Formulation and Evaluation of Gambier (Uncaria gambir)-Chitosan Microparticle Intranasal Delivery for Alzheimer’s Diseases
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Keywords:
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Intranasal Delivery, Polymeric Encapsulation, Uncaria gambir , Alzheimer’s Disease , Acetylcholinesterase Inhibitor
Abstract
Alzheimer’s Disease (AD), the most common form of dementia continues to be the deadliest neuro degenerative disease in recent years. Despite significant efforts to mitigate the progression of the disease, there is no known cure and development towards a more effective treatment is still lacking. AD is marked by exceptionally low amount of acetylcholine in the brain, formation of tau protein, and amyloid beta plaque. Current drugs of choice for treating AD, namely donepezil and memantine, are acetylcholinesterase (AChE) inhibitors which focused on delaying the onset of cognitive decline by maintaining acetylcholine concentration. Gambier water extract (GWE) contains high level of polyphenols which act as an antioxidant, exhibit strong correlation with AChE inhibitor. The aim of this research is to formulate and encapsulate GWE inside a microparticle system composed of chitosan and different crosslinkers, STPP (IMGS) and CaCl2 (IMGC), which were then characterized as AChE inhibitor using Ellman’s method. Variations of the formula were designed following Box-Behnken experimental design with chitosan and crosslinker concentration, crosslinker type, and stirring speed as variables. Initial activity of GWE, IMGS and IMGC as antioxidant were confirmed with DPPH method, obtaining a strong activity of 88.01, 82.11, and 84.99% DPPH inhibition at 100 ppm respectively. Promisingly, at concentration of 100 ppm GWE demonstrated AChE inhibition of 30.36%. However, this activity reduced after encapsulation into IMGS and IMGC, with 14.63% and 18.65% AChE inhibition, which can be linked to the relatively sustained diffusion of GWE from the polymer matrix. IMGS and IMGC diffusion profile showed release of 23.24% and 21.89% after 6 hours, with significant increase in diffusion after 24 hours with 74.92% and 71.19% respectively. Despite showing sustained release behaviour, both IMGS and IMGC ex-vivo diffusion significantly improved when compared to GWE which only diffused 51.84% after 24 hours. This result indicates encapsulation of GWE into a polymeric carrier could increase gambier diffusion through the nasal mucous membrane, significantly improving the potential to penetrate into the brain systemic circulation. Combined with desirable intranasal delivery characteristics, this research was able to demonstrate the promising potential of gambier water extract polymeric system as AChE inhibitors for AD therapy.
References
Akhter, M. and M. M. Alam (2023). Ionization and Ionic Equilibria. Springer Nature Switzerland, Cham, pages 55–77
Al Harthi, S., S. E. Alavi, M. A. Radwan, M. M. El Khatib, and I. A. AlSarra (2019). Nasal Delivery of Donepezil HCl-Loaded Hydrogels for the Treatment of Alzheimer’s Disease. Scientific Reports, 9(1); 9563
Anggraini, T., A. Tai, T. Yoshino, and T. Itani (2011). Antioxidative Activity and Catechin Content of Four Kinds of Uncaria gambir Extracts from West Sumatra, Indonesia. African Journal of Biochemistry Research, 5(1); 33–38
Apea-Bah, F., M. Hanafi, R. Dewi, S. Fajriah, A. Darwaman, N. Artanti, P. Lotulung, P. Ngadymang, and B. Minarti (2009). Assessment of the DPPH and α-Glucosidase Inhibitory Potential of Gambier and Qualitative Identification of Major Bioactive Compound. Journal of Medicinal Plants Research, 3(10); 736–757
Arvanitakis, Z., R. C. Shah, and D. A. Bennett (2019). Diagnosis and Management of Dementia. Jama, 322(16); 1589–1599
Association, A. s. (2023). Alzheimer’s Disease Facts and Figures. Alzheimers Dement, 19(4); 1598–1695
Baliyan, S., R. Mukherjee, A. Priyadarshini, A. Vibhuti, A. Gupta, R. P. Pandey, and C.-M. Chang (2022). Determination of Antioxidants by DPPH Radical Scavenging Activity and Quantitative Phytochemical Analysis of Ficus Religiosa. Molecules, 27(4); 1326
Bhumkar, D. R. and V. B. Pokharkar (2006). Studies on Effect of pH on Cross-Linking of Chitosan with Sodium Tripolyphosphate: A Technical Note. Aaps Pharmscitech, 7(2); 138–143
Boyuklieva, R. and B. Pilicheva (2022). Micro-and Nanosized Carriers for Nose-To-Brain Drug Delivery in Neurodegenerative Disorders. Biomedicines, 10(7); 1706
Caetano, L. A., A. J. Almeida, and L. M. Gonçalves (2016). Effect of Experimental Parameters on Alginate/Chitosan Microparticles for BCG Encapsulation. Marine Drugs, 14(5); 90
Casettari, L. and L. Illum (2014). Chitosan in Nasal Delivery Systems for Therapeutic Drugs. Journal of Controlled Release, 190; 189–200
Centers for Desease Control and Prevention (1978). Occupational Health Guideline for Ethyl Acetate. Centers for Desease Control and Prevention, Atlanta, US
Coates, J. (2000). Interpretation of Infrared Spectra, a Practical Approach. 10815–10837. Encyclopedia of Analytical Chemistry
Colovic, M. B., D. Z. Krstic, T. D. Lazarevic-Pasti, A. M. Bondzic, and V. M. Vasic (2013). Acetylcholinesterase Inhibitors: Pharmacology and Toxicology. Current Neuropharmacology, 11(3); 315–335
Deli, M. A. (2009). Potential Use of Tight Junction Modulators to Reversibly Open Membranous Barriers and Improve Drug Delivery. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1788(4); 892–910
Departemen Kesehatan Republik Indonesia (2000). Parameter Standar Umum Ekstrak Tumbuhan Obat. Departemen Kesehatan Republik Indonesia, Jakarta, Indonesia (In Indonesia)
Departement of Health (2016). Right to Know Hazardous Substance Fact Sheet. Departement of Health, New Jersey, USA
Department Kesehatan Republik Indonesia. (1995). Materia Medika Indonesia Jilid VI. Department Kesehatan Republik Indonesia., Jakarta, Indonesia (In Indonesia)
Estanqueiro, M., J. Conceição, M. H. Amaral, D. Santos, J. B. Silva, and J. M. S. Lobo (2014). Characterization and Stability Studies of Emulsion Systems Containing Pumice. Brazilian Journal of Pharmaceutical Sciences, 50(2); 361–369
Fattahi, S., E. Zabihi, Z. Abedian, R. Pourbagher, A. M. Ardekani, A. Mostafazadeh, and H. Akhavan-Niaki (2014). Total Phenolic and Flavonoid Contents of Aqueous Extract of Stinging Nettle and in Vitro Antiproliferative Effect on Hela and BT-474 Cell Lines. International Journal of Molecular and Cellular Medicine, 3(2); 102
Fithri, N. A., F. Fitrya, T. Shabrina, and D. Yulanri (2019). Antioxidant Activity Analysis and Standardization of Parkia Speciosa (Petai) Pods Ethanol Extract. Science and Technology Indonesia, 4(1); 5–10
Fithri, N. A., M. Mardiyanto, R. P. Novita, and V. Andrean (2017). Furosemide Self Nano Emulsifying Drug Delivery System (SNEDDS) Formulation Comprising of Capryol-90, Polysorbate-80, and Peg-400 with Simplex-Lattice-Design. Science and Technology Indonesia, 2(4); 85–88
Fitrya, F., N. A. Fithri, A. Amriani, A. Haryati, and D. P. Wijaya (2021). Preparation and Characterization of Petai Pods Extract (Parkia speciosa Hassk.) Loaded Ethosomes. Science and Technology Indonesia, 6(1); 19–24
Gebresamuel, N. and T. Gebre-Mariam (2013). Evaluation of the Suspending Properties of Two Local Opuntia spp. Mucilages on Paracetamol Suspension. Pakistan Journal of Pharmaceutical Sciences, 26(1); 23–29
Gulati, N., U. Nagaich, and S. A. Saraf (2013). Intranasal Delivery of Chitosan Nanoparticles for Migraine Therapy. Scientia Pharmaceutica, 81(3); 843–854
Guo, C. and W. H. Doub (2006). The Influence of Actuation Parameters on in Vitro Testing of Nasal Spray Products. Journal of pharmaceutical sciences, 95(9); 2029–2040
Jonassen, H., A.-L. Kjøniksen, and M. Hiorth (2012). Stability of Chitosan Nanoparticles Cross-Linked with Tripolyphosphate. Biomacromolecules, 13(11); 3747–3756
Kalkotwar, R. S., V. V. B. Patil, A. M. Patel, S. D. Tathe, and S. S. Rawat (2012). Evaluation and Quality Control of Nasal Spray. Journal of Drug Delivery and Therapeutics, 2(4); 1–4
Kassim, M. J., M. H. Hussin, A. Achmad, N. H. Dahon, T. K. Suan, and H. S. Hamdan (2011). Determination of Total Phenol, Condensed Tannin and Flavonoid Contents and Antioxidant Activity of Uncaria gambir Extracts. Indonesian Journal of Pharmacy, 22(1); 50–59
Kushwaha, S. K., R. K. Keshari, and A. Rai (2011). Advances in Nasal Trans-Mucosal Drug Delivery. Journal of Applied Pharmaceutical Science, 1(7); 21–28
Lee, D. and T. Minko (2021). Nanotherapeutics for Nose-To-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier. Pharmaceutics, 13(2); 2049
Mardiyanto, M., H. Herlina, N. A. Fithri, and Y. Rahmi (2019). Formulasi Dan Evaluasi Sediaan Submikro Partikel Gelasi-Ionik Pembawa Ekstrak Daun Pluchea Indica Sebagai Antibakteri Pada Kulit Tikus Putih Jantan Galur Wistar. Jurnal Sains Farmasi & Klinis, 6(2); 171–179 (In Indonesia)
Melia, S., D. Novia, and I. Juliyarsi (2015). Antioxidant and Antimicrobial Activities of Gambir (Uncaria gambir Roxb.) Extracts and Their Application in Rendang. Pakistan Journal of Nutrition, 14(12); 938
Molyneux, P. (2004). The Use of the Stable Free Radical Diphenylpicrylhydrazyl (DPPH) for Estimating Antioxidant Activity. Songklanakarin J. sci. technol, 26(2); 211–219
Nazir, N. (2000). Gambir: Budidaya, Pengolahan, Dan Prospek Diversifikasinya. Yayasan Hutanku, Bogor, Indonesia (In Indonesia)
Pambayun, R., M. Gardjito, S. Sudarmadji, and K. Kuswanto (2007). Catechin Type Extracted from Gambier Commercial Which Has the Strongest Antibacterial Activity. Jurnal Agribisnis dan Industri Pertanian, 6(1); 49–55
Pardeshi, C. V. and V. S. Belgamwar (2013). Direct Nose to Brain Drug Delivery Via Integrated Nerve Pathways By-passing the Blood-Brain Barrier: An Excellent Platform for Brain Targeting. Expert Opinion on Drug Delivery, 10(7); 957–972
Pawar, N. and H. Chaudhary (2015). Non-Pressurized Topical Spray of Diclofenac Diethylamine. International Journal Advances in Pharmaceutics, 4(4); 40–8
Peng, Y., H. Jin, Y.-h. Xue, Q. Chen, S.-y. Yao, M.-q. Du, and S. Liu (2023). Current and Future Therapeutic Strategies for Alzheimer’s Disease: An Overview of Drug Development Bottlenecks. Frontiers in Aging Neuroscience, 15; 1–16
Pervin, M., M. A. Hasnat, Y. M. Lee, D. H. Kim, J. E. Jo, and B. O. Lim (2014). Antioxidant Activity and Acetylcholinesterase Inhibition of Grape Skin Anthocyanin (GSA). Molecules, 19(7); 9403–9418
Pohanka, M., M. Hrabinova, K. Kuca, and J.-P. Simonato (2011). Assessment of Acetylcholinesterase Activity Using Indoxylacetate and Comparison with the Standard Ellman’s Method. International Journal of Molecular Sciences, 12(4); 2631–2640
Rajaram, S. and R. Natham (2013). Influence of Formulation and Process Variables on the Formation of Rifampicin Nanoparticles by Ionic Gelation Technique. RJPBCS, 4; 820–832
Ramvikas, M., M. Arumugam, S. Chakrabarti, and K. Jaganathan (2017). Nasal Vaccine Delivery. In Micro and Nanotechnology in Vaccine Development. Elsevier, pages 279–301
Ranjan, N. and M. Kumari (2016). Inhibitory Activity of Acetylcholinesterase (AChE) and Antioxidant Activity of Methanolic Extract of Desmodium angeticum (L.). International Journal of Bioassays, 6(1); 5208–5210
Ribeiro, E. F., T. T. de Barros-Alexandrino, O. B. G. Assis, A. C. Junior, A. Quiles, I. Hernando, and V. R. Nicoletti (2020). Chitosan and Crosslinked Chitosan Nanoparticles: Synthesis, Characterization and Their Role As Pickering Emulsifiers. Carbohydrate Polymers, 250; 116878
Sachdeva, B., P. Sachdeva, A. Negi, S. Ghosh, S. Han, S. Dewanjee, S. K. Jha, R. Bhaskar, J. K. Sinha, A. C. Paiva-Santos (2023). Chitosan Nanoparticles-Based Cancer Drug Delivery: Application and Challenges. Marine Drugs, 21(4); 211
Salatin, S., J. Barar, M. Barzegar-Jalali, K. Adibkia, F. Kiafar, and M. Jelvehgari (2017). Development of a Nanoprecipitation Method for the Entrapment of a Very Water Soluble Drug into Eudragit RL Nanoparticles. Research in Pharmaceutical Sciences, 12(1); 1–14
Sazwi, N. N., T. Nalina, and Z. H. A. Rahim (2013). Antioxidant and Cytoprotective Activities of Piper betle, Areca catechu, Uncaria gambir and Betel quid with and without Calcium Hydroxide. BMC Complementary and Alternative Medicine, 13; 1–12
Sinko, P. J. (2023). Martin’s Physical Pharmacy and Pharmaceutical Sciences. The State University of New Jersey
Sukweenadhi, J., F. Setiawan, O. Yunita, K. Kartini, and C. Avanti (2020). Antioxidant Activity Screening of Seven Indonesian Herbal Extract. Biodiversitas, 21(5); 2062–2067
Taléns-Visconti, R., J. V. de Julián-Ortiz, O. Vila-Busó, O. Diez-Sales, and A. Nácher (2023). Intranasal Drug Administration in Alzheimer-Type Dementia: Towards Clinical Applications. Pharmaceutics, 15(5); 1399
Ünver, Y., S. Deniz, F. Çelik, Z. Akar, M. Küçük, and K. Sancak (2016). Synthesis of New 1, 2, 4-Triazole Compounds Containing Schiff and Mannich Bases (Morpholine) with Antioxidant and Antimicrobial Activities. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(3); 89–95
van der Flier, W. M., M. E. de Vugt, E. M. Smets, M. Blom, and C. E. Teunissen (2023). Towards a Future Where Alzheimer’s Disease Pathology Is Stopped before the Onset of Dementia. Nature Aging, 3(5); 494–505
van Woensel, M., N. Wauthoz, R. Rosière, K. Amighi, V. Mathieu, F. Lefranc, S. W. Van Gool, and S. De Vleeschouwer (2013). Formulations for Intranasal Delivery of Pharmaco logical Agents to Combat Brain Disease: A New Opportunity to Tackle Gbm? Cancers, 5(3); 1020–1048
Wu, D., Q. Chen, X. Chen, F. Han, Z. Chen, and Y. Wang (2023a). The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery. Signal Transduction and Targeted Therapy, 8(1); 217
Wu, M.-Y., I.-F. Kao, C.-Y. Fu, and S.-K. Yen (2023b). Effects of Adding Chitosan on Drug Entrapment Efficiency and Release Duration for Paclitaxel-Loaded Hydroxyapatite-Gelatin Composite Microspheres. Pharmaceutics, 15(8); 2025
Yeni, G., K. Syamsu, O. Suparno, E. Mardliyati, and H. Muchtar (2014). Repeated Extraction Process of Raw Gambiers (Uncaria gambir Robx.) for the Catechin Production As an Antioxidant. International Journal of Applied Engineering Research, 9(24); 24565–24578
Yunarto, N. and N. Aini (2015). Effect of Purified Gambir Leaves Extract to Prevent Atherosclerosis in Rats. Health Science Journal of Indonesia, 6(2); 105–110
Al Harthi, S., S. E. Alavi, M. A. Radwan, M. M. El Khatib, and I. A. AlSarra (2019). Nasal Delivery of Donepezil HCl-Loaded Hydrogels for the Treatment of Alzheimer’s Disease. Scientific Reports, 9(1); 9563
Anggraini, T., A. Tai, T. Yoshino, and T. Itani (2011). Antioxidative Activity and Catechin Content of Four Kinds of Uncaria gambir Extracts from West Sumatra, Indonesia. African Journal of Biochemistry Research, 5(1); 33–38
Apea-Bah, F., M. Hanafi, R. Dewi, S. Fajriah, A. Darwaman, N. Artanti, P. Lotulung, P. Ngadymang, and B. Minarti (2009). Assessment of the DPPH and α-Glucosidase Inhibitory Potential of Gambier and Qualitative Identification of Major Bioactive Compound. Journal of Medicinal Plants Research, 3(10); 736–757
Arvanitakis, Z., R. C. Shah, and D. A. Bennett (2019). Diagnosis and Management of Dementia. Jama, 322(16); 1589–1599
Association, A. s. (2023). Alzheimer’s Disease Facts and Figures. Alzheimers Dement, 19(4); 1598–1695
Baliyan, S., R. Mukherjee, A. Priyadarshini, A. Vibhuti, A. Gupta, R. P. Pandey, and C.-M. Chang (2022). Determination of Antioxidants by DPPH Radical Scavenging Activity and Quantitative Phytochemical Analysis of Ficus Religiosa. Molecules, 27(4); 1326
Bhumkar, D. R. and V. B. Pokharkar (2006). Studies on Effect of pH on Cross-Linking of Chitosan with Sodium Tripolyphosphate: A Technical Note. Aaps Pharmscitech, 7(2); 138–143
Boyuklieva, R. and B. Pilicheva (2022). Micro-and Nanosized Carriers for Nose-To-Brain Drug Delivery in Neurodegenerative Disorders. Biomedicines, 10(7); 1706
Caetano, L. A., A. J. Almeida, and L. M. Gonçalves (2016). Effect of Experimental Parameters on Alginate/Chitosan Microparticles for BCG Encapsulation. Marine Drugs, 14(5); 90
Casettari, L. and L. Illum (2014). Chitosan in Nasal Delivery Systems for Therapeutic Drugs. Journal of Controlled Release, 190; 189–200
Centers for Desease Control and Prevention (1978). Occupational Health Guideline for Ethyl Acetate. Centers for Desease Control and Prevention, Atlanta, US
Coates, J. (2000). Interpretation of Infrared Spectra, a Practical Approach. 10815–10837. Encyclopedia of Analytical Chemistry
Colovic, M. B., D. Z. Krstic, T. D. Lazarevic-Pasti, A. M. Bondzic, and V. M. Vasic (2013). Acetylcholinesterase Inhibitors: Pharmacology and Toxicology. Current Neuropharmacology, 11(3); 315–335
Deli, M. A. (2009). Potential Use of Tight Junction Modulators to Reversibly Open Membranous Barriers and Improve Drug Delivery. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1788(4); 892–910
Departemen Kesehatan Republik Indonesia (2000). Parameter Standar Umum Ekstrak Tumbuhan Obat. Departemen Kesehatan Republik Indonesia, Jakarta, Indonesia (In Indonesia)
Departement of Health (2016). Right to Know Hazardous Substance Fact Sheet. Departement of Health, New Jersey, USA
Department Kesehatan Republik Indonesia. (1995). Materia Medika Indonesia Jilid VI. Department Kesehatan Republik Indonesia., Jakarta, Indonesia (In Indonesia)
Estanqueiro, M., J. Conceição, M. H. Amaral, D. Santos, J. B. Silva, and J. M. S. Lobo (2014). Characterization and Stability Studies of Emulsion Systems Containing Pumice. Brazilian Journal of Pharmaceutical Sciences, 50(2); 361–369
Fattahi, S., E. Zabihi, Z. Abedian, R. Pourbagher, A. M. Ardekani, A. Mostafazadeh, and H. Akhavan-Niaki (2014). Total Phenolic and Flavonoid Contents of Aqueous Extract of Stinging Nettle and in Vitro Antiproliferative Effect on Hela and BT-474 Cell Lines. International Journal of Molecular and Cellular Medicine, 3(2); 102
Fithri, N. A., F. Fitrya, T. Shabrina, and D. Yulanri (2019). Antioxidant Activity Analysis and Standardization of Parkia Speciosa (Petai) Pods Ethanol Extract. Science and Technology Indonesia, 4(1); 5–10
Fithri, N. A., M. Mardiyanto, R. P. Novita, and V. Andrean (2017). Furosemide Self Nano Emulsifying Drug Delivery System (SNEDDS) Formulation Comprising of Capryol-90, Polysorbate-80, and Peg-400 with Simplex-Lattice-Design. Science and Technology Indonesia, 2(4); 85–88
Fitrya, F., N. A. Fithri, A. Amriani, A. Haryati, and D. P. Wijaya (2021). Preparation and Characterization of Petai Pods Extract (Parkia speciosa Hassk.) Loaded Ethosomes. Science and Technology Indonesia, 6(1); 19–24
Gebresamuel, N. and T. Gebre-Mariam (2013). Evaluation of the Suspending Properties of Two Local Opuntia spp. Mucilages on Paracetamol Suspension. Pakistan Journal of Pharmaceutical Sciences, 26(1); 23–29
Gulati, N., U. Nagaich, and S. A. Saraf (2013). Intranasal Delivery of Chitosan Nanoparticles for Migraine Therapy. Scientia Pharmaceutica, 81(3); 843–854
Guo, C. and W. H. Doub (2006). The Influence of Actuation Parameters on in Vitro Testing of Nasal Spray Products. Journal of pharmaceutical sciences, 95(9); 2029–2040
Jonassen, H., A.-L. Kjøniksen, and M. Hiorth (2012). Stability of Chitosan Nanoparticles Cross-Linked with Tripolyphosphate. Biomacromolecules, 13(11); 3747–3756
Kalkotwar, R. S., V. V. B. Patil, A. M. Patel, S. D. Tathe, and S. S. Rawat (2012). Evaluation and Quality Control of Nasal Spray. Journal of Drug Delivery and Therapeutics, 2(4); 1–4
Kassim, M. J., M. H. Hussin, A. Achmad, N. H. Dahon, T. K. Suan, and H. S. Hamdan (2011). Determination of Total Phenol, Condensed Tannin and Flavonoid Contents and Antioxidant Activity of Uncaria gambir Extracts. Indonesian Journal of Pharmacy, 22(1); 50–59
Kushwaha, S. K., R. K. Keshari, and A. Rai (2011). Advances in Nasal Trans-Mucosal Drug Delivery. Journal of Applied Pharmaceutical Science, 1(7); 21–28
Lee, D. and T. Minko (2021). Nanotherapeutics for Nose-To-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier. Pharmaceutics, 13(2); 2049
Mardiyanto, M., H. Herlina, N. A. Fithri, and Y. Rahmi (2019). Formulasi Dan Evaluasi Sediaan Submikro Partikel Gelasi-Ionik Pembawa Ekstrak Daun Pluchea Indica Sebagai Antibakteri Pada Kulit Tikus Putih Jantan Galur Wistar. Jurnal Sains Farmasi & Klinis, 6(2); 171–179 (In Indonesia)
Melia, S., D. Novia, and I. Juliyarsi (2015). Antioxidant and Antimicrobial Activities of Gambir (Uncaria gambir Roxb.) Extracts and Their Application in Rendang. Pakistan Journal of Nutrition, 14(12); 938
Molyneux, P. (2004). The Use of the Stable Free Radical Diphenylpicrylhydrazyl (DPPH) for Estimating Antioxidant Activity. Songklanakarin J. sci. technol, 26(2); 211–219
Nazir, N. (2000). Gambir: Budidaya, Pengolahan, Dan Prospek Diversifikasinya. Yayasan Hutanku, Bogor, Indonesia (In Indonesia)
Pambayun, R., M. Gardjito, S. Sudarmadji, and K. Kuswanto (2007). Catechin Type Extracted from Gambier Commercial Which Has the Strongest Antibacterial Activity. Jurnal Agribisnis dan Industri Pertanian, 6(1); 49–55
Pardeshi, C. V. and V. S. Belgamwar (2013). Direct Nose to Brain Drug Delivery Via Integrated Nerve Pathways By-passing the Blood-Brain Barrier: An Excellent Platform for Brain Targeting. Expert Opinion on Drug Delivery, 10(7); 957–972
Pawar, N. and H. Chaudhary (2015). Non-Pressurized Topical Spray of Diclofenac Diethylamine. International Journal Advances in Pharmaceutics, 4(4); 40–8
Peng, Y., H. Jin, Y.-h. Xue, Q. Chen, S.-y. Yao, M.-q. Du, and S. Liu (2023). Current and Future Therapeutic Strategies for Alzheimer’s Disease: An Overview of Drug Development Bottlenecks. Frontiers in Aging Neuroscience, 15; 1–16
Pervin, M., M. A. Hasnat, Y. M. Lee, D. H. Kim, J. E. Jo, and B. O. Lim (2014). Antioxidant Activity and Acetylcholinesterase Inhibition of Grape Skin Anthocyanin (GSA). Molecules, 19(7); 9403–9418
Pohanka, M., M. Hrabinova, K. Kuca, and J.-P. Simonato (2011). Assessment of Acetylcholinesterase Activity Using Indoxylacetate and Comparison with the Standard Ellman’s Method. International Journal of Molecular Sciences, 12(4); 2631–2640
Rajaram, S. and R. Natham (2013). Influence of Formulation and Process Variables on the Formation of Rifampicin Nanoparticles by Ionic Gelation Technique. RJPBCS, 4; 820–832
Ramvikas, M., M. Arumugam, S. Chakrabarti, and K. Jaganathan (2017). Nasal Vaccine Delivery. In Micro and Nanotechnology in Vaccine Development. Elsevier, pages 279–301
Ranjan, N. and M. Kumari (2016). Inhibitory Activity of Acetylcholinesterase (AChE) and Antioxidant Activity of Methanolic Extract of Desmodium angeticum (L.). International Journal of Bioassays, 6(1); 5208–5210
Ribeiro, E. F., T. T. de Barros-Alexandrino, O. B. G. Assis, A. C. Junior, A. Quiles, I. Hernando, and V. R. Nicoletti (2020). Chitosan and Crosslinked Chitosan Nanoparticles: Synthesis, Characterization and Their Role As Pickering Emulsifiers. Carbohydrate Polymers, 250; 116878
Sachdeva, B., P. Sachdeva, A. Negi, S. Ghosh, S. Han, S. Dewanjee, S. K. Jha, R. Bhaskar, J. K. Sinha, A. C. Paiva-Santos (2023). Chitosan Nanoparticles-Based Cancer Drug Delivery: Application and Challenges. Marine Drugs, 21(4); 211
Salatin, S., J. Barar, M. Barzegar-Jalali, K. Adibkia, F. Kiafar, and M. Jelvehgari (2017). Development of a Nanoprecipitation Method for the Entrapment of a Very Water Soluble Drug into Eudragit RL Nanoparticles. Research in Pharmaceutical Sciences, 12(1); 1–14
Sazwi, N. N., T. Nalina, and Z. H. A. Rahim (2013). Antioxidant and Cytoprotective Activities of Piper betle, Areca catechu, Uncaria gambir and Betel quid with and without Calcium Hydroxide. BMC Complementary and Alternative Medicine, 13; 1–12
Sinko, P. J. (2023). Martin’s Physical Pharmacy and Pharmaceutical Sciences. The State University of New Jersey
Sukweenadhi, J., F. Setiawan, O. Yunita, K. Kartini, and C. Avanti (2020). Antioxidant Activity Screening of Seven Indonesian Herbal Extract. Biodiversitas, 21(5); 2062–2067
Taléns-Visconti, R., J. V. de Julián-Ortiz, O. Vila-Busó, O. Diez-Sales, and A. Nácher (2023). Intranasal Drug Administration in Alzheimer-Type Dementia: Towards Clinical Applications. Pharmaceutics, 15(5); 1399
Ünver, Y., S. Deniz, F. Çelik, Z. Akar, M. Küçük, and K. Sancak (2016). Synthesis of New 1, 2, 4-Triazole Compounds Containing Schiff and Mannich Bases (Morpholine) with Antioxidant and Antimicrobial Activities. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(3); 89–95
van der Flier, W. M., M. E. de Vugt, E. M. Smets, M. Blom, and C. E. Teunissen (2023). Towards a Future Where Alzheimer’s Disease Pathology Is Stopped before the Onset of Dementia. Nature Aging, 3(5); 494–505
van Woensel, M., N. Wauthoz, R. Rosière, K. Amighi, V. Mathieu, F. Lefranc, S. W. Van Gool, and S. De Vleeschouwer (2013). Formulations for Intranasal Delivery of Pharmaco logical Agents to Combat Brain Disease: A New Opportunity to Tackle Gbm? Cancers, 5(3); 1020–1048
Wu, D., Q. Chen, X. Chen, F. Han, Z. Chen, and Y. Wang (2023a). The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery. Signal Transduction and Targeted Therapy, 8(1); 217
Wu, M.-Y., I.-F. Kao, C.-Y. Fu, and S.-K. Yen (2023b). Effects of Adding Chitosan on Drug Entrapment Efficiency and Release Duration for Paclitaxel-Loaded Hydroxyapatite-Gelatin Composite Microspheres. Pharmaceutics, 15(8); 2025
Yeni, G., K. Syamsu, O. Suparno, E. Mardliyati, and H. Muchtar (2014). Repeated Extraction Process of Raw Gambiers (Uncaria gambir Robx.) for the Catechin Production As an Antioxidant. International Journal of Applied Engineering Research, 9(24); 24565–24578
Yunarto, N. and N. Aini (2015). Effect of Purified Gambir Leaves Extract to Prevent Atherosclerosis in Rats. Health Science Journal of Indonesia, 6(2); 105–110
Authors
Fithri, N. A., Mardiyanto, Fitrya, Rahmah, A., & Annisa, N. M. (2024). Formulation and Evaluation of Gambier (Uncaria gambir)-Chitosan Microparticle Intranasal Delivery for Alzheimer’s Diseases. Science and Technology Indonesia, 9(2), 284–298. https://doi.org/10.26554/sti.2024.9.2.284-298
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