PERANAN KEGIATAN EKSTRAKURIKULER PASKIBRA DALAM MEMBENTUK CIVIC DISPOSITION PESERTA DIDIK (Studi Deskriptif terhadap Ekstrakurikuler Paskibra di SMKN 3 Sukatani Purwakarta)

Penelitian ini membahas peranan kegiatan ekstrakurikuler Paskibra dalam membentuk civic disposition peserta didik di SMKN 3 Sukatani Purwakarta. Tujuan penelitian ini untuk memperoleh gambaran civic disposition yang di bentuk dalam proses kegiatan ekstrakurikuler paskibra. Civic disposition sebagai komponen dasar ketiga civic education menunjuk pada karakter publik maupun privat. Penelitian ini menyoroti masalah-masalah yang di hadapi peserta didik sebagai warga negara yang kelak akan menjadi penerus bangsa namun tidak memiliki karakter-karakter kewarganegaraan pada dirinya. Hal tersebut terlihat dari maraknya tauran di kalangan peserta didik, peserta didik yang bolos sekolah, serta tidak memiliki kesopanan layaknya seorang warga negara yang baik. Ekstrakurikuler Paskibra sebagai sebuah organisasi di sekolah memiliki tujuan dalam pembentukan kepribadian pesrta didik. Oleh karena itu penelitian ini di lakukan untuk mengetahui peranan ekstrakurikuler paskibra dalam membentuk civic disposition peserta didik. Penelitian ini di lakukan dengan menggunakan metode deskriptif, dan pendekatan kualitatif. Pengumpulan data dengan observasi, wawancara, angket, dan dokumentasi. Temuan penelitian bahwa civic disposition yang di bentuk meliputi kesopanan, kepedulian, patuh terhadap hukum, berpikir kritis, kemauan untuk mendengar, bernegosiasi dan berkompromi, tanggung jawab moral, disiplin diri, menghargai harkat dan martabat manusia dari setiap individu terbentuk bentuk dari adanya program-prgram kerja ekstrakurikuler paskibra seperti program latihan rutin mingguan, program latihan pengibaran bendera di sekolah dan pelaksanaan upacara bendera, LKBB/LTUB, upacara pengibaran bendera pada tanggal 17 Agustus, Diklatsar, serta LATGAB (Latihan Gabungan). Kata kunci: Ekstrakurikuler Paskibra, civic dispositio

Chain length affects pancreatic lipase activity and the extent and pH–time profile of triglyceride lipolysis

Triglycerides (TG) are one of the most common excipients used in oral lipid-based formulations. The chain length of the TG plays an important role in the oral bioavailability of the co-administered drug. Fatty acid (FA) chain-length specificity of porcine pancreatic lipase was studied by means of an in vitro lipolysis model under bio-relevant conditions at pH 6.80. In order to determine the total extent of lipolysis, back-titration experiments at pH 11.50 were performed. Results suggest that there is a specific chain length range (C2–C8) for which pancreatic lipase shows higher activity. This specificity could result from a combination of physicochemical properties of TGs, 2-monoglycerides (2-MGs) and FAs, namely the droplet size of the TGs, the solubility of 2-MGs within mixed micelles, and the relative stability of the FAs as leaving groups in the hydrolysis reaction. During experimentation, it was evident that an optimisation of lipolysis conditions was needed for tighter control over pH levels so as to better mimic in vivo conditions. 1 M NaOH, 3.5 mL/min maximum dosing rate, and 3 μL/min minimum dosing rate were the optimised set of conditions that allowed better pH control, as well as the differentiation of the lipolysis of different lipid loads

Understanding the determinants of drug absorption following oral administration of lipid-based drug delivery systems

The current project has explored the determinants of drug absorption following oral administration of lipid-based drug delivery systems (LBDDS) and the role of intestinal digestive processes on formulation performance. Particular focus has been directed to the role of formulation excipients and drug loading on the generation and maintenance of drug supersaturation during LBDDS processing and the subsequent impact on drug bioavailability. The data show that initiation of digestion by pancreatic enzymes functions as an effective supersaturation trigger and that addition of polymeric precipitation inhibitors (PPI) may be utilised to stabilise supersaturation for longer periods and therefore to enhance absorption. Formulation performance was highly correlated with the maximum degree of supersaturation that the formulation generated on dispersion and digestion. In vitro, increasing drug dose initially increased drug thermodynamic activity in the aqueous colloidal phases formed by formulation digestion. Above a critical drug loading, however, supersaturation ‘pressure’ increased to a point above which nucleation and crystal growth dominated, resulting in drug precipitation. The utilisation of lower drug loads, higher surfactant levels, reduced cosolvent and the addition of PPI all enhanced formulation performance in vitro (i.e. supported ongoing solubilisation), however, subsequent studies showed that only in some cases was the addition of PPI able to support enhanced absorption in vivo. Consistent with the potential for increases in thermodynamic activity with increase in drug dose, non-linear increases in bioavailability were evident after administration of a series of LBDDS containing increasing quantities of drug to beagle dogs. In further alignment with the in vitro data, non-linear increases in bioavailability were also only evident up to a critical point, beyond which further increases in drug dose resulted in a reduction in bioavailability. The initial in vivo studies were therefore highly consistent with the in vitro supersaturation data. Replication of the in vivo study in a younger cohort of animals, however, was not able to reproduce the same trends and linear increases in exposure with dose were apparent in this animal cohort. Further studies failed to show a significant difference in hepatic function across the two cohorts, and instead suggested that age-related changes in GI solubilisation, potentially through increased bile salt secretion in the older cohort, may have led to better stabilisation of supersaturation and therefore increases in danazol absorption. Increases in the quantity of drug absorbed at higher doses in the older cohort may have also magnified differences in exposure due to greater saturation of first pass metabolism. The latter data led to a more detailed evaluation of the role of drug dose on the bioavailability of danazol from LBDDS. These studies were conducted in rats to allow more direct exploration of the role of first pass metabolism, and gastric and intestinal processing on danazol bioavailability. Surprisingly, danazol exposure in the rat following oral administration of danazol formulated in similar LBDDS as those used in the dog studies was low (< 12%), and incorporation of PPI had limited effect. In contrast, co-administration of an inhibitor of CYP450 enzymes resulted in a large increase in bioavailability suggesting that the major limitation to oral bioavailability was first pass metabolism. The applicability of previous in vitro models of lipid digestion to events in the rat was also examined, and a number of modifications to the model suggested. The data obtained indicate that in the rat, lipid digestion may be less efficient than it is in the dog (or human), and therefore that digestion-mediated reductions in solubilisation capacity are less important, that danazol absorption from LBDDS formulations is high (> 50%) and that the principle limitation to danazol bioavailability in the rat is first pass metabolism. In summary, this thesis contributes to a better understanding of the mechanisms by which LBDDS promote drug solubilisation and absorption and specifically to the influence of drug dose, animal model and the inclusion of polymeric precipitation inhibitors (PPI) on supersaturation generation and stabilisation

Understanding the determinants of drug absorption following oral administration of lipid-based drug delivery systems

The current project has explored the determinants of drug absorption following oral administration of lipid-based drug delivery systems (LBDDS) and the role of intestinal digestive processes on formulation performance. Particular focus has been directed to the role of formulation excipients and drug loading on the generation and maintenance of drug supersaturation during LBDDS processing and the subsequent impact on drug bioavailability. The data show that initiation of digestion by pancreatic enzymes functions as an effective supersaturation trigger and that addition of polymeric precipitation inhibitors (PPI) may be utilised to stabilise supersaturation for longer periods and therefore to enhance absorption. Formulation performance was highly correlated with the maximum degree of supersaturation that the formulation generated on dispersion and digestion. In vitro, increasing drug dose initially increased drug thermodynamic activity in the aqueous colloidal phases formed by formulation digestion. Above a critical drug loading, however, supersaturation ‘pressure’ increased to a point above which nucleation and crystal growth dominated, resulting in drug precipitation. The utilisation of lower drug loads, higher surfactant levels, reduced cosolvent and the addition of PPI all enhanced formulation performance in vitro (i.e. supported ongoing solubilisation), however, subsequent studies showed that only in some cases was the addition of PPI able to support enhanced absorption in vivo. Consistent with the potential for increases in thermodynamic activity with increase in drug dose, non-linear increases in bioavailability were evident after administration of a series of LBDDS containing increasing quantities of drug to beagle dogs. In further alignment with the in vitro data, non-linear increases in bioavailability were also only evident up to a critical point, beyond which further increases in drug dose resulted in a reduction in bioavailability. The initial in vivo studies were therefore highly consistent with the in vitro supersaturation data. Replication of the in vivo study in a younger cohort of animals, however, was not able to reproduce the same trends and linear increases in exposure with dose were apparent in this animal cohort. Further studies failed to show a significant difference in hepatic function across the two cohorts, and instead suggested that age-related changes in GI solubilisation, potentially through increased bile salt secretion in the older cohort, may have led to better stabilisation of supersaturation and therefore increases in danazol absorption. Increases in the quantity of drug absorbed at higher doses in the older cohort may have also magnified differences in exposure due to greater saturation of first pass metabolism. The latter data led to a more detailed evaluation of the role of drug dose on the bioavailability of danazol from LBDDS. These studies were conducted in rats to allow more direct exploration of the role of first pass metabolism, and gastric and intestinal processing on danazol bioavailability. Surprisingly, danazol exposure in the rat following oral administration of danazol formulated in similar LBDDS as those used in the dog studies was low (< 12%), and incorporation of PPI had limited effect. In contrast, co-administration of an inhibitor of CYP450 enzymes resulted in a large increase in bioavailability suggesting that the major limitation to oral bioavailability was first pass metabolism. The applicability of previous in vitro models of lipid digestion to events in the rat was also examined, and a number of modifications to the model suggested. The data obtained indicate that in the rat, lipid digestion may be less efficient than it is in the dog (or human), and therefore that digestion-mediated reductions in solubilisation capacity are less important, that danazol absorption from LBDDS formulations is high (> 50%) and that the principle limitation to danazol bioavailability in the rat is first pass metabolism. In summary, this thesis contributes to a better understanding of the mechanisms by which LBDDS promote drug solubilisation and absorption and specifically to the influence of drug dose, animal model and the inclusion of polymeric precipitation inhibitors (PPI) on supersaturation generation and stabilisation

Recombinant Spider Silk Hydrogels for Sustained Release of Biologicals

Therapeutic biologics (i.e., proteins) have been widely recognized for the treatment, prevention, and cure of a variety of human diseases and syndromes. However, design of novel protein-delivery systems to achieve a nontoxic, constant, and efficient delivery with minimal doses of therapeutic biologics is still challenging. Here, recombinant spider silk-based materials are employed as a delivery system for the administration of therapeutic biologicals. Hydrogels made of the recombinant spider silk protein eADF4­(C16) were used to encapsulate the model biologicals BSA, HRP, and LYS by direct loading or through diffusion, and their release was studied. Release of model biologicals from eADF4­(C16) hydrogels is in part dependent on the electrostatic interaction between the biological and the recombinant spider silk protein variant used. In addition, tailoring the pore sizes of eADF4­(C16) hydrogels strongly influenced the release kinetics. In a second approach, a particles-in-hydrogel system was used, showing a prolonged release in comparison with that of plain hydrogels (from days to week). The particle-enforced spider silk hydrogels are injectable and can be 3D printed. These initial studies indicate the potential of recombinant spider silk proteins to design novel injectable hydrogels that are suitable for delivering therapeutic biologics