Development of solid pharmaceutical forms based on gastroretentive floating carriers with encapsulated gentian root extract (Gentiana lutea L., Gentianaceae)

[J. R. Mudrić]

137 str.

Farmacija - Farmaceutska tehnologija / Pharmacy - Pharmaceutical technology

Koren lincure (Gentiana lutea L., Gentianaceae) se primenjuje kao tradicionalni biljni lek kod kratkotrajnog gubitka apetita i blagih dispeptičnih/gastrointestinalnih problema. Smatra se da su za povoljno delovanje ekstrakta korena lincure (EKL) lokalno na nivou gastrointestinalnog trakta i sistemski odgovorna bioaktivna jedinjenja iz grupa sekoiridoida, ksantona i iridoida. Genciopikrozid (GP), dominantno bioaktivno jedinjenje u EKL ima nisku biološku raspoloživost, kratko poluvreme eliminacije i neadekvatnu stabilnost pri pH vrednostima karakterističnim za donje delove gastrointestinalnog trakta. Stoga, cilj ovog istraživanja obuhvatao je optimizaciju ekstrakcije korena lincure i razvoj tableta i kapsula na bazi gastroretentivnih lipidnih nosača sa inkapsuliranim EKL. U okviru prve faze istraživanja pokazano je da se visok sadržaj GP, izogentizina i fenolnih jedinjenja iz korena lincure može ekstrahovati korišćenjem vodeno-etanolnog rastvora koncentracije 49 % (v/v) pri temperaturi od 65 °C, kada je odnos droga/rastvarač 1:40, a trajanje ekstrakcije iznosi 129 minuta. Veštačke neuronske mreže su bile pouzdanije i efikasnije u predviđanju i modelovanju ispitivanih odgovora u odnosu na metodologiju površine odgovora. U okviru druge faze istraživanja su dobijeni gastroretentivni nosači (črste lipidne mikročestice) adekvatnih karakteristika u koji je inkapsuliran EKL inovativnom metodom koja je podrazumevala liofilizaciju dvostrukih (voda/ulje/voda) emulzija sa čvrstim lipidom (Gelucire 43/01®). U okviru treće faze razvijene su tablete i kapsule na bazi gastroretentivnih nosača sa inkapsuliranim ekstraktom korena lincure primenom koncepta dizajna kvaliteta. Odabrane formulacije su okarakterisane visokim prinosom (> 92 %) i efikasnošću inkapsulacije (> 95 %), kao i zadovoljavajućim mehaničkim karakteristikama. Stabilnost ovih formulacija je bila adekvatna, s obzirom da su očuvani visok sadržaj genciopikrozida tokom 18 meseci i antioksidativna aktivnost tokom 12 meseci prirodnog starenja. Rezultati in vitro testa su pokazali da su formulisane tablete i kapsula flotirale duže od 6 sati. Pored toga, tablete su posedovale i mukoadhezivna svojstva, te se njihova gastroretencija zasnivala na dualnom mehanizmu. Rezultati ispitivanja in vitro brzine oslobađanja GP iz odabrane formulacije tableta pokazali su da je postignuto bifazno oslobađanje (29,04 % za 45 minuta i 67,95 % za 6 sati). U slučaju odabrane formulacije kapsula postignuto je produženo oslobađanje GP (30,56 % za 45 minuta i 100,57 % za 6 sati). Takođe, uočeno je da je u slučaju kapsula tokom ovog testa formirana disperzija nanoasocijata već nakon 15 minuta, pri čemu je indeks polidisperznosti bio manji od 0,250, što bi moglo da bude od značaja sa aspekta povećanja biološke raspoloživosti. Rezultati testa in vitro digestije su ukazali da gastrični i intestinalni enzimi mogu značajno uticati na oslobađanje GP iz formulisanih tableta i kapsula na bazi lipidnih gastroretentivnih nosača. Dobijeni rezultati ukazuju da je optimizovan proces ekstrakcije bioaktivnih jedinjenja iz korena lincure i da je razvijen postupak kojim je moguće dobiti tablete i kapsule na bazi gastroretentivnih nosača sa inkapsuliranim ekstraktom korena lincure.

Gentian (Gentiana lutea L., Gentianaceae) root is used as a traditional herbal medicinal product for temporary loss of appetite and mild dyspeptic/gastrointestinal disorders. Systematic and local gastrointestinal (GI) actions of gentian root extract are associated mainly with the presence of secoiridoid compounds, xanthones as well as iridoids. Gentiopicroside (GP), the dominant bioactive compound in gentian root extract, has a low bioavailability, short elimination half-life and inadequate stability at pH values in the lower part of the GI tract. Therefore, the aim of the research was the optimization of gentian root extraction and the development of tablets and capsules based on gastroretentive carriers with encapsulated gentian root extract. In the first phase of the research, it was shown that the high content of GP, isogentisine and phenolic compounds was extracted from gentian roots using a water-ethanol solution (49 %, v/v) at a temperature of 65 °C, when the drug/solvent ratio was 1: 40, and the duration of the extraction is 129 minutes. The prediction capacity of the model obtained by using artificial neural networks (ANN) was superior in comparison with models obtained by using response surface methodology (RSM). In the second phase of the research, a suitable gastroretentive carrier (solid lipid microparticles) with encapsulated gentian root extract was obtained by an innovative method that involved lyophilization of double (water/oil/water) emulsion with the solid lipid (Gelucire 43/01®). In the third phase, tablets and capsules based on gastroretentive carriers with encapsulated gentian root extract were developed using the quality by design (QbD) approach. Selected tablet and capsule formulations were characterized with high yield (> 92 %) and encapsulation efficiency (> 95 %) of GP, as well as appropriate mechanical properties. The results showed that the high gentiopicroside content (during 18 months) and antioxidant activity (during one year) were preserved, indicating that the stability of the selected formulations was high. The flotation of tablets and capsules lasted longer than 6 hours. Furthermore, tablets showed mucoadhesive properties, and thus gastroretention of tablets was based on a dual mechanism. Results of the in vitro release study have shown that the dissolution of GP from the selected tablet formulation was biphasic (29.04 % in 45 minutes; 67.95 % in 6 hours). Prolonged release of GP (30.56 % in 45 minutes; 100.57 % in 6 hours) from selected capsules formulation was achieved. It was shown that during this test dispersion of nanoassociates was formed after 15 minutes, while the polydispersity index was less than 0.250 in the case of capsules, that may be beneficial for a prospective increase of bioavailability. The results of the in vitro digestion test indicated that influence of gastric and intestinal enzymes on the release of GP could be significant in the case of formulated lipid-based gastroretentive tablets and capsules. The obtained results implied that extraction of bioactive compounds from gentian root was optimized. Also, capsules and tablets based on gastroretentive carriers with encapsulated gentian root extract were developed.

optimizacija ekstrakcije, veštačke neuronske mreže, metodologija površine odgovora, genciopikrozid, čvrste lipidne mikročestice, dvostruke emulzije, koncept dizajna kvaliteta, lipidni gastroretentivni nosači, tablete, tvrde kapsule, in vitro digestija

extraction optimization, artificial neural networks, response surface methodology, gentiopicroside, solid lipid microparticles, double emulsions, quality by design, lipid-based gastroretentive carriers, tablets, hard capsules, in vitro digestion

615.453:661.12(043.3)

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