Development and study of reactive hot-melt extruded granules based on interpolymer combinations of Eudragit® copolymers for indomethacin delivery

Introduction. As a result of the study, 4 types of pellets with indomethacin based on Eudragit® copolymers of EPO and L100-55 grades, their physical mixture (PM) being similar in composition to the synthesised interpolyelectrolyte complex (IPEC) EPO/L100-55 – 1.95 : 1 (mole/mole) were obtained using reactive HME method. The development of thermal extrusion conditions using the modulated DSC method showed the applicability of this approach for preliminary modelling of the occurring processes. Characterised using thermal and spectral analysis methods, the obtained granules include indomethacin in the amorphous form formed from the original γ-form as a result of reactive thermal extrusion of the samples. The study of indomethacin (IND) release from the obtained granules in modelling the progression through the GI tract under mimicking conditions has shown the prospectivity of all types of the developed systems for the creation of constructs with targeted release of IND into model buffer media corresponding to: the fasted or feed state simulated gastric fluids, as well as the fasted state simulated intestinal fluid correspondent to the upper parts of the small intestine (EPO and PM EPO/L100-55), the cecum and right half of the colon (L100-55) and the proximal colon (IPEC). Recently, due to the pronounced plasticity resulting from the low glass transition temperature (T_g), many of the Eudragit® copolymer types (E, RL, RS, FS, NE, NM) have found increasing application in the intensively developing field of pharmaceutical technology – thermo extrusion granulation, called pharmaceutical melt extrusion (PME). Despite the progressive number of studies on the use of the PME method, there is an undeserved lack of research on the feasibility of polycomplex systems based on copolymers of the Eudragit® family. At the same time, it is known that combining oppositely charged pairs of thermoplastic Eudragits using PME technology allows the development of oral delivery systems with adjustable permeability of polymer links in the structure of pellet coatings due to the formation of interpolymer-bonded chain sequences of reacting macromolecules during drug release in gastrointestinal (GI) simulating media with progressive increase of pH values from the stomach to the colon. Unfortunately, although there are many examples in the literature on the application of PME, including reactive HME, to produce drug delivery systems based on Eudragit® EPO copolymer (due to its low T_g value), there are practically no studies in which an interpolyelectrolyte complex (IPEC) involving chemically complementary pairs of Eudragits is used as a thermoextruded carrier.

Aim. Development and study of hot-melt extruded granules based on interpolymer anionic-cationic combinations of Eudragit® copolymers for indomethacin delivery.

Materials and methods. Thermal extrusion conditions were selected and refined using rheometry, high-temperature microscopy and modulated differential scanning calorimetry (mDSC) to simulate and reproduce the thermal extrusion conditions. The pellets obtained on a single screw extruder were characterised using mDSC, thermogravimetric analysis (TGA), IR and NIR spectroscopy. The study of indomethacin release from granules under mimicking GI tract conditions was carried out by method 2 – ‘rotating paddle’ according to GPh. RF.

Results and discussion. Hot melt extruded pellets were obtained from the compositions of binary mixtures (EPO-IND, L100-55-IND, IPEC (EPO-L100-55)-IND), at which they had the maximum value of glass transition temperature – T_gmax. For EPO-IND it was 30/70, and for IPEC (EPO-L100-55)-IND and L100-55-IND – 40/60. According to the results of IR spectroscopy, the samples of thermoextrudates containing EPO in their composition, namely EPO-IND, EPO-L100-55-IND PM and IPEC-IND, are characterized by a shift of the IND band from 1689 to 1678 cm^–1, indicating the transition of the initial crystalline form of IND into amorphous form as a result of physicochemical interaction of EPO with IND, which is also confirmed by the results of thermal analysis. In addition, in all thermoextruded samples containing EPO, IR spectra are characterized by the appearance of a band at 1570 cm^–1, confirming the formation of ionic bonds due to the interaction of ionized carboxyl groups of IND and L100-55 with dimethylamino groups of EPO. NIR spectroscopy confirmed the presence of both amorphous and crystalline forms of the γ-form of IND in the structure of the IPEC (EPO-L100-55)-IND-based extrudate, which is apparently due to the partial transition of the metastable amorphous form to the crystalline form over time. The release of IND from EPO-IND extrudates at pH 1.2 is very rapid, reaching 100 % within half an hour. The character of IND release from extrudates with L100-55-IND is a delayed-sustained profile, the control of the release rate being determined by the properties of the forming copolymer (L100-55). The release of IND from EPO-L100-55-IND PM-based extrudates, as in the case of EPO-IND extrudates, starts at pH 1.2, but provides only a negligible yield of IND release (about 30 %). Due to the content of acid-resistant L100-55 in the PM composition, the rapid IND release shifts from acidic environment (pH = 1.2) to slightly acidic (pH = 5.8) providing 100 % IND release by 2.5 hours of the experiment. The release of IND from polycomplex extrudates (EPO-L100-55)-IND is characterized by a pulse release profile.

Conclusion. As a result of the study, 4 types of pellets with indomethacin based on Eudragit® copolymers of EPO and L100-55 grades, IPEC with their participation and a physical mixture similar to it were obtained by reactive thermal extrusion. The resulting granules were characterised using thermal and spectral techniques. The study of indomethacin release from the obtained granules showed the promising application of the developed systems for targeted delivery to different parts of the GI tract, from the stomach to the proximal colon.

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