljana, Fak. za farmacijo
Strani: VIII, 62 f.
ID: 12040845