Dermalna raspoloživost lekova sa antiinflamatornim delovanjem iz podloga sa šećernim emulgatorom : komparativna primena in vitro / in vivo karakterizacije

Abstract

Uvod Aktuelna farmakoekonomska situacija ima za posledicu čest nedostatak lekova u potrebnim dozama/jačinama, a za neke lekovite supstance nisu odabrani pogodni nosači. Značaj primene odgovarajućeg vehikuluma/podloge naročito je izražen u slučaju lekova koji se primenjuju na koži. Ova grupa lekova podložna je i uticajima koji dolaze iz kozmetičke industrije, a odnose se na zadovoljavajući izgled, teksturu i senzorne karakteristike nosača, što se direktno reflektuje u kojoj meri će se pacijenti pridržavati propisanoj terapiji. Nedostatak lekova na tržištu može se prevazići izradom lekova u apoteci čime se, čak i u zemljama sa veoma razvijenom farmaceutskom industrijom, ponovo potencira značaj znanja i veština farmaceuta u ex tempore izradi lekova. Iz tog razloga, prepoznata je potreba za inoviranjem sastava takvih lekova, pre svega uvođenjem formulacija sa savremenim farmaceutskim ekscipijensima. S druge strane, ostaje otvoreno pitanje procene dermalne raspoloživosti ovakvih lekova, s obzirom da regulatorno prihvaćene metode nisu univerzalno primenljive (poput ograničene primenljivosti vazokonstriktornog testa na lekove iz grupe kortikosteroida) ili se smatraju neracionalnim u fazi razvoja formulacije (podrazumevaju značajna ulaganja i veliki broj ispitanika). Cilj istraživanja Cilj istraživanja ove disertacije bio je razvoj formulacije, fizičkohemijska i biofarmaceutska karakterizacija emulzionih sistema (podloga) stabilizovanih prirodnim mešanim emulgatorom tipa alkil poliglukozida (APG), sastava cetostearil glukozid i cetostearil alkohol, koji je od skora sertificiran kao farmaceutski ekscipijens. Razvijene formulacije poslužile su kao modeli za razvoj i optimizaciju protokola metode sa adhezivnim trakama (tape stripping metode) kao perspektivne in vivo tehnike za ispitivanje penetracije lekova kroz kožu, uz sprovođenje korelacije datih rezultata sa onim dobijenim prihvaćenim in vitro i in vivo metodama kroz nekoliko studija slučaja (ketoprofen, diklofenak dietilamin i hidrokortizon kao model lekovite supstance sa antiinflamatornim delovanjem, različitih fizičkohemijskih karakteristika)...

Introduction Current pharmacoeconomic situation has resulted in a frequent shortage in certain drug doses/strengths or suitable dosage forms. The importance of the appropriate choice of the vehicle/base is especially emphasized in case of topical drugs. These are prone to influences stemming from the cosmetic industry, relating to satisfactory appearance, texture and sensorial properties of the carrier, which directly reflects patient adherence. Such drug deficiencies may be overcome through compounding practice in pharmacies which is, even in countries with highly developed pharmaceutical industry, reevaluating the importance of pharmacist’s knowledge and skills in extemporaneous drug preparation. Therefore, there is a need to innovate the composition of such drugs, particularly via introduction of formulations based on novel pharmaceutical excipients. On the other hand, the issue of dermal bioavailability assessment of these drugs remains, considering the regulatory accepted methods are not universally applicable (use of the skin blanching assay is limited to corticosteroid drugs) or their use is irrational in the formulation development phase (require substantial funds and a large number of volunteers). Aim The aim of this work was the development, physicochemical and biopharmaceutical characterization of emulsion systems (bases) stabilized with naturalorigin mixed alkyl polyglucoside (APG) emulsifier comprising cetostearyl glucoside and cetostearyl alcohol, recently given a status of pharmaceutical excipient. These formulations served as models for development and optimization of the tape stripping method protocol that could serve as a prospective in vivo technique for skin penetration studies, along with correlation of the obtained results with those provided through the acknowledged in vitro and in vivo methods via several case-studies (ketoprofen, diclofenac diethylamine and hydrocortisone as anti-inflammatory model drugs with diverse physicochemical characteristics). Methods Experimental work was organized in three phases: 1) With the aim of assessing physical stability and colloidal structure of the model bases stabilized with the sugar emulsifier, a comprehensive characterization was performed using polarization microscopy, pH and conductivity measurements, saturation concentration of model drugs, continual rheology, differential scanning calorimetry, thermogravimetric analysis, in vitro screening of model drugs liberation profiles, assessing the safety profiles of model bases: in vitro – citotoxicity assay and in vivo – non-invasive skin bioengineering techniques...