University of Rijeka. Department of Biotechnology.
Abstract
Novi sustavi prijenosa i kontrolirane isporuke lijekova se razvijaju s ciljem
poboljšavanja učinkovitosti lijekova i stavljanja pod nadzor postojećih
nuspojava. Sintetizirana su dva tripeptidna gelatora 1. organogelator Z-LPhe-
L-Phe-L-AlaNH2 i 2. hidrogelator Ac-L-Phe-L-Phe-L-AlaNH2 s ciljem
studiranja njihovih potencijala za skladištenje i kontrolirano otpuštanje
nesteroidnih antireumatika (NSAR). Nakon dugotrajne oralne uporabe NSAR,
poput ibuprofena i acetilsalicilne kiseline mogu se pojaviti ozbiljne nuspojave
u gastrointestinalnom traktu. Transdermalna kontrolirana isporuka lijekova
pomoću gelova predstavlja alternativnu metodu primjene lijeka pomoću koje
se zaobilaze nepoželjni učinci.
Za tekuću komponentu organogela odabrano je sojino ulje, a za tekuću
komponentu hidrogela vodeni fosfatni pufer. U tripeptidne gelove su
ugrađeni ibuprofen i acetilsalicilna kiselina, te se pratilo otpuštanje lijekova
ovisno o vremenu u fosfatni pufer pomoću UV-Vis spektroskopije.
Nadalje, proučavao se utjecaj pH prihvatnog medija na otpuštanje
ibuprofena iz organogela. Otpuštanje je mjereno pomoću dva različita
sustava. Kumulativno, uzimanjem uzorka kroz određen vremenski period i
određivanjem koncentracije lijeka pomoću UV Vis spektroskopije (u kiveti) ili
direktno optičkom sondom. Uspoređivani su rezultati dobiveni različitim
metodama mjerenja. Mehanokemijskom reakcijom hidrogelatora i ibuprofena
u kugličnom mlinu ispitivao se potencijal hidrogelatora za poboljšanje
topljivosti hidrofobnog lijeka u vodenoj otopini.
Rezultati pokazuju da su studirani gelatori veoma dobri mediji za skladištenje
navedenih lijekova. pH prihvatnog medija ima veliki utjecaj na otpuštanje
molekula ibuprofena. Alkalni medij je pogodniji za otpuštanje od kiselog. UVVis
spektrofotometrijska sonda je pogodna za praćenje otpuštanja u
stvarnom vremenu, no zbog zasićenja prihvatnog pufera ne postižu se visoke
stope otpuštanja. Kumulativnom metodom, premještanjem pola volumena
prihvatnog medija (0,1M fosfatni pufer, pH 7,4) u kivetu i dodatkom jednake
količine nove otopine prihvatnog medija, ne postiže se zasićenje prihvatne
otopine te su dobivene više stope otpuštanja. Mehanokemijskim miješanjem
hidrogelatora i lipofilnog lijeka, omogućeno je uvođenje lipofilnog lijeka u
vodenu fazu i olakšano samoudruživanje u hidrogelu.New controlled drug delivery systems are being developed to improve the
therapeutic efficacy of drugs and to keep under control existing side effects.
Two tripeptide gelators were synthesized 1. organogelator Z-L-Phe-L-Phe-LAlaNH2
and 2. hydrogelator Ac-L-Phe-L-Phe-L-AlaNH2 with the aim of
studying their potential to develop drug depot systems and controlled release
systems of nonsteroidal antireumatics (NSAR). After long-term oral
administration of NSAR, such as ibuprofen and acetylsalicylic acid, serious
side effects may occur in the gastrointestinal tract. Transdermal controlled
drug delivery by gels represents an alternative method of drug
administration by which unwanted effects are avoided.
For the liquid component of organogel a soybean oil was selected, and
phosphate buffer was selected for the hydrogel liquid component. Ibuprofen
and acetylsalicylic acid were loaded in the tripeptide gels and the release
behavior of drugs in phosphate buffer was investigated by using UV-Vis
spectroscopy. Further, the influence of the pH values of the accepting media
on the release behavior of ibuprofen from organogel was investigated.
Release behavior was measured by two different systems. Cumulative,
taking the sample through a certain period of time and determining drug
concentration using UV Vis spectroscopy (in cuvette cell) or directly using
optic probe. The results obtained by different measurement methods were
compared. The hydrogelator potential during the mechanochemical reaction
of hydrogelator and ibuprofen in the mill was studied in order to improve the
solubility of the hydrophobic drug in aqueous solution.
The results indicated that studied gelators are very good media for drug
depot systems. pH of the accepting media has a major impact on the release
behavior of ibuprofen molecules. Alkaline media is more suitable for release.
The UV-Vis spectrophotometric probe is suitable for real-time drug delivery
monitoring but due to saturation of the accepting buffer, high release rates
are not achieved. Cumulative method, by transferring the half volume of the
accepting media (0.1M phosphate buffer, pH 7.4) to a cuvette and adding
equal amounts of a new solution of the accepting media, the saturation of
the accepting solution is not achieved and higher release rates are obtained.
By mechanochemical mixing of hydrogelator and lipophilic drug, it is possible
to introduce a lipophilic drug into the aqueous phase and facilitate self
assembly in the hydrogel