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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Self-double Emulsified Drug Delivery System of Pyridostigmine Bromide Augmented Permeation Across Caco-2 Cells

Author(s): Shiwani Dharwal, Neha Bajwa, Jitender Madan, Uttam K. Mandal, Kamalinder K. Singh and Ashish Baldi*

Volume 19, Issue 6, 2022

Published on: 11 March, 2022

Page: [520 - 529] Pages: 10

DOI: 10.2174/1570180819666220124113436

Price: $65

Abstract

Aim: The study aims to enhance the permeability of pyridostigmine bromide by developing a self-double emulsifying drug delivery system (SDEDDS) and enteric-coated spheroids.

Background: Pyridostigmine bromide is a reversible anticholinesterase used to treat Myasthenia Gravis, reverse neuromuscular blockade, and prevent nerve gas (i.e., soman) poisoning. It is readily soluble in water, but its poor and irregular intestinal absorption is responsible for its poor oral bioavailability (7.6±2.4%). Many approaches have been made to increase the bioavailability of this drug, but no significant improvement has been achieved to date. Presently pyridostigmine tablets are given orally, and a treatment schedule of multiple doses every day (3–6 times per day) is recommended for adult patients, while sustained-release pyridostigmine (Timespan®) tablets can be taken once or twice daily. An increase in permeability of pyridostigmine bromide may also result in reduced dosage frequency.

Objective: In the present work, it is proposed to develop a self-double emulsifying drug delivery system (SDEDDS) of pyridostigmine bromide which will increase its intestinal permeability and hence its oral bioavailability.

Methods: For the preparation of PB-SDEDDS, the primary water in oil emulsion was mixed with the optimized concentration of Tween 80 using a magnetic stirrer. PB-SDEDDS were converted into spheroids and were then characterized.

Results: The pseudo ternary phase diagram was constructed, showing a double emulsion region. The viscosity of PB-SDEDDS at the different shear rates was found to be 125 mPas. The optimized PBSDEDDS formulation formed a bright white emulsion within 2 minutes, having droplet size around 20-25 μm. In vitro uptake studies of PB-SDEDDS on Caco2 cells demonstrated the increase in Papp value from (4.38±0.27) ×10-4 cm/s to (9.488±0.182) ×10-4 cm/s (2.166 folds) that was attributed to the PB-SDEDDS formulation. In vitro cytotoxicity studies on Caco2 cells revealed that the blank SDEDDS showed almost no toxicity after incubation for 2 hours at various dilutions tested.

Among all formulations, F3 was optimized for the concentration of adsorbent and binder at a concentration of 10% each. SEM showed that the spheroids were spherical, and 73.92% of spheroids were in between 0.595-0.841 mm of size. The optimized formulation had 70.29% spheroids retained on sieve no. 30. The angle of repose showed good flow properties with 25.20 and stability with friability of 0.52 %. The disintegration time of the developed formulation was 3.30 minutes, and drug content was found to be 97.83%. The release studies showed that PB-SDEDDS improved the release significantly compared to the market formulation.

Conclusion: The solid PB-SDEDDS resulted in favorable physical properties and did not affect its drug content and in vitro drug release profile. The self-double emulsifying drug delivery system of pyridostigmine bromide can be explored as a suitable alternative to its solid oral dosage form.

Keywords: Myasthenia gravis, permeability, poor oral bioavailability, pyridostigmine bromide, SDEDDS, SDEDDSspheroids.

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[1]
Abdalla, A.; Mäder, K. Preparation and characterization of a self-emulsifying pellet formulation. Eur. J. Pharm. Biopharm., 2007, 66(2), 220-226.
[http://dx.doi.org/10.1016/j.ejpb.2006.11.015] [PMID: 17196807]
[2]
Cornaire, G.; Woodley, J.; Hermann, P.; Cloarec, A.; Arellano, C.; Houin, G. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int. J. Pharm., 2004, 278(1), 119-131.
[http://dx.doi.org/10.1016/j.ijpharm.2004.03.001] [PMID: 15158955]
[3]
Chopade, V.V.; Chaudhari, P.D. Development and evaluation of self-emulsifying drug delivery system for lornoxicam. Int. J. Res. Dev. Pharm. L. Sci, 2013, 2, 531-537.
[4]
Gales, B.J.; Gales, M.A. Pyridostigmine in the treatment of orthostatic intolerance. Ann. Pharmacother., 2007, 41(2), 314-318.
[http://dx.doi.org/10.1345/aph.1H458] [PMID: 17284509]
[5]
Dixit, R.P.; Nagarsenker, M.S. Self-nanoemulsifying granules of ezetimibe: Design, optimization and evaluation. Eur. J. Pharm. Sci., 2008, 35(3), 183-192.
[http://dx.doi.org/10.1016/j.ejps.2008.06.013] [PMID: 18652892]
[6]
Dong, L. A novel osmotic delivery system: L-OROS SOFTCAP. In: Proceedings of the International Symposium on Controlled Release of Bioactive Materials; Paris, 2000; pp. 23-30.
[7]
Edward, L.L.; Steven, C.S. In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement. Adv. Drug Deliv. Rev., 1997, 23, 163-183.
[http://dx.doi.org/10.1016/S0169-409X(96)00434-6]
[8]
Goodman, L.S.; Gilman, A.; Hardman, J.G.; Limbird, L.E. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed; McGraw-Hill Education: New York, USA, 1996.
[9]
Gursoy, R.N.; Benita, S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed. Pharmacother., 2004, 58(3), 173-182.
[http://dx.doi.org/10.1016/j.biopha.2004.02.001] [PMID: 15082340]
[10]
Iosio, T.; Voinovich, D.; Perissutti, B.; Serdoz, F.; Hasa, D.; Grabnar, I.; Acqua, S.D.; Zara, G.P.; Muntoni, E.; Pinto, J.F. Oral bioavailability of silymarin phytocomplex formulated as self-emulsifying pellets. Phytomedicine, 2011, 18(6), 505-512.
[http://dx.doi.org/10.1016/j.phymed.2010.10.012] [PMID: 21111585]
[11]
Kluwe, W.M.; Page, J.G.; Toft, J.D.; Ridder, W.E.; Chung, H. Pharmacological and toxicological evaluation of orally administered pyridostigmine in dogs. Fundam. Appl. Toxicol., 1990, 14(1), 40-53.
[http://dx.doi.org/10.1016/0272-0590(90)90229-D] [PMID: 2307321]
[12]
Fihn, B.M.; Jodal, M. Permeability of the proximal and distal rat colon crypt and surface epithelium to hydrophilic molecules. Pflugers Arch., 2001, 441(5), 656-662.
[http://dx.doi.org/10.1007/s004240000440] [PMID: 11294247]
[13]
Kanjwal, K.; Karabin, B.; Sheikh, M.; Elmer, L.; Kanjwal, Y.; Saeed, B.; Grubb, B.P. Pyridostigmine in the treatment of postural orthostatic tachycardia: A single-center experience. Pacing Clin. Electrophysiol., 2011, 34(6), 750-755.
[http://dx.doi.org/10.1111/j.1540-8159.2011.03047.x] [PMID: 21410722]
[14]
More, H.N.; Hazare, A.A. Practical pharmaceutics (Physical pharmacy). Manas Prakashan, Kolhapur, 2004, 1, 86-105.
[15]
Morishita, M.; Matsuzawa, A.; Takayama, K.; Isowa, K.; Nagai, T. Improving insulin enteral absorption using water-in-oil-in-water emulsion. Int. J. Pharm., 1998, 172, 189-198.
[http://dx.doi.org/10.1016/S0378-5173(98)00210-5]
[16]
Onuki, Y.; Morishita, M.; Takayama, K. Formulation optimization of water-in-oil-water multiple emulsion for intestinal insulin delivery. J. Control. Release, 2004, 97(1), 91-99.
[http://dx.doi.org/10.1016/j.jconrel.2004.03.010] [PMID: 15147807]
[17]
Panahi, Y.; Yousefi, G.; Sahebkar, A.; Foroutan, S.M.; Zarghi, A.; Shafahatid, A.; Khoddam, A.; Saadat, A. Validation of a high-performance liquid chromatography method for the determination of pyridostigmine in plasma. Asian Biomed., 2013, 7, 275-279.
[18]
Rege, B.D.; Kao, J.P.; Polli, J.E. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur. J. Pharm. Sci., 2002, 16(4-5), 237-246.
[http://dx.doi.org/10.1016/S0928-0987(02)00055-6] [PMID: 12208453]
[19]
Ruan, J.; Liu, J.; Zhu, D.; Gong, T.; Yang, F.; Hao, X.; Zhang, Z. Preparation and evaluation of self-nanoemulsified drug delivery systems (SNEDDSs) of matrine based on drug-phospholipid complex technique. Int. J. Pharm., 2010, 386(1-2), 282-290.
[http://dx.doi.org/10.1016/j.ijpharm.2009.11.026] [PMID: 19961910]
[20]
Setthacheewakul, S.; Mahattanadul, S.; Phadoongsombut, N.; Pichayakorn, W.; Wiwattanapatapee, R. Development and evaluation of self-microemulsifying liquid and pellet formulations of curcumin, and absorption studies in rats. Eur. J. Pharm. Biopharm., 2010, 76(3), 475-485.
[http://dx.doi.org/10.1016/j.ejpb.2010.07.011] [PMID: 20659556]
[21]
Sweetman, S.C. Martinedale, the complete drug reference, 35th ed.; Pharmaceutical Press: London, 2007, p. 576.
[22]
Wang, Z.; Sun, J.; Wang, Y.; Liu, X.; Liu, Y.; Fu, Q.; Meng, P.; He, Z. Solid self-emulsifying nitrendipine pellets: Preparation and in vitro/in vivo evaluation. Int. J. Pharm., 2010, 383(1-2), 1-6.
[http://dx.doi.org/10.1016/j.ijpharm.2009.08.014] [PMID: 19698771]
[23]
Williams, J.I. Human Response to Pyridostigmine Bromide; Macaulay-Brown, Inc.: Fairborn, OH, 1984.
[http://dx.doi.org/10.21236/ADA140960]
[24]
Lv, L.Z.; Tong, C.Q.; Lv, Q.; Tang, X.J.; Li, L.M.; Fang, Q.X.; Yu, J.; Han, M.; Gao, J.Q. Enhanced absorption of hydroxysafflor yellow A using a self-double-emulsifying drug delivery system: In vitro and in vivo studies. Int. J. Nanomedicine, 2012, 7, 4099-4107.
[PMID: 22888246]
[25]
Balakrishnan, P.; Lee, B.J.; Oh, D.H.; Kim, J.O.; Hong, M.J.; Jee, J.P.; Kim, J.A.; Yoo, B.K.; Woo, J.S.; Yong, C.S.; Choi, H.G. Enhanced oral bioavailability of dexibuprofen by a novel solid self-emulsifying drug delivery system (SEDDS). Eur. J. Pharm. Biopharm., 2009, 72(3), 539-545.
[http://dx.doi.org/10.1016/j.ejpb.2009.03.001] [PMID: 19298857]
[26]
Bhikshapathi, D.; Madhukar, P.; Kumar, B.D.; Kumar, G.A. Formulation and characterization of pioglitazone HCl self- emulsifying drug delivery system. Pharm. Lett., 2013, 5, 292-305.
[27]
Boltri, L.; Coceani, N.; De Curto, D.; Dobetti, L.; Esposito, P. Enhancement and modification of etoposide release from crospovidone particles loaded with oil-surfactant blends. Pharm. Dev. Technol., 1997, 2(4), 373-381.
[http://dx.doi.org/10.3109/10837459709022636] [PMID: 9552466]
[28]
Gao, P.; Rush, B.D.; Pfund, W.P.; Huang, T.; Bauer, J.M.; Morozowich, W.; Kuo, M.S.; Hageman, M.J. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J. Pharm. Sci., 2003, 92(12), 2386-2398.
[http://dx.doi.org/10.1002/jps.10511] [PMID: 14603484]
[29]
Giri, T.K.; Choudhary, C.; Ajazuddin, A.; Alexander, A.; Badwaik, H.; Tripathi, D.K. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery. Saudi Pharm. J., 2013, 21(2), 125-141.
[http://dx.doi.org/10.1016/j.jsps.2012.05.009] [PMID: 23960828]
[30]
Kazi, M.; Alhajri, A.; Alshehri, S.M.; Elzayat, E.M.; Al Meanazel, O.T.; Shakeel, F.; Noman, O.; Altamimi, M.A.; Alanazi, F.K. Enhancing oral bioavailability of apigenin using a bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS): In vitro, in vivo and stability evaluations. Pharmaceutics, 2020, 12(8), 749.
[http://dx.doi.org/10.3390/pharmaceutics12080749] [PMID: 32785007]
[31]
Chen, H.; Chang, X.; Weng, T.; Zhao, X.; Gao, Z.; Yang, Y.; Xu, H.; Yang, X. A study of microemulsion systems for transdermal delivery of triptolide. J. Control. Release, 2004, 98(3), 427-436.
[http://dx.doi.org/10.1016/j.jconrel.2004.06.001] [PMID: 15312998]
[32]
Singh, S.K.; Verma, P.R.P.; Razdan, B. Glibenclamide-loaded self-nanoemulsifying drug delivery system: Development and characterization. Drug Dev. Ind. Pharm., 2010, 36(8), 933-945.
[http://dx.doi.org/10.3109/03639040903585143] [PMID: 20184416]
[33]
Zhong, F.; Yu, M.; Luo, C.; Shoemaker, C.F.; Li, Y.; Xia, S.; Ma, J. Formation and characterisation of mint oil/S and CS/water microemulsions. Food Chem., 2009, 115(2), 539-544.
[http://dx.doi.org/10.1016/j.foodchem.2008.12.048]
[34]
Patel, D.; Sawant, K.K. Oral bioavailability enhancement of acyclovir by self-microemulsifying drug delivery systems (SMEDDS). Drug Dev. Ind. Pharm., 2007, 33(12), 1318-1326.
[http://dx.doi.org/10.1080/03639040701385527] [PMID: 18097805]
[35]
Banker, G.S. Tablets. In: The theory and practice of industrial pharmacy, 3rd ed; Lachman, L.; Liberman, H.A., Eds.; Varghese Publishing House: Mumbai, India, 1987.
[36]
Indian Pharmacopoeia. Government of India, Ministry of Health and Family Welfare; Indian Pharmacopoeia Commission: Ghaziabad, India, 2014.

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