Difenhidramin HCl'nin Yüklenmesi ve Salımı için Diyatomit-Kitosan Kompozitlerinin Hazırlanması

Öz

Diyatomit cevherleri, doğada bol miktarda bulunmaları, biyouyumlulukları ve yüksek yüzey alanları nedeniyle adsorban ve ilaç taşıyıcı sistem olarak büyük potansiyele sahiptir. Bu çalışmanın ilk aşamasında ham diatomit cevheri öğütme ve kalsinasyon işlemleri ile zenginleştirilmiştir. Ham diyatomit için yüzey alanı 21.7 m2/g iken zenginleştirme sonrası kalsine diyatomit için 75.1 m2/g olarak bulunmuştur. Daha sonra, farklı bileşim oranlarına sahip bir dizi diatomit-kitosan kompoziti üretilmiştir. Antihistaminik ajan olan difenhidramin hidroklorürün (DPH) hazırlanan kompozitler üzerindeki yükleme (adsorpsiyon) performansları incelenmiştir. Hazırlanan DPH yüklü formülasyonlarda en yüksek yükleme kapasitesi 91.1 mg/g, en düşük yükleme kapasitesi 48.8 mg/g olmuştur. DPH yükleme çalışmalarından sonra DPH salım profilleri (desorpsiyon) ve kompozitlerden salım kinetikleri incelenmiştir. In vitro salım çalışmaları sonucunda kitosan polimeri içeren formülasyonların kitosan içermeyen formülasyonlara göre daha yavaş salım gösterdiği gözlemlenmiştir. Formülasyonların %70-90 aralığında kümülatif DPH salıma sahip olduğu ve salımın 45-90 dakika arasında tamamlandığı belirlenmiştir. Hazırlanan formülasyonların in vitro salım profilleri Higuchi kinetiği ile uyumlu olduğu belirlenmiştir.

Anahtar Kelimeler

• Diyatomit
• Kitosan
• Difenhidramin

Preparation of Diatomite-Chitosan Composites for Loading and Release of Diphenhydramine HCl

Abstract

Diatomite ores have great potential as an adsorbent and drug carrier system due to their natural abundance, biocompatible, and high surface area. In the first stage of this study, raw diatomite ore was enriched by grinding and calcination processes. As a result of the enrichment process, the surface area was found to be 21.7 m2/g for raw diatomite and 75.1 m2/g for calcined diatomite. Subsequently, a series of diatomite-chitosan composites with different composition ratios were produced. Then, the loading (adsorption) performances of diphenhydramine hydrochloride (DPH), an antihistaminic agent, were investigated on the prepared composites. The highest loading capacity was 91.1 mg/g, and the lowest loading capacity was 48.8 mg/g in the prepared DPH-loaded formulations. After DPH loading studies, DPH release profiles (desorption) and release kinetics from composites were investigated. As a result of in vitro release studies, it was observed that formulations containing chitosan polymer had slower release than chitosan free formulations. It was determined that the formulations had a cumulative release in the 70-90% range, and the release processes were completed between 45-90 minutes. In vitro release profiles of the prepared formulations were compatible with Higuchi kinetics.

Keywords

• Diatomite
• Chitosan
• Diphenhydramine
• Release kinetic.

Kaynakça

1. Abbas H.K., AbdulRazzaq I.F., Salal Y.A., Shaheed D.Q., Preparation and evaluation of proniosomal gel containing diphenhydramine HCl, Drug Invention Today, 13(2), 2020.
2. Abdel-Bary A.S., Tolan D.A., Nassar M.Y., Taketsugu T., El-Nahas A.M., Chitosan, magnetite, silicon dioxide, and graphene oxide nanocomposites: Synthesis, characterization, efficiency as cisplatin drug delivery, and DFT calculations, International Journal of Biological Macromolecules, 154, 621-633, 2020.
3. Akyuz L., Kaya M., Koc B., Mujtaba M., Ilk S., Labidi J., Yildiz A., Diatomite as a novel composite ingredient for chitosan film with enhanced physicochemical properties, International journal of biological macromolecules, 105, 1401-1411, 2017.
4. Arpa M.D., Okur N.Ü., Gök M.K., Özgümüş S., Cevher E., Chitosan-based buccal mucoadhesive patches to enhance the systemic bioavailability of tizanidine, International Journal of Pharmaceutics, 123168, 2023.
5. Arpa M.D., Seçen İ.M., Erim Ü.C., Hoş A., Üstündağ Okur N., Azelaic acid loaded chitosan and HPMC based hydrogels for treatment of acne: formulation, characterization, in vitro-ex vivo evaluation, Pharmaceutical Development and Technology, 27(3), 268-281, 2022.
6. Arpa M.D., Ünükür M.Z., Erim Ü.C., Formulation, characterization and in vitro release studies of terbinafine hydrochloride loaded buccal films, Journal of Research in Pharmacy, 25(5): 667-680, 2021.
7. Arpa M.D., Yağcılar A.P., Biltekin S.N., Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections, Journal of Drug Delivery Science and Technology, 84, 104497, 2023.
8. Burkhanova N.D., Yugai S.M., Pulatova K.P., Nikononvich G.V., Milusheva R.Y., Voropaeva N.L., Rashidova S.S., Structural investigations of chitin and its deacetylation products, Chemistry of Natural Compounds, 36, 352-355, 2000.

9. Çiftçi H., Arpa M.D., Gülaçar İ.M., Özcan L., Ersoy B., Development and evaluation of mesoporous montmorillonite/magnetite nanocomposites loaded with 5-Fluorouracil, Microporous and Mesoporous Materials, 303, 110253, 2020.
10. Çiftçi H., Arpa M.D., Gülaçar İ.M., Özcan L., Ersoy B., Development and evaluation of mesoporous montmorillonite/magnetite nanocomposites loaded with 5-Fluorouracil, Microporous and Mesoporous Materials, 303, 110253, 2020.
11. Çiftçi H., Ersoy B., Evcin A., Purification of Turkish bentonites and investigation of the contact angle, surface free energy and zeta potential profiles of organo-bentonites as a function of CTAB concentration, Clays and Clay Minerals, 68, 250-261, 2020.
12. Coneac G., Vlaia V., Olariu I., Muţ A.M., Anghel D.F. Ilie C., Vlaia L., Development and evaluation of new microemulsion-based hydrogel formulations for topical delivery of fluconazole, Aaps Pharmscitech, 16, 889-904, 2015.
13. Damian F., Harati M., Schwartzenhauer J., Van Cauwenberghe O., Wettig S.D., Challenges of dissolution methods development for soft gelatin capsules, Pharmaceutics, 13(2), 214, 2021.
14. Ediz N., Bentli İ., Tatar İ., Improvement in filtration characteristics of diatomite by calcination, International Journal of Mineral Processing, 94(3-4), 129-134, 2010.
15. Fowler C.E., Buchber C., Lebeau B., Patarin J., Delacôte C., Walcarius A., An aqueous route to organically functionalized silica diatom skeletons, Applied surface science, 253(12), 5485-5493, 2007.
16. Gao B., Jiang P., An F., Zhao S., Ge Z., Studies on the surface modification of diatomite with polyethyleneimine and trapping effect of the modified diatomite for phenol, Applied surface science, 250(1-4), 273-279, 2005.
17. Gârea S.A., Mihai A.I., Vasile E., Nistor C., Sârbu A., Mitran R., Synthesis of new porous clay heterostructures: The influence of co-surfactant type, Materials Chemistry and Physics, 179, 17-26, 2016.
18. Gaware S.A., Rokade K.A., Kale S.N., Silica-chitosan nanocomposite mediated pH-sensitive drug delivery, Journal of Drug Delivery Science and Technology, 49, 345-351, 2019.
19. Ghebaur A., Garea S.A., Iovu H., New polymer–halloysite hybrid materials—potential controlled drug release system, International journal of pharmaceutics, 436(1-2), 568-573, 2012.
20. Gültürk E., Güden M., Thermal and acid treatment of diatom frustules, Journal of Achievements in Materials and Manufacturing Engineering, 46(2), 196-203, 2011.
21. Hadi A., Rao N.G., Rao A.S., Shiva G., Akram J.W., Impact of capsules as a carrier for multiple unit drug delivery and the importance of HPMC capsules, Research Journal of Pharmacy and Technology, 6(1), 34-43, 2013.
22. Ibrahim S.M., Bin Jumah M.N., Othman S.I., Alruhaimi R.S., Al-Khalawi N., Salama Y.F., Abukhadra M.R., Synthesis of chitosan/diatomite composite as an advanced delivery system for ibuprofen drug; equilibrium studies and the release profile, Acs Omega, 6(20), 13406-13416, 2021.
23. Kevadiya B.D., Patel T.A., Jhala D.D., Thumbar R.P., Brahmbhatt H., Pandya M.P., Bajaj H.C., Layered inorganic nanocomposites: a promising carrier for 5-fluorouracil (5-FU), European Journal of Pharmaceutics and Biopharmaceutics, 81(1), 91-101, 2012.
24. Kumar N., Sangeetha D., Sunil Reddy P., Malleswara Reddy A., Development and validation of a dissolution test for delayed release capsule formulation of duloxetine hydrochloride, Current Pharmaceutical Analysis, 8(3), 236-246, 2012.
25. Laxmi M., Bhardwaj A., Mehta S., Mehta A., Development and characterization of nanoemulsion as carrier for the enhancement of bioavailability of artemether, Artificial cells, nanomedicine, and biotechnology, 43(5), 334-344, 2015.
26. Lo L., Lu X., Lloyd D., Dissolution testing of a controlled-release capsule formulation: Challenges and solutions using a semi-automated dissolution system, Dissolut. Technol, 20(2), 6-12, 2013.
27. Luo H., Ji D., Li C., Zhu Y., Xiong G., Wan Y., Layered nanohydroxyapatite as a novel nanocarrier for controlled delivery of 5-fluorouracil, International Journal of Pharmaceutics, 513(1-2), 17-25, 2016.
28. Lv G., Chang P.H., Xing X., Jiang W.T., Jean J.S., Li Z., Investigation of intercalation of diphenhydramine into the interlayer of smectite by XRD, FTIR, TG-DTG analyses and molecular simulation, Arabian Journal of Chemistry, 10(6), 855-861, 2017.
29. M Rosenholm J., Sahlgren C., Linden M., Multifunctional mesoporous silica nanoparticles for combined therapeutic, diagnostic and targeted action in cancer treatment, Current drug targets, 12(8), 1166-1186, 2011.
30. Moradı A.N., Yıldız A., Seydiler (Afyonkarahisar) diyatomitleri ile modifiye edilmiş bitümlerin reolojik özelliklerinin araştırılması, Afyon Kocatepe University Graduate School of Natural and Applied Sciences, Master Thesis (Printed), 2021.
31. Queiroz M.F., Teodosio Melo K.R., Sabry D.A., Sassaki G.L., Rocha H.A.O., Does the use of chitosan contribute to oxalate kidney stone formation?, Marine drugs, 13(1), 141-158, 2014.
32. Rea I., Martucci N.M., De Stefano L., Ruggiero I., Terracciano M., Dardano P., Lamberti A., Diatomite biosilica nanocarriers for siRNA transport inside cancer cells, Biochimica et Biophysica Acta (BBA)-General Subjects, 1840(12), 3393-3403, 2014.
33. Reka, A.A., Pavlovski, B., Fazlija, E., Berisha, A., Pacarizi, M., Daghmehchi, M., & Oral, A., Diatomaceous Earth: Characterization, thermal modification, and application, Open Chemistry, 19(1), 451-461, 2021.
34. Rezaeifar M., Mahmoudvand H., Amiria M., Formulation and evaluation of diphenhydramine gel using different gelling agents, Der Pharma Chemica, 8(5), 243-9, 2016.
35. Ruggiero I., Terracciano M., Martucci N.M., De Stefano L., Migliaccio N., Tatè R., Rea I., Diatomite silica nanoparticles for drug delivery, Nanoscale research letters, 9, 1-7, 2014.
36. Silvestri S., Foletto E.L., Preparation and characterization of Fe2O3/TiO2/clay plates and their use as photocatalysts, Ceramics International, 43(16), 14057-14062, 2017.
37. Tang C., Hu D., Cao Q., Yan W., Xing B., Silver nanoparticles-loaded activated carbon fibers using chitosan as binding agent: Preparation, mechanism, and their antibacterial activity, Applied Surface Science, 394, 457-465, 2017.
38. Taş B., Çetin M., Biyolojik orijinli tek doğal mineral: diyatomit, Tübav Bilim Dergisi, 5(2), 28-46, 2012.
39. Thakur G., Singh A., Singh I., Formulation and evaluation of transdermal composite films of chitosan-montmorillonite for the delivery of curcumin, International journal of pharmaceutical investigation, 6(1), 23, 2016.
40. Tian L., Abukhadra M.R., Mohamed A.S., Nadeem A., Ahmad S.F., Ibrahim K.E., Insight into the loading and release properties of an exfoliated kaolinite/cellulose fiber (EXK/CF) composite as a carrier for oxaliplatin drug: cytotoxicity and release kinetics, ACS omega, 5(30), 19165-19173, 2020.
41. Tsai W.T., Lai C.W., Hsien, K.J., Characterization and adsorption properties of diatomaceous earth modified by hydrofluoric acid etching, Journal of Colloid and Interface Science, 297(2), 749-754, 2006.
42. Vilar G., Tulla-Puche J., Albericio F., Polymers and drug delivery systems, Current drug delivery, 9(4), 367-394, 2012.
43. Vona, D., Flemma, A., Piccapane, F., Cotugno, P., Cicco, S.R., Armenise, V., & Ragni, R., Drug delivery through epidermal tissue cells by functionalized biosilica from diatom microalgae, Marine Drugs, 21(8), 438, 2023.
44. Wang C., Hu S., Sun C.C., Expedited development of diphenhydramine orally disintegrating tablet through integrated crystal and particle engineering, Molecular pharmaceutics, 14(10), 3399-3408, 2017.
45. Wang Y., Cai J., Jiang Y., Jiang X., Zhang D., Preparation of biosilica structures from frustules of diatoms and their applications: current state and perspectives, Applied microbiology and biotechnology, 97, 453-460, 2013.
46. Wu X.J., Wang J.D., Cao L.Q., Characterization and adsorption performance of chitosan/diatomite membranes for Orange G removal, e-Polymers, 16(2), 99-109, 2016.
47. Yang, H., Ma, Z., Guan, X., Xiang, Z., Ke, Y., Xia, Y., & Yin, J, Facile fabrication of diatomite‐based sponge with high biocompatibility and rapid hemostasis, Journal of Applied Polymer Science, 138(46), 51360, 2021.
48. Yusan S., Gok C., Erenturk S., Aytas, S., Adsorptive removal of thorium (IV) using calcined and flux calcined diatomite from Turkey: Evaluation of equilibrium, kinetic and thermodynamic data, Applied Clay Science, 67, 106-116, 2012.
49. Yusan S., Korzhynbayeva K., Aytas S., Tazhibayeva S., Musabekov K., Preparation and investigation of structural properties of magnetic diatomite nanocomposites formed with different iron content, Journal of Alloys and Compounds, 608, 8-13, 2014.
50. Zargarian S.S., Haddadi-Asl V., Hematpour H., Carboxylic acid functionalization of halloysite nanotubes for sustained release of diphenhydramine hydrochloride, Journal of Nanoparticle Research, 17, 1-13, 2015.
51. Zhang H., Shahbazi M.A., Mäkilä E.M., da Silva T.H., Reis R.L., Salonen J.J., Santos H.A., Diatom silica microparticles for sustained release and permeation enhancement following oral delivery of prednisone and mesalamine, Biomaterials, 34(36), 9210-9219, 2013.
52. Zheng Y., Fang H., Wang F., Huang H., Yang J., Zuo, G., Fabrication and characterization of mesoporous Si/SiC derived from diatomite via magnesiothermic reduction, Journal of Solid State Chemistry, 277, 654-657, 2019.
53. Zheng Y., Wang A., Enhanced adsorption of ammonium using hydrogel composites based on chitosan and halloysite, Journal of Macromolecular Science, Part A, 47(1), 33-38, 2009.