İNDOMETAZİN İÇEREN YÜZEN-PULSATİL İÇİ BOŞ BONCUKLARIN HAZIRLANMASI VE İN-VİTRO KARAKTERİZASYONU

Year 2022, Volume: 46 Issue: 3, 931 - 954, 30.09.2022

Emrah Özakar , Hasan Burak Güneş , Rukiye Sevinç Özakar

https://doi.org/10.33483/jfpau.1130916

Abstract

Amaç: Polimerlerin veya mumsu lipidlerin kullanılması ile matriks yapılı kontrollü salım sağlayan sistemler tasarlamak günümüzde popüler bir seçenektir. İçi boş boncuklar (hollowbeads), içinde hava dolu bir boşluğun oluşması ile karakterize formülasyonlardır. Çalışmamızda, indometazin model ilaç olarak seçilmiştir. Hollowbeads yapısını oluşturmak için setil alkol ve uzun süreli salım elde edebilmek için de NaCMC seçilmiştir. Ülser oluşumunu azaltmak ve/veya önlemek ve salımı kontollü elde etmek için Kollicoat® MAE100P kullanılmıştır.
Gereç ve Yöntem: Formülasyonlar, yeni bir teknik olan “wax removol” tekniği kullanılarak hazırlanmıştır. Çapraz bağlayıcı olarak ZnCl2 ve CaCl2’nin farklı konsantrasyonları kullanılmıştır. Önformülasyon çalışmalarında, NaCMC miktarı, çapraz bağlayıcı miktarı ve çapraz bağlanma sürelerini de değiştirerek 24 farklı formülasyon hazırlanmıştır. Formülasyonların yapısı, boyutu, enkapsülasyon etkinliği, verimi, hollow yapısı, uzun süreli salım kapasiteleri incelenmiştir. Bu parametreler NaCMC miktarına, çapraz bağlayıcı tipine, çapraz bağlayıcı miktarına ve çapraz bağlayıcıyla olan temas sürelerine bağlı olarak istatistiksel olarak değerlendirilmiştir.
Sonuç ve Tartışma: Hollowbeads’ler, SEM ve FT-IR ile karakterize edilmiştir. pH 1.2 HCl ve pH 6.8 fosfat tamponu ortamlarında in vitro salım, şişme ve yüzme çalışmaları gerçekleştirilmiştir. Salım kinetikleri ve salım mekanizmaları açıklanmıştır. Formülasyonların uzun süreli stabiliteleri, enkapsülasyon etkinlikleri, ilaç yükleme etkinlikleri ve verimleri de değerlendirilmiştir. Umut vadeden iki formülasyonun (F2 ve F19), 24 saat süreyle hem mide hem de bağırsak ortamında indometazin salımı gerçekleştirebildiği tespit edilmiştir.

Keywords

İndometazin, kontrollü salım, mum yerdeğiştirme, oyuk boncuk, polimer

Supporting Institution

Atatürk Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi

Project Number

TLP-2021-8892

Thanks

Bu çalışmayı desteklediği için Atatürk Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimine teşekkür ederiz.

PREPARATION AND IN-VITRO CHARACTERIZATION OF FLOATING-PULSATILE HOLLOWBEADS CONTAINING INDOMETHACIN

Abstract

Objective: Objective: Designing matrix structured controlled release systems using polymers or waxy lipids is a popular option today. Hollowbeads are formulations characterized by the formation of an air-filled cavity inside. In our study, indomethacin was chosen as a model drug. Cetyl alcohol was selected to create the hollowbeads structure, and NaCMC was chosen to achieve long-term release. Kollicoat® MAE100P was used to reduce and/or prevent ulcer formation and control release.
Material and Method: The formulations were prepared using a new “wax removal” technique. Different concentrations of ZnCl2 and CaCl2 were used as crosslinkers. In the preformulation studies, 24 different formulations were prepared by changing the amount of NaCMC, the amount of crosslinker, and the crosslinking time. The structure, size, encapsulation efficiency, yield, hollow structure, and long-term release capacity were investigated in the formulations. These parameters were statistically evaluated depending on the amount of NaCMC, the type of crosslinker, the amount of crosslinker, and contact times with the crosslinker.
Result and Discussion: Hollowbeads were characterized by SEM and FT-IR. In vitro release studies, release kinetics, and release mechanisms were performed in pH 1.2 HCl and pH 6.8 phosphate buffer media. Swelling, and buoyancy studies were performed. The long-term stability, encapsulation efficiencies, drug loading efficiencies, and yields of the formulations were also evaluated. Two promising formulations (F2 and F19) were found to be able to release indomethacin in both the stomach and intestinal media for 24 hours.

Keywords

Controlled release, hollowbeads, indomethacin, polymer, wax removal

Project Number

TLP-2021-8892

References

• Hsu, Y.T., Kao, C.Y., Ho, M.H., Lee, S.P. (2021). To control floating drug delivery system in a simulated gastric environment by adjusting the Shell layer formulation. Biomaterials Research, 25(1), 31. [CrossRef]
• 2. Abdul, S., Chandewar, A.V., Jaiswal, S.B.. (2010). A flexible technology for modified-release drugs: Multiple-unit pellet system (MUPS). Journal of Controlled Release, 147(1), 2-16. [CrossRef]
• 3. Uhrich, K.E., S.M. Cannizzaro, R.S. Langer, K.M. Shakesheff. (1999). Polymeric systems for controlled drug release. Chemical Reviews, 99(11), 3181-3198. [CrossRef]
• 4. Bhowmik, D., Goinath, H., Kumar, B.P., Duraivel, S., Kumar, K.P.S. (2012). Controlled Release Drug Delivery Systems. Pharma Innovation 1(10), 24-32. 5. Miyazaki, S., A. Nakayama, M. Oda, M. Takada, D. Attwood. (1995). Drug release from oral mucosal adhesive tablets of chitosan and sodium alginate. International Journal of Pharmaceutics, 118(2), 257-263. [CrossRef]
• 6. Ulbrich, K., Holá, K., Šubr, V., Bakandritsos, A., Tuček, J., Zbořil, R. (2016). Targeted drug delivery with polymers and magnetic nanoparticles: covalent and noncovalent approaches, release control, and clinical studies. Chemical Reviews, 116(9), 5338-5431. [CrossRef]
• 7. Geraili, A., Xing, M., Mequanint, K. (2021). Design and fabrication of drug-delivery systems toward adjustable release profiles for personalized treatment. View, 2(5), 20200126. [CrossRef]
• 8. Srivastava, A., Yadav, T., Sharma, S., Nayak, A., Kumari, A.A., Mishra, N. (2015). Polymers in drug delivery. Journal of Biosciences and Medicines, 4(1), 69-84.
• 9. Rokhade, A.P., Agnihotri, S.A., Patil, S.A., Mallikarjuna, N.N., Kulkarni, P.V., Aminabhavi, T.M. (2006). Semi-interpenetrating polymer network microspheres of gelatin and sodium carboxymethyl cellulose for controlled release of ketorolac tromethamine. Carbohydrate Polymers, 65(3), 243-252. [CrossRef]
• 10. Kaushik, A.Y., Tiwari, A.K., Gaur, A. (2015). Role of excipients and polymeric advancements in preparation of floating drug delivery systems. International Journal of Pharmaceutical Investigation, 5(1), 1-12. [CrossRef]
• 11. Kumar, K., Dhawan, N., Sharma, H., Vaidya, S., Vaidya, B. (2014). Bioadhesive polymers: novel tool for drug delivery. Artif Cells Nanomed Biotechnol, 42(4), 274-283. [CrossRef]
• 12. Awasthi, R., Kulkarni, G.T. (2014). Development of novel gastroretentive drug delivery system of gliclazide: hollow beads. Drug Development and Industrial Pharmacy, 40(3), 398-408. [CrossRef]
• 13. Singh, B.N., Kim, K.H. (2000). Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. Journal of Controlled Release, 63(3), 235-259. [CrossRef]
• 14. Sriamornsak, P., Asavapichayont, P., Nunthanid, J., Luangtana-Anan, M., Limmatvapirat, S., Piriyaprasarth, S. (2008). Wax-incorporated emulsion gel beads of calcium pectinate for intragastric floating drug delivery. AAPS PharmSciTech, 9(2), 571-576. [CrossRef]
• 15. Prajapati, S., Patel, L., Patel, C. (2011). Polymers for floating drug delivery system. Systematic reviews in pharmacy, 2(1), 1. [CrossRef]
• 16. Ramli, R.A. (2017). Hollow polymer particles: a review. RSC Advances, 7(83), 52632-52650. [CrossRef]
• 17. Huanbutta, K., Nernplod, T., Akkaramongkolporn, P., Sriamornsak, P. (2017). Design of porous Eudragit® L beads for floating drug delivery by wax removal technique. Asian Journal of Pharmaceutical Sciences, 12(3), 227-234. [CrossRef]
• 18. Lucas, S. (2016). The pharmacology of indomethacin. Headache: The Journal of Head and Face Pain, 56(2), 436-446. [CrossRef]
• 19. Elkhodairy, K.A., Elsaghir, H.A. , Al-Subayiel, A.M. (2014). Formulation of indomethacin colon targeted delivery systems using polysaccharides as carriers by applying liquisolid technique. BioMed Research International, 2014. [CrossRef]
• 20. El-Leithy, E.S., Ibrahim, H.K., Sorour, R.M. (2015). In vitro and in vivo evaluation of indomethacin nanoemulsion as a transdermal delivery system. Drug Delivery, 22(8), 1010-1017. [CrossRef]
• 21. Helleberg, L. (1981). Clinical pharmacokinetics of indomethacin. Clinical pharmacokinetics, 6(4), 245-258. [CrossRef]
• 22. Vane, J.R., Botting, R.M. (1998). Mechanism of action of nonsteroidal anti-inflammatory drugs. The American Journal of Medicine, 104(3S1), 2S-8S. [CrossRef]
• 23. Suleyman, H., Albayrak, A., Bilici, M., Cadirci, E., Halici, Z. (2010). Different mechanisms in formation and prevention of indomethacin-induced gastric ulcers. Inflammation, 33(4), 224-234. [CrossRef]
• 24. Badve, S.S., Sher, P., Korde, A., Pawar, A.P.. (2007). Development of hollow/porous calcium pectinate beads for floating-pulsatile drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 65(1), 85-93. [CrossRef]
• 25. Özakar, R.S., Özakar, E.. (2021). The effect of polymer amount and crosslinker ratio in polymeric hydrogel beads on characterization. Journal of Research in Pharmacy, 25(5). [CrossRef]
• 26. Taranalli, S.S., Dandagi, P.M., Mastiholimath, V.S. (2015). Development of hollow/porous floating beads of metoprolol for pulsatile drug delivery. European Journal of Drug Metabolism and Pharmacokinetics, 40(2), 225-233. [CrossRef]
• 27. Lin, H.R., Ou, L.H., Lin, Y.J., Ling, M.H.. (2010). Hollow, pH‐sensitive calcium–alginate/poly (acrylic acid) hydrogel beads as drug carriers for vancomycin release. Journal of Applied Polymer Science, 118(4), 1878-1886. [CrossRef]
• 28. Özakar, R.S. (2022). Development and in vitro characterization of gastroretentive formulations as calcium pectinate hydrogel pellets of pregabalin by ionotropic gelation method. Indian Journal of Pharmaceutical Education and Research, 56(1), S9-S20. [CrossRef]
• 29. Ozakar, R.S., Ozakar, E. (2022). Different biopolymers' effects on the evaluation and characterization of floating tablets prepared by lyophilization technique to improve the quality control parameters. Polymer-Korea, 46(2), 145-158. [CrossRef]
• 30. Koca, M., Özakar, R.S., Ozakar, E., Sade, R., Pirimoğlu, B., Özek, N.Ş., Aysin, F. (2022). Preparation and characterization of nanosuspensions of triiodoaniline derivative new contrast agent, and investigation into its cytotoxicity and contrast properties. Iranian Journal of Pharmaceutical Research, 21(1), e123824. [CrossRef]
• 31. Chauhan, Y.S., Kataria, U., Dashora, A. (2018). Formulation and evaluation of floating tablet for indomethacin. Journal of Drug Delivery and Therapeutics, 8(4), 338-345. [CrossRef]
• 32. Giri, T., Choudhary, C., Alexander, A., Badwaik, H., Tripathy, M., Tripathi, D. (2013). Sustained release of diltiazem hydrochloride from cross-linked biodegradable IPN hydrogel beads of pectin and modified xanthan gum. Indian Journal of Pharmaceutical Sciences, 75(6), 619. [CrossRef]
• 33. Damiati, S.A., Damiati, S.. (2021). Microfluidic synthesis of indomethacin-loaded plga microparticles optimized by machine learning. Frontiers in Molecular Biosciences, 8, .677547. [CrossRef]
• 34. Verma, A., Kumar, P., Rastogi, V., Mittal, P. (2021). Preparation and evaluation of polymeric beads composed of chitosan–gellan gum–gum ghatti/-gum karaya polyelectrolyte complexes as polymeric carrier for enteric sustained delivery of diclofenac sodium. Future Journal of Pharmaceutical Sciences, 7(1), 1-13. [CrossRef]
• 35. Chemate, S., Godge, G., Pawa, K., Rupnar, K. (2016). Preparation and evaluation of hollow calcium pectinate beads for floating-pulsatile drug delivery. Turkish Journal of Pharmaceutical Sciences, 13(1), 91-102.
• 36. Somani, V., Shahi, S., Udavant, Y., Atram, S., Satpute, R., Shinde, N. (2009). A floating pulsatile drug delivery system based on hollow calcium pectinate beads. Asian Journal of Pharmaceutics (AJP), 3(2). [CrossRef]
• 37. Akhgari, A., Heshmati, Z., Garekani, H.A., Sadeghi, F., Sabbagh, A., Makhmalzadeh, B.S., Nokhodchi, A. (2017). Indomethacin electrospun nanofibers for colonic drug delivery: In vitro dissolution studies. Colloids and Surfaces B: Biointerfaces, 152, 29-35. [CrossRef]
• 38. Penjuri, S.C.B., Damineni, S., Ravouru, N., Poreddy, S.R. (2017). Self-emulsifying formulation of indomethacin with improved dissolution and oral absorption. Turkish Journal of Pharmaceutical Sciences, 14(2), 108. [CrossRef]
• 39. Senthilnathan, B., Suba, V. (2013). Formulation and evaluation of pulsatile drug delivery of miglitol using pulsincap technology. Inventi Rapid:NDDS. 12 (2), 557.