Sebuah Studi Pengembangan Bentuk Sediaan Obat : Olsalazine Sebagai Colonic Drug Targeting

Penyakit inflamasi usus (IBD) merupakan kondisi yang mempengaruhi sistem pencernaan dan dapat menyebabkan gejala seperti diare, sakit perut, dan penurunan berat badan. IBD terdiri dari dua jenis yaitu colitis ulserativa dan penyakit Crohn. Kedua jenis IBD disebabkan oleh respon sistem kekebalan tubuh yang tidak tepat terhadap bakteri usus normal dan kemudian menyebabkan peradangan pada usus. Pengobatan IBD tergantung pada tingkat keparahan dan jenis penyakit. Olsalazine, suatu prodrug salisilat, telah digunakan secara luas untuk mengobati colitis ulseratif dan ditemukan memiliki efek samping yang lebih sedikit dibandingkan dengan sulfasalazine, obat yang serupa. olsalazine diserap dengan cepat dalam usus halus dan kemudian diubah menjadi dua molekul asam salisilat. Namun, hanya sebagian kecil dari asam salisilat ini yang mencapai usus besar, di mana colitis ulseratif paling sering terjadi. Salah satu pendekatan yang diusulkan adalah dengan menggunakan olsalazine sebagai colonic drug targeting. Pada pendekatan ini, olsalazine dimodifikasi dengan pengikat yang spesifik untuk sel epitel usus besar, sehingga obat tersebut dapat diantarkan langsung ke daerah yang terkena penyakit. Dari absorpsi dan ekskresi 5-ASA terjadi sangat cepat dan intensif sehingga didapatkan total 5-ASA yang tinggi di urin. Penggunaan 5-ASA (tanpa modifikasi senyawa atau formula) sebagai terapi IBD tidak akan efektif karena jumlah obat yang akan sampai ke kolon akan kecil.  Sedangkan penggunaan Olsalazine dengan diformulasi menjadi tablet konvensional efektif sebagai terapi IBD karena olsalazine sangat sedikit diabsorpsi di lambung dan usus halus.  Kajian selanjutnya tentang olsalazine sebagai colonic drug targeting dapat membuka pintu bagi pengembangan obat yang lebih efektif dan efisien dalam pengobatan IBD

Calcium Coordination Solids for pH-Triggered Release of Olsalazine

Calcium coordination solids were synthesized and evaluated for delivery of olsalazine (H_4olz), an anti-inflammatory compound used for treatment of ulcerative colitis. The materials include one-dimensional Ca(H_2olz)⋅4 H_2O chains, two-dimensional Ca(H_2olz)⋅2 H_2O sheets, and a three-dimensional metal-organic framework Ca(H_2olz)⋅2DMF (DMF=N,N-dimethylformamide). The framework undergoes structural changes in response to solvent, forming a dense Ca(H_2olz) phase when exposed to aqueous HCl. The compounds Ca(H_2olz)⋅x H_2O (x=0, 2, 4) were each pressed into pellets and exposed to simulated gastrointestinal fluids to mimic the passage of a pill from the acidic stomach to the pH-neutral intestines. All three calcium materials exhibited a delayed release of olsalazine relative to Na_2(H_2olz), the commercial formulation, illustrating how formulation of a drug within an extended coordination solid can serve to tune its solubility and performance

Double Drug Delivery Using Capped Mesoporous Silica Microparticles for the Effective Treatment of Inflammatory Bowel Disease

[EN] Silica mesoporous microparticles loaded with both rhodamine B fluorophore (S1) or hydrocortisone (S2), and capped with an olsalazine derivative, are prepared and fully characterized. Suspensions of Si and S2 in water at an acidic and a neutral pH show negligible dye/drug release, yet a notable delivery took place when the reducing agent sodium dithionite is added because of hydrolysis of an azo bond in the capping ensemble. Additionally, olsalazine fragmentation induced 5-aminosalicylic acid (5-ASA) release. In vitro digestion models show that S1 and S2 solids are suitable systems to specifically release a pharmaceutical agent in the colon. In vivo pharmacokinetic studies in rats show a preferential rhodamine B release from Si in the colon. Moreover, a model of ulcerative colitis is induced in rats by oral administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) solutions, which was also used to prove the efficacy of S2 for colitis treatment. The specific delivery of hydrocortisone and 5-ASA from S2 material to the colon tissue in injured rats markedly lowers the colon/body weight ratio and the clinical activity score. Histological studies showed a remarkable reduction in inflammation, as well as an intensive regeneration of the affected tissues.We thank the Generalitat Valenciana (Project PROMETE02018/024) and the Spanish Government (Projects AGL2015-70235-C2-2-R and MAT2015-64139-C4-1-R (MINECO/FEDER)) for support. A.H.T. thanks the Spanish MEC for his FPU fellowship. The authors also thank the support of the Electron Microscopy Service at the UPV. The SCSIE (of the Universitat de Valencia) is also gratefully acknowledged for all the equipment used. NMR spectra were measured at the U26 facility of ICTS "NANBIOSIS" at the Universitat de Valencia.Hernández Teruel, A.; Pérez-Esteve, É.; González-Álvarez, I.; González-Álvarez, M.; Costero Nieto, AM.; Ferri, D.; Gaviña, P.... (2019). Double Drug Delivery Using Capped Mesoporous Silica Microparticles for the Effective Treatment of Inflammatory Bowel Disease. Molecular Pharmaceutics. 16(6):2418-2429. https://doi.org/10.1021/acs.molpharmaceut.9b00041S24182429166Baumgart, D. C., & Sandborn, W. J. (2012). Crohn’s disease. The Lancet, 380(9853), 1590-1605. doi:10.1016/s0140-6736(12)60026-9Pierik, M., Yang, H., Barmada, M. M., Cavanaugh, J. A., Annese, V., Brant, S. R., … Vlietinck, R. (2005). The IBD International Genetics Consortium Provides Further Evidence for Linkage to IBD4 and Shows Gene-Environment Interaction. Inflammatory Bowel Diseases, 11(1), 1-7. doi:10.1097/00054725-200501000-00001Loftus, E. V. (2004). Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology, 126(6), 1504-1517. doi:10.1053/j.gastro.2004.01.063Lupp, C., Robertson, M. L., Wickham, M. E., Sekirov, I., Champion, O. L., Gaynor, E. C., & Finlay, B. B. (2007). Host-Mediated Inflammation Disrupts the Intestinal Microbiota and Promotes the Overgrowth of Enterobacteriaceae. Cell Host & Microbe, 2(2), 119-129. doi:10.1016/j.chom.2007.06.010Takaishi, H., Matsuki, T., Nakazawa, A., Takada, T., Kado, S., Asahara, T., … Hibi, T. (2008). Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. International Journal of Medical Microbiology, 298(5-6), 463-472. doi:10.1016/j.ijmm.2007.07.016Sokol, H., Seksik, P., Furet, J. P., Firmesse, O., Nion-Larmurier, I., Beaugerie, L., … Doré, J. (2009). Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflammatory Bowel Diseases, 15(8), 1183-1189. doi:10.1002/ibd.20903Friswell, M., Campbell, B., & Rhodes, J. (2010). The Role of Bacteria in the Pathogenesis of Inflammatory Bowel Disease. Gut and Liver, 4(3), 295-306. doi:10.5009/gnl.2010.4.3.295Qiu, X., Zhang, M., Yang, X., Hong, N., & Yu, C. (2013). Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. Journal of Crohn’s and Colitis, 7(11), e558-e568. doi:10.1016/j.crohns.2013.04.002Yu, C. G., & Huang, Q. (2013). Recent progress on the role of gut microbiota in the pathogenesis of inflammatory bowel disease. Journal of Digestive Diseases, 14(10), 513-517. doi:10.1111/1751-2980.12087Kappelman, M. D., Rifas–Shiman, S. L., Porter, C. Q., Ollendorf, D. A., Sandler, R. S., Galanko, J. A., & Finkelstein, J. A. (2008). Direct Health Care Costs of Crohn’s Disease and Ulcerative Colitis in US Children and Adults. Gastroenterology, 135(6), 1907-1913. doi:10.1053/j.gastro.2008.09.012Kappelman, M. D., Rifas–Shiman, S. L., Porter, C. Q., Ollendorf, D. A., Sandler, R. S., Galanko, J. A., & Finkelstein, J. A. (2008). Direct Health Care Costs of Crohn’s Disease and Ulcerative Colitis in US Children and Adults. Gastroenterology, 135(6), 1907-1913. doi:10.1053/j.gastro.2008.09.012Rocchi, A., Benchimol, E. I., Bernstein, C. N., Bitton, A., Feagan, B., Panaccione, R., … Ghosh, S. (2012). Inflammatory Bowel Disease: A Canadian Burden of Illness Review. Canadian Journal of Gastroenterology, 26(11), 811-817. doi:10.1155/2012/984575Burisch, J., Jess, T., Martinato, M., & Lakatos, P. L. (2013). The burden of inflammatory bowel disease in Europe. Journal of Crohn’s and Colitis, 7(4), 322-337. doi:10.1016/j.crohns.2013.01.010Marchetti, M., & Liberato, N. L. (2014). Biological therapies in Crohn’s disease: are they cost-effective? A critical appraisal of model-based analyses. Expert Review of Pharmacoeconomics & Outcomes Research, 14(6), 815-824. doi:10.1586/14737167.2014.957682Park, S. J. (2014). Clinical characteristics and treatment of inflammatory bowel disease: A comparison of Eastern and Western perspectives. World Journal of Gastroenterology, 20(33), 11525. doi:10.3748/wjg.v20.i33.11525Ng, S. C., Tang, W., Ching, J. Y., Wong, M., Chow, C. M., Hui, A. J., … Chan, F. K. L. (2013). Incidence and Phenotype of Inflammatory Bowel Disease Based on Results From the Asia-Pacific Crohn’s and Colitis Epidemiology Study. Gastroenterology, 145(1), 158-165.e2. doi:10.1053/j.gastro.2013.04.007Sood, A. (2003). Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut, 52(11), 1587-1590. doi:10.1136/gut.52.11.1587Tozun, N., Atug, O., Imeryuz, N., Hamzaoglu, H. O., Tiftikci, A., Parlak, E., … Yurdaydin, C. (2009). Clinical Characteristics of Inflammatory Bowel Disease in Turkey. Journal of Clinical Gastroenterology, 43(1), 51-57. doi:10.1097/mcg.0b013e3181574636Victoria, C. R., Sassak, L. Y., & Nunes, H. R. de C. (2009). Incidence and prevalence rates of inflammatory bowel diseases, in midwestern of São Paulo State, Brazil. Arquivos de Gastroenterologia, 46(1), 20-25. doi:10.1590/s0004-28032009000100009Fakhoury, M., Al-Salami, H., Negrulj, R., & Mooranian, A. (2014). Inflammatory bowel disease: clinical aspects and treatments. Journal of Inflammation Research, 113. doi:10.2147/jir.s65979Mowat, C., Cole, A., Windsor, A., Ahmad, T., Arnott, I., … Driscoll, R. (2011). Guidelines for the management of inflammatory bowel disease in adults. Gut, 60(5), 571-607. doi:10.1136/gut.2010.224154Di Sario, A., Bendia, E., Schiadà, L., Sassaroli, P., & Benedetti, A. (2016). Biologic Drugs in Crohn’;s Disease and Ulcerative Colitis: Safety Profile. Current Drug Safety, 11(1), 55-61. doi:10.2174/157488631101160212171757Collnot, E.-M., Ali, H., & Lehr, C.-M. (2012). Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. Journal of Controlled Release, 161(2), 235-246. doi:10.1016/j.jconrel.2012.01.028Lamprecht, A., Rodero Torres, H., Schäfer, U., & Lehr, C.-M. (2000). Biodegradable microparticles as a two-drug controlled release formulation: a potential treatment of inflammatory bowel disease. Journal of Controlled Release, 69(3), 445-454. doi:10.1016/s0168-3659(00)00331-xTeruel, A., Coll, C., Costero, A., Ferri, D., Parra, M., Gaviña, P., … Sancenón, F. (2018). Functional Magnetic Mesoporous Silica Microparticles Capped with an Azo-Derivative: A Promising Colon Drug Delivery Device. Molecules, 23(2), 375. doi:10.3390/molecules23020375Teruel, A. H., Pérez-Esteve, É., González-Álvarez, I., González-Álvarez, M., Costero, A. M., Ferri, D., … Sancenón, F. (2018). Smart gated magnetic silica mesoporous particles for targeted colon drug delivery: New approaches for inflammatory bowel diseases treatment. Journal of Controlled Release, 281, 58-69. doi:10.1016/j.jconrel.2018.05.007Sancenón, F., Pascual, L., Oroval, M., Aznar, E., & Martínez-Máñez, R. (2015). Gated Silica Mesoporous Materials in Sensing Applications. ChemistryOpen, 4(4), 418-437. doi:10.1002/open.201500053Aznar, E., Oroval, M., Pascual, L., Murguía, J. R., Martínez-Máñez, R., & Sancenón, F. (2016). Gated Materials for On-Command Release of Guest Molecules. Chemical Reviews, 116(2), 561-718. doi:10.1021/acs.chemrev.5b00456Llopis-Lorente, A., Díez, P., Sánchez, A., Marcos, M. D., Sancenón, F., Martínez-Ruiz, P., … Martínez-Máñez, R. (2017). Interactive models of communication at the nanoscale using nanoparticles that talk to one another. Nature Communications, 8(1). doi:10.1038/ncomms15511De la Torre, C., Domínguez-Berrocal, L., Murguía, J. R., Marcos, M. D., Martínez-Máñez, R., Bravo, J., & Sancenón, F. (2018). ϵ -Polylysine-Capped Mesoporous Silica Nanoparticles as Carrier of the C 9h Peptide to Induce Apoptosis in Cancer Cells. Chemistry - A European Journal, 24(8), 1890-1897. doi:10.1002/chem.201704161Oroval, M., Díez, P., Aznar, E., Coll, C., Marcos, M. D., Sancenón, F., … Martínez-Máñez, R. (2016). Self-Regulated Glucose-Sensitive Neoglycoenzyme-Capped Mesoporous Silica Nanoparticles for Insulin Delivery. Chemistry - A European Journal, 23(6), 1353-1360. doi:10.1002/chem.201604104De la Torre, C., Casanova, I., Acosta, G., Coll, C., Moreno, M. J., Albericio, F., … Martínez-Máñez, R. (2014). Gated Mesoporous Silica Nanoparticles Using a Double-Role Circular Peptide for the Controlled and Target-Preferential Release of Doxorubicin in CXCR4-Expresing Lymphoma Cells. Advanced Functional Materials, 25(5), 687-695. doi:10.1002/adfm.201403822Giménez, C., Climent, E., Aznar, E., Martínez-Máñez, R., Sancenón, F., Marcos, M. D., … Rurack, K. (2014). Towards Chemical Communication between Gated Nanoparticles. Angewandte Chemie International Edition, n/a-n/a. doi:10.1002/anie.201405580García-Fernández, A., García-Laínez, G., Ferrándiz, M. L., Aznar, E., Sancenón, F., Alcaraz, M. J., … Orzáez, M. (2017). Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles. Journal of Controlled Release, 248, 60-70. doi:10.1016/j.jconrel.2017.01.002Llopis-Lorente, A., Lozano-Torres, B., Bernardos, A., Martínez-Máñez, R., & Sancenón, F. (2017). Mesoporous silica materials for controlled delivery based on enzymes. Journal of Materials Chemistry B, 5(17), 3069-3083. doi:10.1039/c7tb00348jCabrera, S., El Haskouri, J., Guillem, C., Latorre, J., Beltrán-Porter, A., Beltrán-Porter, D., … Amorós *, P. (2000). Generalised syntheses of ordered mesoporous oxides: the atrane route. Solid State Sciences, 2(4), 405-420. doi:10.1016/s1293-2558(00)00152-7Lunn, G. (2005). HPLC Methods for Recently Approved Pharmaceuticals. doi:10.1002/0471711683Navarro, C., González-Álvarez, I., González-Álvarez, M., Manku, M., Merino, V., Casabó, V. G., & Bermejo, M. (2011). Influence of polyunsaturated fatty acids on Cortisol transport through MDCK and MDCK-MDR1 cells as blood–brain barrier in vitro model. European Journal of Pharmaceutical Sciences, 42(3), 290-299. doi:10.1016/j.ejps.2010.12.005Mura, C., Nácher, A., Merino, V., Merino-Sanjuan, M., Carda, C., Ruiz, A., … Diez-Sales, O. (2011). N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: In vivo study with TNBS-induced colitis model in rats. International Journal of Pharmaceutics. doi:10.1016/j.ijpharm.2011.06.025Sandborn, W. J., & Hanauer, S. B. (2002). The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Alimentary Pharmacology & Therapeutics, 17(1), 29-42. doi:10.1046/j.1365-2036.2003.01408.xMladenovska, K., Raicki, R. S., Janevik, E. I., Ristoski, T., Pavlova, M. J., Kavrakovski, Z., … Goracinova, K. (2007). Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles. International Journal of Pharmaceutics, 342(1-2), 124-136. doi:10.1016/j.ijpharm.2007.05.028Oomen, A. G., Rompelberg, C. J. M., Bruil, M. A., Dobbe, C. J. G., Pereboom, D. P. K. H., & Sips, A. J. A. M. (2003). Development of an In Vitro Digestion Model for Estimating the Bioaccessibility of Soil Contaminants. Archives of Environmental Contamination and Toxicology, 44(3), 281-287. doi:10.1007/s00244-002-1278-0Versantvoort, C. H. M., Oomen, A. G., Van de Kamp, E., Rompelberg, C. J. M., & Sips, A. J. A. M. (2005). Applicability of an in vitro digestion model in assessing the bioaccessibility of mycotoxins from food. Food and Chemical Toxicology, 43(1), 31-40. doi:10.1016/j.fct.2004.08.007Tozaki, H., Fujita, T., Komoike, J., Kim, S.-I., Terashima, H., Muranishi, S., … Yamamoto, A. (1999). Colon-specific Delivery of Budesonide with Azopolymer-coated Pellets: Therapeutic Effects of Budesonide with a Novel Dosage Form against 2,4,6-Trinitrobenzenesulphonic Acid-induced Colitis in Rats. Journal of Pharmacy and Pharmacology, 51(3), 257-261. doi:10.1211/0022357991772420Tozaki, H., Odoriba, T., Okada, N., Fujita, T., Terabe, A., Suzuki, T., … Yamamoto, A. (2002). Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. Journal of Controlled Release, 82(1), 51-61. doi:10.1016/s0168-3659(02)00084-6Yoo, J.-W., Naeem, M., Cao, J., Choi, M., Kim, W., Moon, H. R., … Jung, Y. (2015). Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles. International Journal of Nanomedicine, 4565. doi:10.2147/ijn.s8781

Medical management of inflammatory bowel disease

Patients who have recently been diagnosed as suffering from inflammatory bowel disease face two disturbing realities: firstly the true cause of the disease has not yet been defined and secondly the long term prognosis is unpredictable. In this article the author attempts to put in perspective the therapeutic regimens that have established themselves so far in this field, and to provide practical guidelines for their use in commonly encountered scenarios.peer-reviewe

Thermoanalytical, Spectroscopic and Chromatographic Approach to Physicochemical Compatibility Investigation of 5-Aminosalicylates and Folic Acid

Fixed-dose combinations have shown to be a great alternative to traditional polytherapy; however, development of such formulation requires thorough physicochemical compatibility investigation of active pharmaceutical ingredients to provide a stable, safe and therapeutically effective product. In this work, differential scanning calorimetry, X-ray powder diffraction, isothermal stress testing followed by Fourier-transform infrared spectroscopy and chromatographic analysis as well as dissolution studies were used for physicochemical compatibility investigation of folic acid and balsalazide or olsalazine. Balsalazide and olsalazine as well as their blend were successfully characterised regarding their physicochemical properties using the mentioned techniques. Differential scanning calorimetry gave ambiguous results due to premature degradation of balsalazide. On the contrary, other techniques have implied the absence of any chemical reactions or physical changes in prepared blends. Obtained result imply that folic acid is compatible with both balsalazide and olsalazine which goes in favour of developing proposed fixed-dose combinations. This work is licensed under a Creative Commons Attribution 4.0 International License

Recent bio-advances in metal-organic frameworks

Metal-organic frameworks (MOFs) have found uses in adsorption, catalysis, gas storage and other industrial applications. Metal Biomolecule Frameworks (bioMOFs) represent an overlap between inorganic, material and medicinal sciences, utilising the porous frameworks for biologically relevant purposes. This review details advances in bioMOFs, looking at the synthesis, properties and applications of both bioinspired materials and MOFs used for bioapplications, such as drug delivery, imaging and catalysis, with a focus on examples from the last five years

Biodegradation and biotransformation of polycyclic non-steroidal anti-inflammatory drugs

In recent years the increased use of polycyclic non-steroidal anti-inflammatory drugs has resulted in their presence in the environment. This in turn may cause potential negative effects on living organisms. While the biotransformation mechanisms of polycyclic non-steroidal anti-inflammatory drugs in the human body and in other mammals have been extensively studied, degradation of these drugs by microorganisms has seldom been investigated and is largely unknown. Biotransformation/biodegradation of polycyclic non-steroidal anti-inflammatory drugs is caused by fungal microorganisms, mainly white-rot fungi, and a few strains of bacteria. However, hitherto only complete degradation of olsazine was described. The first step of the transformation is most often hydroxylation catalyzed by cytochrom P-450 monooxygenases, or oxygenation by laccases and three peroxidases: lignin peroxidase, manganese-dependent peroxidase and versatile peroxidase manganese-dependent peroxidase. The aim of this work is to summarize the knowledge about the biotransformation and/or biodegradation of polycyclic non-steroidal anti-inflammatory drugs and to present their biotransformation pathways

Quantum mechanical polar surface area

A correlation has been established between the absorbed fraction of training-set molecules after oral administration in humans and the Quantum Mechanical Polar Surface Area (QMPSA). This correlation holds for the QMPSA calculated with structures where carboxyl groups are deprotonated. The correlation of the absorbed fraction and the QMPSA calculated on the neutral gas phase optimized structures is much less pronounced. This suggests that the absorption process is mainly determined by polar interactions of the drug molecules in water solution. Rules are given to derive the optimal polar/apolar ranges of the electrostatic potential