Synthesis and characterization supramolecular hydrogels for the drug delivery and controlled relase

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