20.500.12556/RUL-120987
Vpliv pogojev mletja ter različnih stabilizatorjev na učinkovitost mletja ter kemijsko stabilnost atorvastatina
[diplomska naloga]
The effect of milling conditions and various stabilizers on milling efficiency and chemical stability of atorvastatin
V zadnjih letih je velik del raziskav na področju novih zdravil usmerjen v izboljšanje topnosti slabo topnih učinkovin v vodnem mediju. Tvorba nanosuspenzij predstavlja enega izmed pristopov za povečevanje topnosti in s tem biološke uporabnosti teţko topnih učinkovin. Nanosuspenzije so koloidno disperzni sistemi delcev učinkovine nanometrskih velikosti v vodnem mediju. Obstajata dva glavna pristopa izdelave nanosuspenzij. Mokro mletje spada v »top down« pristop, za katerega je značilno, da večje delce zmanjšamo na delce nanometrskih velikosti. Mletje zaradi sil, ki vplivajo na zmanjševanje delcev, vpliva tudi na kemijsko in fizikalno nestabilnost učinkovine. Nanosuspenzijo teţko topne učinkovine smo izdelali z mokrim mletjem v planetarnem krogličnem mlinu. Kot učinkovino smo uporabili kalcijev atorvastatinat (v nadaljevanju atorvastatin), ki se uporablja za zdravljenje hiperlipidemij in je selektivni, kompetitivni inhibitor HMG-CoA reduktaze. V prvem delu smo mleli učinkovino z različnimi polimeri (hidroksipropilmetilceluloza, kopovidon, poloksamer 188 in polisorbat 80). Med mletjem pride zaradi trkov med kroglicami in kroglicami ter steno posode do povišanja temperature in nastanka znanih ter neznanih nečistot atorvastatina. Te smo analizirali z reverzno fazno tekočinsko kromatografijo visoke ločljivosti. Nanosuspenzije s kopovidonom in poloksamerom 188 po lastnostih (velikost delcev, količina nastalih nečistot in moţnost vgradnje v farmacevtsko obliko) najbolj ustrezajo, zato smo jih uporabili v nadaljnjih testih. Pri vzorcih nanosuspenzij z dodatkom antioksidantov (butilhidroksitoluen, roţmarinska kislina) oziroma pripravljenih v inertnih pogojih, smo opazili najmanjši nastanek nečistot. S preliminarnimi stresnimi in pospešenimi testi stabilnosti trdnih (posušenih v vakuumskem sušilniku) in tekočih vzorcev nanosuspenzij s kopovidonom in poloksamerom 188 z dodatkom antioksidantov smo ugotovili, da je prisotnost medija (vode) ključni dejavnik za kemijsko nestabilnost atorvastatina oziroma njegov oksidacijski razpad. Suhi vzorci so stabilnejši. Opisani pristop predstavlja dobro moţnost pri razvoju trdnih farmacevtskih oblik s slabo vodotopnimi zdravilnimi učinkovinami. Kljub temu se je potrebno zavedati, da s tem pristopom in izbranimi pomoţnimi snovmi ne moremo izboljšati topnostnih karakteristik vsem slabo topnim zdravilnim učinkovinam.
In recent years, numbers of researches in the field of new active pharmaceutical ingredients (API) are focused on creating new formulations with improvement on low water solubility. One of the approaches for enhancing low water solubility and low bioavailability is the formation of nanosuspensions. The nanosuspensions can be defined as colloidal dispersions of nano-sized drug particles in water. There are two main approaches to obtain them. Wet milling is a »top down« technique for reducing drug particles to the sub-micron size. During the milling process forces also have an impact on the chemical and physical stability of drugs. We made nanosuspensions with the wet ball milling in a planetary ball mill. Atorvastatine calcium (AT) was used as an active pharmaceutical ingredient, which is a selective, competitive inhibitor of HMG-CoA reductase (statin) and it is used in a treatment of the hyperlipidemia. In the first part of our research atorvastatine was milled with different polymers (hydroxypropyle methylecellulose, copovidone, poloxamer 188 and polysorbate 80). During the milling process, because of the friction between the balls, temperature increased in the milling chamber, which led to chemical instability of the atorvastatin. We analyzed this with the reverse phase chromatography. Since nanosuspensions with copovidone and poloxamer 188 had better properties (size, quantity of impurities and the possibility to produce pharmaceutical formulation) they were used in further tests. In the samples with added antioxidants (butylhydroxytoluene, rosmarinic acid) and samples prepared in the inert conditions were the least impurities we observed. During the stability testing of solid and liquid samples of nanosuspensions with copovidone and poloxamer 188 with the addition of antioxidants, we established that medium (water) is the main cause of the atorvastatin’s chemical instability. Solid samples were more stable. Our research represents a promising direction in the development of solid pharmaceutical formulations of drugs with low water solubility. Despite that, we have to be aware that with selected approach and excipients, we can not improve solubility of all poorly soluble drugs.
nanosuspenzije
izdelava nanosuspenzij
stabilnost nanosuspenzij
kalcijev atorvastatin
mletje atorvastatina
topnost učinkovin
true
false
false
[M. Glušič]
Slovenski jezik
Angleški jezik
Diplomsko delo
2020-09-28 12:56:42
2020-09-28 12:56:42
2022-09-01 04:01:00
0000-00-00 00:00:00
2015
0
Ljubljana
2015
Ljubljana
VI, 79 f.
0000-00-00
NiDoloceno
NiDoloceno
NiDoloceno
0000-00-00
0000-00-00
0000-00-00
54.055:615:661.12(043.2)
3805809
UNI_Glusic_Mateja_2015.pdf
UNI_Glusic_Mateja_2015.pdf
1
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f14363726840400e3c33332d1d3745ace4ab694ec4def5b09f39758de8ebea9a
334e97c6-a1ba-11eb-a523-00155dcfd717
https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=135823
Fakulteta za farmacijo
0
0
0