 |
 |
 |
 |
 |
 |
Sains Malaysiana 53(11)(2024): 3747-3759
http://doi.org/10.17576/jsm-2024-5311-17
The Effects of
Different Solubilizing Agents on the Transport and Pharmacokinetic Profiles of
Indomethacin: in vitro and in vivo Approach
(Kesan Agen Pelarut Berbeza Terhadap Profil Pengangkutan dan Farmakokinetik Indometasin: Pendekatan in
vitro dan in vivo)
SITI
AISYAH ZAINUDDIN1,3, ABDUL LATIP AB HAMID1, AQILA IMAN
RAFANDI1, MASHANI MOHAMAD2,4, KHURIAH ABDUL HAMID1,4,* &
SYED HAROON KHALID1,4
1Department
of Pharmaceutical Technology, Faculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor, 42300 Puncak Alam,
Selangor, Malaysia
Received: 26 July
2024/Accepted: 27 September 2024
Abstract
The poor
water solubility of new chemical entities (NCEs) discovered in pharmaceutical
screening programs hampers their development and limits effective treatment
delivery. Solubilizing agents offer a direct approach to increase solubility
and oral bioavailability. This study employed indomethacin as a model drug from
Biopharmaceutical Classification System (BCS) class II. Solubilizing agents,
including propylene glycol, Transcutol P, Labrasol, PEG 400, and Tween 80, were separately added at
10% (v/v) to 1 mg/5 mL for in vitro diffusion chamber and 10 mg/kg body
weight for in vivo oral absorption studies of indomethacin. Drug
concentrations were analysed using reversed-phase high-performance liquid
chromatography (HPLC). In vitro, 10% (v/v) labrasol,
PEG 400, and Tween 80 significantly (p<0.01) increased indomethacin
permeability across the rat intestinal layer. However, Transcutol P and PG (propylene glycol 10%v/v) showed no discernible impact on in vitro permeability. In the in vivo oral absorption study, PG (propylene glycol
10%v/v) and Transcutol P significantly (p<0.05)
enhanced indomethacin absorption, while 10% (v/v) labrasol,
PEG 400, and Tween 80 did not show significant effects. No in vitro-in vivo correlation (IVIVC) was observed, likely due to the physicochemical properties
of indomethacin and the complex physiological environment in the
gastrointestinal (GI) tract. Further investigations are necessary to
comprehensively understand the factors affecting indomethacin solubility and
absorption, considering both the drug’s properties and the GI tract’s
physiological conditions.
Keywords: Drug
transport; indomethacin; pharmacokinetic profiles; solubility; solubilizing
agents
Abstrak
Keterlarutan air yang rendah bagi entiti kimia baharu (NCEs) yang ditemui dalam program penyaringan farmaseutikal menghalang perkembangan ubatan tersebut dan mengehadkan keberkesanan rawatan. Agen pelarut menawarkan pendekatan langsung untuk meningkatkan keterlarutan dan bioketersediaan oral. Kajian ini menggunakan indometasin sebagai model sebatian ubat berdasarkan Sistem Pengelasan Biofarmaseutikal (BCS) kelas II. Setiap agen pelarut, termasuk propilena glikol, Transcutol P, Labrasol, PEG 400 dan Tween 80 pada kepekatan 10% (v/v) ditambah kepada 1
mg/5 mL sebatian indometasin secara berasingan untuk kajian resapan in vitro dan sebanyak 10 mg/kg berat badan diberikan kepada tikus untuk kajian penyerapan sebatian indometasin secara oral. Sebatian indometasin dianalisis menggunakan kaedah kromatografi cecair berprestasi tinggi – fasa terbalik (KCPT-Fasa Terbalik). Dalam kajian in vitro, sebanyak 10% (v/v) labrasol, PEG
400 dan Tween 80 telah meningkatkan kebolehtelapan indometasin merentasi lapisan usus tikus dengan signifikan (p<0.01). Walau bagaimanapun, 10% (v/v) propilena glikol dan Transcutol P tidak menunjukkan kesan yang signifikan terhadap kebolehtelapan melalui kajian in vitro. Dalam kajian penyerapan oral secara in vivo, 10% (v/v) propilena glikol dan Transcutol P meningkatkan penyerapan sebatian indometasin secara signifikan (p<0.05), manakala 10% (v/v) labrasol, PEG 400 dan Tween 80 tidak menunjukkan kesan yang signifikan. Keputusan kajian menunjukkan tiada korelasi in vitro-in
vivo (IVIVC), berkemungkinan disebabkan oleh sifat fizikokimia indometasin dan persekitaran fisiologi yang kompleks dalam saluran gastrointestinal
(GI). Kajian lanjut diperlukan untuk memahami secara menyeluruh faktor yang mempengaruhi keterlarutan dan penyerapan indometasin dengan mempertimbangkan kedua-dua sifat sebatian dan keadaan fisiologi saluran GI.
Kata kunci: Pengangkutan ubat; indometasin; profil farmakokinetik; keterlarutan; agen pelarut
REFERENCES
Abdollahi, A.R., Firouzian,
F., Haddadi, R. & Nourian, A. 2021. Indomethacin
loaded dextran stearate polymeric micelles improve adjuvant-induced arthritis
in rats: Design and in vivo evaluation. Inflammopharmacology 29(1): 107-121.
Aguiar, G.P.S., Arcari,
B.D., Chaves, L.M.P.C., Magro,
C.D., Boschetto, D.L., Piato,
A.L., Lanza, M. & Vladimir Oliveira, J. 2018. Micronization of trans-resveratrol by supercritical fluid: Dissolution, solubility and in
vitro antioxidant activity. Ind. Crops Prod. 112: 1-5.
Alqahtani, M.S., Kazi, M., Alsenaidy, M.A. & Ahmad, M.Z. 2021. Advances in
oral drug delivery. Front Pharmacol. 12:
618411.
Amaral Silva, D., Le Merdy,
M., Alam, K.D., Wang, Y., Bao, Q., Malavia, N., Burgess, D. & Lukacova,
V. 2024. Development of mechanistic in vitro–in vivo extrapolation to
support bioequivalence assessment of long-acting injectables. Pharmaceutics 16(4): 522.
Andrusenko, I., Hamilton, V., Lanza, A.E., Hall,
C.L., Mugnaioli, E., Potticary,
J., Buanz, A., Gaisford,
S., Piras, A.M., Zambito,
Y., Hall, S.R. & Gemmi, M. 2021. Structure
determination, thermal stability and dissolution rate of δ-indomethacin. International
Journal of Pharmaceutics 608: 121067.
https://doi.org/10.1016/j.ijpharm.2021.121067
Anuar, N., Sabri, A.H., Bustami Effendi, T.J. & Hamid, K.A. 2020. Development and characterisation of
ibuprofen-loaded nanoemulsion with enhanced oral
bioavailability. Heliyon 6: e04570.
Azman, M., Sabri, A.H., Anjani, Q.K., Mustaffa, M.F. & Hamid, K.A. 2022. Intestinal
absorption study: Challenges and absorption enhancement strategies in improving
oral drug delivery. Pharmaceuticals 15(8): 975.
Bertoni, S., Albertini, B., Ferraro, L., Beggiato, S., Dalpiaz, A. & Passerini, N. 2019. Exploring the use of spray congealing
to produce solid dispersions with enhanced indomethacin bioavailability: in
vitro characterization and in vivo study. Eur. J. Pharm. Biopharm. 139: 132-141.
Bhoopathy, S., Bode, C., Naageshwaran,
V., Weiskircher-Hildebrant, E., Mukkavilli,
V. & Hidalgo, I.J. 2021. Principles and experimental considerations for in
vitro transporter interaction assays. In Enzyme Kinetics in Drug Metabolism.
Methods in Molecular Biology, vol 2342, edited by Nagar, S., Argikar,
U.A. & Tweedie, D. New York: Humana. pp. 339-365.
Broesder, A., Woerdenbag,
H.J., Prins, G.H., Nguyen, D.N., Frijlink,
H.W. & Hinrichs, W.L.J. 2020. pH-dependent ileocolonic drug delivery, part
I: In vitro and clinical evaluation of novel systems. Drug Discov. Today 25(8): 1362-1373.
Buckley, S.T., Frank, K.J., Fricker, G.
& Brandl, M. 2013. Biopharmaceutical
classification of poorly soluble drugs with respect to “enabling formulations”. Eur. J. Pharm. Sci. 50(1): 8-16.
Deshpande, T.M., Shi, H., Pietryka, J., Hoag, S.W. & Medek,
A. 2018. Investigation of polymer/surfactant interactions and their impact on
itraconazole solubility and precipitation kinetics for developing spray-dried
amorphous solid dispersions. Mol. Pharm. 15(3): 962-974.
Di Cagno, M.P.
& Stein, P.C. 2019. Studying the effect of solubilizing agents on drug
diffusion through the unstirred water layer (UWL) by localized spectroscopy. Eur.
J. Pharm. Biopharm. 139: 205-212.
Fedi, A., Vitale, C., Ponschin,
G., Ayehunie, S., Fato, M.
& Scaglione, S. 2021. In vitro models replicating the human
intestinal epithelium for absorption and metabolism studies: A systematic
review. Journal of Controlled Release 335: 247-268.
Hamid, K.A., Katsumi, H., Sakane, T. & Yamamoto, A. 2009. The effects of common
solubilizing agents on the intestinal membrane barrier functions and membrane
toxicity in rats. Int. J. Pharm. 379(1-2): 100-108.
Hansch, C. & Fujita, T. 1964. A method for
the correlation of biological activity and chemical structure. J. Am. Chem.
Soc. 86(8): 1616-1626.
Hu, L., Sun, C., Song, A., Chang, D.,
Zheng, X., Gao, Y., Jiang, T. & Wang, S. 2014. Alginate encapsulated
mesoporous silica nanospheres as a sustained drug delivery system for the
poorly water-soluble drug indomethacin. Asian Journal of Pharmaceutical
Sciences 9(4): 183-190.
Huang, S. & Williams, R.O. 2017.
Effects of the preparation process on the properties of amorphous solid
dispersions. AAPS PharmSciTech. 19(5):
1971-1984.
Ismail, A., Kerdpol,
K., Rungrotmongkol, T., Tananuwong,
K., Ueno, T., Ekasit, S., Muangsin,
N. & Krusong, K. 2021. Solubility enhancement of
poorly water soluble domperidone by complexation with the large ring
cyclodextrin. Int. J. Pharm. 606: 120909.
Jaafar, M.H.M. & Hamid, K.A. 2019.
Chitosan-coated alginate nanoparticles enhanced absorption profile of insulin
via oral administration. Curr. Drug Deliv. 16(7): 672-686.
Johnson, K.C. & Swindell, A.C. 1996.
Guidance in the setting of drug particle size specifications to minimize
variability in absorption. Pharmaceutical Research 13(12): 1795-1798.
Kong, D., Zhao, J., Tang, S., Shen, W.
& Kee Lee, H. 2021. Logarithmic data processing can be used justifiably in
the plotting of a calibration curve. Anal Chem. 93(36): 12156-12161.
Koonrungsesomboon, N., Teekachunhatean,
S., Chansakaow, S. & Hanprasertpong,
N. 2020. Clinical efficacy and safety of yellow oil formulations 3 and 4 versus
indomethacin solution in patients with symptomatic osteoarthritis of the knee:
A randomized controlled trial. Evidence-Based Complement. Altern. Med. 2020: 5782178.
Kramer, S.D. 1999. Absorption prediction
from physicochemical parameters. Pharm. Sci. Technol. Today 2(9):
373-380.
Kratz, J.M., Teixeira, M.R., Ferronato, K., Teixeira, H.F., Koester, L.S. & Simões, C.M.O. 2012. Preparation, characterization, and in
vitro intestinal permeability evaluation of
thalidomide-hydroxypropyl-β-cyclodextrin complexes. AAPS PharmSciTech. 13(1): 118-124.
Kumar, S., Bhargava, D., Thakkar, A. &
Arora, S. 2013. Drug carrier systems for solubility enhancement of BCS class II
drugs: A critical review. Crit. Rev. Ther. Drug
Carrier Syst. 30(3): 217-256.
Larregieu, C.A. & Benet, L.Z. 2014.
Distinguishing between the permeability relationships with absorption and
metabolism to improve BCS and BDDCS predictions in early drug discovery. Mol.
Pharm. 11(4): 1335-1344.
Lehto, P., Kortejärvi,
H., Liimatainen, A., Ojala,
K., Kangas, H., Hirvonen, J., Tanninen,
V.P. & Peltonen, L. 2011. Use of conventional
surfactant media as surrogates for FaSSIF in
simulating in vivo dissolution of BCS class II drugs. Eur. J. Pharm. Biopharm. 78(3): 531-538.
Liu, X., Feng, X., Williams, R.O. &
Zhang, F. 2017. Characterization of amorphous solid dispersions. J. Pharm. Investig. 48(1): 19-41.
Lu, Y., Kim, S. & Park, K. 2011. In
vitro-in vivo correlation: Perspectives on model development. Int. J.
Pharm. 418(1): 142-148.
Lucas, S. 2016. The pharmacology of
indomethacin. Headache 56(2): 436-446.
Mistry, B., Patel, N., Jamei,
M., Rostami-Hodjegan, A. & Martinez, M.N. 2016.
Examining the use of a mechanistic model to generate an in vivo/in vitro correlation: Journey through a thought process. AAPS Journal 18(5):
1144-1158.
Norouzi Zahra & Abdouss Majid. 2023. Electrospun nanofibers using
β-cyclodextrin grafted chitosan macromolecules loaded with indomethacin as
an innovative drug delivery system. International Journal of Biological
Macromolecules 233: 123518.
Palanisamy, M. & Khanam, J. 2014. Effect of
physiochemical variables on phase solubility and dissolution behavior of indomethacin solid dispersion system. Journal
of Pharmaceutical Investigation 44(3): 147-162.
Park, C., Meghani,
N.M., Shin, Y., Oh, E., Park, J.B., Cui, J.H., Cao, Q.R., Tran, T.T-D., Tran,
P.H-L. & Lee, B-J. 2019. Investigation of crystallization and salt
formation of poorly water-soluble telmisartan for enhanced solubility.
Pharmaceutics 11(3): 102.
Ranjan, A. & Jha, P.K. 2022. Recent
advances in dissolution testing and their use to improve in vitro–in vivo correlations in oral drug formulations. Journal of Pharmaceutical Innovation 17(3): 1011-1026.
Sathisaran, I. & Dalvi, S.V. 2018. Engineering
cocrystals of poorly water-soluble drugs to enhance dissolution in aqueous
medium. Pharmaceutics 10(3): 108.
Savjani, K.T., Gajjar,
A.K. & Savjani, J.K. 2012. Drug solubility:
Importance and enhancement techniques. ISRN Pharm. 2012: 195727.
Shakeel, F., Haq,
N., Alanazi, F.K. & Alsarra,
I.A. 2014. Thermodynamic modeling for solubility
prediction of indomethacin in self-nanoemulsifying drug delivery system
(SNEDDS) and its individual components. Drug Development and Industrial
Pharmacy 40(9): 1240-1245.
Shakeel, F., Haq,
N., El-Badry, M., Alanazi,
F.K. & Alsarra, I.A. 2013. Ultra
fine super self-nanoemulsifying drug delivery system (SNEDDS) enhanced
solubility and dissolution of indomethacin. Journal of Molecular Liquids 180: 89-94.
Shriniwas, Y., Sumit, P.,
Pankaj, S. & Anurag, B. 2014. Design & development of solid self micro-emulsifying osmotic drug delivery system for isradipine. J. Drug Deliv. Ther. 4(3-s): 28-41.
Song, D., Guo, J., Han, F., Zhang, W.,
Wang, Y. & Wang, Y. 2013. Establishment of an in vitro model of the
human placental barrier by placenta slice culture and ussing chamber. Biosci. Biotechnol. Biochem. 77(5): 1030-1034.
Vandana, K.R., Raju, Y.P., Chowdary, V.H.,
Sushma, M. & Kumar, N.V. 2014. An overview on in situ micronization technique - An emerging novel concept in
advanced drug delivery. Saudi Pharm J. 22(4): 283-289.
Villar-Martínez, M.D., Moreno-Ajona,
D., Chan, C. & Goadsby, P.J. 2021.
Indomethacin-responsive headaches - A narrative review. Headache 61(5):
700-714.
Vinarov, Z., Abdallah, M., Agundez, J.A.G., Allegaert, K., Basit, A.W., Braeckmans, M., Ceulemans, J., Corsetti, M.,
Griffin, B.T., Grimm, M., Keszthelyi, D., Koziolek, M., Madla, C.M.,
Matthys, C., McCoubrey, L.E., Mitra, A., Reppas, C., Stappaerts, J., Steenackers, N., Trevaskis, N.L., Vanuytsel, T., Vertzoni,
M., Weitschies, W., Wilson, C. & Augustijns, P. 2021. Impact of gastrointestinal tract variability on oral drug
absorption and pharmacokinetics: An UNGAP review. European Journal of
Pharmaceutical Sciences 162: 105812.
Wang, L.Y., Yu Y.M.,, Jiang, F.B., Li, Y.T., Wu, Z.Y. & Yan, C.W. 2020. The first zwitterionic
cocrystal of indomethacin with amino acid showing optimized physicochemical
properties as well as accelerated absorption and slowed elimination: in vivo. New Journal of Chemistry 44(10): 3930-3939.
https://doi.org/10.1039/c9nj06180k
Wang, W., Li, M., Yang, Q., Liu, Q., Ye, M.
& Yang, G. 2020. The opposed effects of polyvinylpyrrolidone K30 on
dissolution and precipitation for indomethacin supersaturating drug delivery
systems. AAPS PharmSciTech. 21(3): 107.
https://doi.org/10.1208/s12249-020-01647-7
Xi, Z., Zhang, W., Fei, Y., Cui, M., Xie, L., Chen, L. & Xu, L. 2020. Evaluation of the
solid dispersion system engineered from mesoporous silica and polymers for the
poorly water soluble drug indomethacin: in vitro and in vivo. Pharmaceutics 12(2): 144.
Yeh, K.C., Yeh, T.K., Huang, C.Y., Hu,
C.B., Wang, M.H., Huang, Y.W., Chou, L.H., Ho, H.H., Song, J.S., Hsu, T., Jiaang, W.T., Chao, Y.S. & Chen, C.T. 2021. DBPR108, a novel dipeptidyl
peptidase-4 inhibitor with antihyperglycemic activity. Life Sci. 278:
119574.
Zhang, W., Zheng, N., Chen, L., Xie, L., Cui, M., Li, S. & Xu, L. 2018. Effect of shape
on mesoporous silica nanoparticles for oral delivery of indomethacin. Pharmaceutics 11(1): 4.
Zhao, W., Uehera,
S., Tanaka, K., Tadokoro, S., Kusamori, K., Katsumi,
H., Sakane, T. & Yamamoto, A. 2016. Effects of polyoxyethylene alkyl ethers on the intestinal transport
and absorption of rhodamine 123 : A
P-glycoprotein substrate by in vitro and in vivo studies. J.
Pharm. Sci. 105(4): 1526-1534.
|
|||
|
