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Razvoj oleogela za peroralno dostavo amlodipina in atorvastatina
Kerčmar, Tina (Avtor), Gašperlin, Mirjana (Mentor) Več o mentorju... Povezava se odpre v novem oknu, Bolko Seljak, Katarina (Komentor)

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Izvleček
Z vedno večjim številom slabo vodotopnih zdravilnih učinkovin (ZU) narašča tudi potreba po razvoju optimalnih dostavnih sistemov za izboljšanje topnost le teh. Med uspešnejše pristope spadajo lipidni dostavni sistemi, kamor uvrščamo tudi oleogele, poltrdne lipidne sisteme, sestavljene iz oleogelatorja in olja. Ker se le ti kot peroralni dostavni sistemi do sedaj še niso uporabljali, smo želeli v magistrski nalogi razviti oleogel, ki bi bil primeren za peroralno aplikacijo. Vanj bi vgradili vodotopno (amlodipin (AML)) in lipidotopno (atorvastatin (ATV)) ZU, ki se že uporabljata v kombinaciji. Z vgradnjo v oleogel želimo izboljšati topnost ATV ter doseči podaljšano sproščanje obeh ZU. Za nastanek oleogela smo uporabili indirektni pristop oleogelacije, kjer smo hidrofilni oleogelator najprej raztopili v vodi. Pri izbiri najbolj primernega oleogelatorja smo iskali takšnega, ki bi bil primeren za peroralno aplikacijo, hkrati pa bi bil topen v vodi, da bi v fazi raztapljanja vanj lahko vgradili AML. Izbrali smo hidroksipropilmetilcelulozo (HPMC). Nato smo s procesom liofilizacije odstranili vodo. Nastalo pogačo HPMC smo zdrobili in vanjo vgradili olje. Pri izbiri oljne faze smo iskali takšno, v kateri bo ATV topen, bo primerna za peroralno aplikacijo in bo hkrati pripomogla k primerni viskoznosti oleogela. V prvi fazi smo izbrali dve in sicer olivno olje ter Capmul MCM EP. Z obema smo pripravili oleogele z različnimi koncentracijami vodnih raztopin HPMC (1 %, 2 % ter 3 % (m/m)) in jih nato reološko ovrednotili. Pri tem smo iskali optimalno koncentracijo HPMC ter ugotavljali vpliv vrste olja ter dodatka površinsko aktivne snovi (PAS) na viskoznost oleogelov. Na podlagi reoloških testov in topnosti ATV smo se odločili za pripravo oleogelov s Capmul MCM EP ter 2 % (m/m) vodne raztopine HPMC. Pripravljene oleogele smo ovrednotili z in vitro testom sproščanja po USP 2. Preizkuse sproščanja smo izvedli za dve različni formulaciji oleogelov z vgrajenima ZU (z dodatkom Tween-a 20 (2,7% (m/m) in brez) ter za obe čisti ZU v kislem (s pH 1,2) in v bazičnem mediju (s pH 6,8). Z vgradnjo lipidotopnega ATV v formulacijo oleogela, smo povečali obseg sproščene ZU, hkrati pa smo dosegli podaljšano sproščanje obeh vgrajenih ZU. Ker z dodatkom PAS k formulaciji oleogela nismo uspeli povečati obsega sproščene ZU, smo poskušali še z dodatkom le te v sam medij za sproščanje. K kislemu mediju smo dodali 0,25, k bazičnemu pa 0,5 % (m/m) natrijevega dodecil sulfata. Z dodatkom PAS k kislemu mediju smo uspeli povečati le obseg sproščanja ATV, medtem ko se je obseg sproščanja AML v tem primeru zmanjšal. V bazičnem mediju se je ob dodatku PAS povečal le obseg sproščanja čistega AML, obseg sproščanja AML in ATV iz formulacij oleogelov pa se je zmanjšal. Obe formulaciji oleogelov smo ovrednotili tudi z metodo in vitro lipolize. Razgradnja lipidnih formulacij je bila na začetku zelo počasna. Nekoliko hitrejša je bila razgradnja oleogelov brez dodane PAS. Prav tako sta se obe ZU iz formulacij brez dodane PAS sproščali v večjem obsegu. Pri obeh formulacijah se je sprostilo več AML v primerjavi z ATV. V magistrski nalogi smo uspeli dokazati, da bi bili lahko HPMC oleogeli v prihodnosti primerni lipidni dostavni sistemi za sočasno dostavo različnih ZU v eni farmacevtski obliki s podaljšanim sproščanjem. Prav tako smo dokazali, da z vgradnjo lipidotopne ZU v oleogel izboljšamo topnost le te in posledično dosežemo večji delež sproščene ZU.

Jezik:Slovenski jezik
Ključne besede:oleogeli, HPMC, amlodipin, atorvastatin, in vitro lipoliza
Vrsta gradiva:Magistrsko delo/naloga (mb22)
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2019
Število ogledov:16
Število prenosov:7
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
 
Skupna ocena:(0 glasov)
Vaša ocena:Ocenjevanje je dovoljeno samo prijavljenim uporabnikom.
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:Development of oleogel for oral administration of amlodipine and atorvastatin
Izvleček:
With an increasing number of poor water-soluble active substances (AS) the need for developing optimal delivery systems for improving solubility is increasing. Among the most successful approaches are lipid delivery systems, including oleogels, semi-solid lipid systems consisting of oleogelator and oil. Since they have not yet been used as oral delivery systems, we wanted to develop an oleogel, which would be suitable for oral application. It would incorporate water-soluble amlodipine (AML) and lipid soluble atorvastatin (ATV), which are already used in combination. By incorporating it in an oleogel, we want to improve the solubility of ATV and achieve a prolonged release of both AS. For oleogel formation, an indirect oleogelation approach was used, where the hydrophilic oleogelator was first dissolved in water. In selecting the most suitable oleogelator, we looked for one which would be suitable for oral administration, and at the same time be water-soluble in order to be able to incorporate AML in the dissolution phase. Hydroxypropylmethylcellulose (HPMC) was selected. The water was then removed by the lyophilization process. The resulting HPMC cake was crushed, and then the liquid oil was incorporated into it. When choosing an oil phase, we looked for one in which ATV would be soluble, suitable for oral administration and would at the same time contribute to the appropriate viscosity of the oleogel. In the first phase we selected two, olive oil and Capmul MCM EP. With both we prepared oleogels with different concentrations of aqueous HPMC solutions (1 %, 2 % and 3 % (w/w)) and then rheologically evaluated them. We were searching for the optimum HPMC concentration and studying what kind of effect different types of oil and additions of a surfactant had on the viscosity of oleogels. Based on rheological tests and the solubility of ATV, we decided to prepare oleogels with Capmul MCM EP and 2 % (w/w) of HPMC aqueous solution. Prepared oleogels were evaluated by an in vitro release test according to USP 2. The release tests were carried out for two different formulations of oleogels with AS (with addition of Tween 20 (2,7% (m/m) and without) and for both pure AS in acidic (pH 1.2) and in a basic medium (pH 6.8). By incorporating a lipid soluble ATV into the oleogel formulation, we increased the extent of the released AS, while the prolonged release of both AS was achieved. With the addition of a surfactant to the oleogel formulation we were unable to improve the release of AS, so we tried to add it to the release medium itself. To the acid medium we added 0.25 and to the base medium 0.5 % (w/w) of sodium dodecyl sulfate. By adding a surfactant to the acidic medium, we managed to improve the ATV release, while the release of AML was diminished. In the basic medium with the addition of a surfactant, only the release of pure AML was improved, while the releases of AML and ATV from oleogel formulations, were diminished. Both formulations of oleogels were also evaluated using the in vitro lipolysis method. Decomposition of lipid formulations was in the beginning very slow. The degradation of oleogels without the addition of a surfactant was a bit faster. Likewise, both AS from the formulations without added PAS were released to a greater extent. In both formulations, more AML was released compared to ATV. In the master's thesis, we succeeded to prove that HPMC oleogels could be suitable lipid delivery systems in the future for the simultaneous delivery of different AS in one prolonged-release pharmaceutical form. It has also been shown that the incorporation of a lipid soluble AS into oleogel improves its solubility and consequently a greater proportion of the released AS was achieved.

Ključne besede:oleogels, HPMC, amlodipine, atorvastatin, in vitro lipolysis

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