Login Register Cart 0
Generic placeholder image

Drug Delivery Letters

Editor-in-Chief

ISSN (Print): 2210-3031
ISSN (Online): 2210-304X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Effect of Surface Charge Density of a w/o/w Emulsion on the Brain Targeting of Levodopa in Rats for the Treatment of Parkinson’s Disease

Author(s): Chandir C. Ramani*, R. Jayachandra Babu*, Muralikrishnan Dhanasekaran, S.S. Apte and Devaraj Rambhau

Volume 12, Issue 4, 2022

Published on: 29 August, 2022

Page: [302 - 310] Pages: 9

DOI: 10.2174/2210303112666220817100319

Price: $65

Abstract

Background: Amidst levodopa being considered as the “Gold standard” in the treatment of Parkinson’s disease (PD), it still has critical therapeutic issues with its dose regimen and dosage forms leading to severe adverse drug effects, decreased drug efficacy during chronic use, and requires an enforced “drug holiday” in PD patients. Hence, in this study, we designed a novel levodopa and carbidopa water-in-oil-in-water (w/o/w) formulation for bioavailability improvement in the central nervous system (CNS).

Methods: The new one-in-one embedment of the w/o/w levodopa and carbidopa emulsion formulation was obtained by a double emulsion technique. The plasma and brain levels following intravenous administration of the emulsions in rats were determined.

Results: The incorporation of stearylamine (a cationic surfactant) considerably increased the surface charge density of the emulsion droplets. This formulation exhibited a narrow particle size distribution enabling parenteral administration. The formulation also provided a high drug loading capacity. In in vivo study, this novel formulation significantly increased the bioavailability of levodopa in the CNS (P < 0.001). The strong resistance to desorption (due to higher charge density) and the presence of positive charge on the particles upon dilution may be the main reason for enhanced brain levels of levodopa.

Conclusion: Our current formulation F5 may decrease the dose of levodopa, leading to decreased adverse effects and dosing problems, thus appreciably benefit PD patients in the future.

Keywords: Levodopa, brain targeting, CNS bioavailability, surface charge density, multiple emulsion, Parkinson’s disease.

« Previous Next »
Graphical Abstract

[1]
Muralikrishnan, D.; Mohanakumar, K.P. Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. FASEB J., 1998, 12(10), 905-912.
[http://dx.doi.org/10.1096/fasebj.12.10.905] [PMID: 9657530]
[2]
Manyam, B.V.; Dhanasekaran, M.; Hare, T.A. Effect of antiparkinson drug HP-200 (Mucuna pruriens) on the central monoaminergic neurotransmitters. Phytother. Res., 2004, 18(2), 97-101.
[http://dx.doi.org/10.1002/ptr.1407] [PMID: 15022157]
[3]
Van, B.M.; Sierra, M.A.; Alarcon, G.J.; Perez, C.A.; Morales, J.A. Novel approaches for the treatment of Alzheimer’s and Parkinson’s disease. Int. J. Mol. Sci., 2019, 20(3), 719.
[http://dx.doi.org/10.3390/ijms20030719] [PMID: 30743990]
[4]
Ellis, J.M.; Fell, M.J. Current approaches to the treatment of Parkinson’s Disease. Bioorg. Med. Chem. Lett., 2017, 27(18), 4247-4255.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.075] [PMID: 28869077]
[5]
Urso, D.; Chaudhuri, K.R.; Qamar, M.A.; Jenner, P. Improving the delivery of levodopa in Parkinson’s disease: A review of approved and emerging therapies. CNS Drugs, 2020, 34(11), 1149-1163.
[http://dx.doi.org/10.1007/s40263-020-00769-7] [PMID: 33146817]
[6]
Olanow, C.W.; Calabresi, P.; Obeso, J.A. Continuous dopaminergic stimulation as a treatment for Parkinson’s disease: Current status and future opportunities. Mov. Disord., 2020, 35(10), 1731-1744.
[http://dx.doi.org/10.1002/mds.28215] [PMID: 32816321]
[7]
Olanow, C.W.; Stocchi, F. Levodopa: A new look at an old friend. Mov. Disord., 2018, 33(6), 859-866.
[http://dx.doi.org/10.1002/mds.27216] [PMID: 29178365]
[8]
Kreuter, J. Nanoparticulate systems for brain delivery of drugs. Adv. Drug Deliv. Rev., 2001, 47(1), 65-81.
[http://dx.doi.org/10.1016/S0169-409X(00)00122-8] [PMID: 11251246]
[9]
Seymour, L.W. Passive tumor targeting of soluble macromolecules and drug conjugates. Crit. Rev. Ther. Drug Carrier Syst., 1992, 9(2), 135-187.
[PMID: 1386002]
[10]
Kwon, G.S.; Okano, T. Polymeric micelles as new drug carriers. Adv. Drug Deliv. Rev., 1996, 21(2), 107-116.
[http://dx.doi.org/10.1016/S0169-409X(96)00401-2]
[11]
Mishra, B.; Patel, B.B.; Tiwari, S. Colloidal nanocarriers: A review on formulation technology, types and applications toward targeted drug delivery. Nanomedicine, 2010, 6(1), 9-24.
[http://dx.doi.org/10.1016/j.nano.2009.04.008] [PMID: 19447208]
[12]
Florence, A.T.; Whitehill, D. The formulation and stability of multiple emulsions. Int. J. Pharm., 1982, 11(4), 277-308.
[http://dx.doi.org/10.1016/0378-5173(82)90080-1]
[13]
He, C.; Hu, Y.; Yin, L.; Tang, C.; Yin, C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials, 2010, 31(13), 3657-3666.
[http://dx.doi.org/10.1016/j.biomaterials.2010.01.065] [PMID: 20138662]
[14]
Kim, C.K.; Lee, M.K.; Han, J.H.; Lee, B.J. Pharmacokinetics and tissue distribution of methotrexate after intravenous injection of differently charged liposome entrapped methotrexate to rats. Int. J. Pharm., 1994, 108(1), 21-29.
[http://dx.doi.org/10.1016/0378-5173(94)90412-X]
[15]
Storm, G.; Belliot, S.O.; Daemen, T.; Lasic, D.D. Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system. Adv. Drug Deliv. Rev., 1995, 17(1), 31-48.
[http://dx.doi.org/10.1016/0169-409X(95)00039-A]
[16]
Huwyler, J.; Wu, D.; Pardridge, W.M. Brain drug delivery of small molecules using immunoliposomes. Proc. Natl. Acad. Sci. USA, 1996, 93(24), 14164-14169.
[http://dx.doi.org/10.1073/pnas.93.24.14164] [PMID: 8943078]
[17]
Qin, Y.; Chen, H.; Yuan, W.; Kuai, R.; Zhang, Q.; Xie, F.; Zhang, L.; Zhang, Z.; Liu, J.; He, Q. Liposome formulated with TAT-modified cholesterol for enhancing the brain delivery. Int. J. Pharm., 2011, 419(1-2), 85-95. [a].
[http://dx.doi.org/10.1016/j.ijpharm.2011.07.021] [PMID: 21807083]
[18]
Qin, Y.; Chen, H.; Zhang, Q.; Wang, X.; Yuan, W.; Kuai, R.; Tang, J.; Zhang, L.; Zhang, Z.; Zhang, Q.; Liu, J.; He, Q. Liposome formulated with TAT-modified cholesterol for improving brain delivery and therapeutic efficacy on brain glioma in animals. Int. J. Pharm., 2011, 420(2), 304-312. [b].
[http://dx.doi.org/10.1016/j.ijpharm.2011.09.008] [PMID: 21945185]
[19]
Mora, M.; Sagristá, M.L.; Trombetta, D.; Bonina, F.P.; De Pasquale, A.; Saija, A. Design and characterization of liposomes containing long-chain n-acylpes for brain delivery: Penetration of liposomes incorporating GM1 into the rat brain. Pharm. Res., 2002, 19(10), 1430-1438.
[http://dx.doi.org/10.1023/A:1020440229102] [PMID: 12425459]
[20]
Schnyder, A.; Huwyler, J. Drug transport to brain with targeted liposomes. NeuroRx, 2005, 2(1), 99-107.
[http://dx.doi.org/10.1602/neurorx.2.1.99] [PMID: 15717061]
[21]
Lu, W.; Zhang, Y.; Tan, Y.Z.; Hu, K.L.; Jiang, X.G.; Fu, S.K. Cationic albumin conjugated pegylated nanoparticles as novel drug carrier for brain delivery. J. Control. Release, 2005, 107(3), 428-448.
[http://dx.doi.org/10.1016/j.jconrel.2005.03.027] [PMID: 16176844]
[22]
Juliano, R.L.; Stamp, D. Pharmacokinetics of liposome encapsulated anti tumor drugs. Studies with vinblastine, actinomycin D, cytosine arabinoside, and daunomycin. Biochem. Pharmacol., 1978, 27(1), 21-27.
[http://dx.doi.org/10.1016/0006-2952(78)90252-6] [PMID: 619903]
[23]
Jonah, M.M.; Cerny, E.A.; Rahman, Y.E. Tissue distribution of EDTA encapsulated within liposomes of varying surface properties. Biochim. Biophys. Acta, 1975, 401(3), 336-348.
[http://dx.doi.org/10.1016/0005-2736(75)90234-5] [PMID: 810161]
[24]
Kimelberg, H.K. Differential distribution of liposome entrapped [3H] methotrexate and labelled lipids after intravenous injection in a primate. Biochim. Biophys. Acta, 1976, 448(4), 531-550.
[http://dx.doi.org/10.1016/0005-2736(76)90108-5] [PMID: 823974]
[25]
Yoshioka, T.; Ikeuchi, K.; Hashida, M.; Muranishi, S.; Sezaki, H. Prolonged release of bleomycin from parenteral gelatin sphere in oil-in-water multiple emulsion. Chem. Pharm. Bull., 1982, 30(4), 1408-1415.
[http://dx.doi.org/10.1248/cpb.30.1408] [PMID: 6179640]
[26]
Gresham, P.A.; Barnett, M.; Smith, S.V.; Schneider, R. Use of a sustained release multiple emulsion to extend the period of radio protection conferred by cysteamine. Nature, 1971, 234(5325), 149-150.
[http://dx.doi.org/10.1038/234149a0] [PMID: 4942677]
[27]
Bonnet, M.; Cansell, M.; Berkaoui, A.; Ropers, M.H.; Anton, M.; Leal, C.F. Release rate profiles of magnesium from multiple W/O/W emulsions. Food Hydrocoll., 2009, 23(1), 92-101.
[http://dx.doi.org/10.1016/j.foodhyd.2007.11.016]
[28]
Benichou, A.; Aserin, A.; Garti, N. Double emulsions stabilized with hybrids of natural polymers for entrapment and slow release of active matters. Adv. Colloid Interface Sci., 2004, 108-109, 29-41.
[http://dx.doi.org/10.1016/j.cis.2003.10.013] [PMID: 15072926]
[29]
Elworthy, P.H.; Florence, A.T. Stabilization of oil-in-water emulsions by non ionic detergents: properties of synthetic detergents at anisole and chlorobenzene water surface. J. Pharm. Pharmacol., 1969, 21(2), 72-78.
[http://dx.doi.org/10.1111/j.2042-7158.1969.tb08200.x] [PMID: 4388316]
[30]
Elworthy, P.H.; Florence, A.T. Stabilization of oil-in-water emulsions by non ionic detergents: Electrical and entropic contributions to stability. J. Pharm. Pharmacol., 1969, 21(S1), 79S-90S. [b].
[PMID: 4391173]
[31]
Dash, B.C.; Réthoré, G.; Monaghan, M.; Fitzgerald, K.; Gallagher, W.; Pandit, A. The influence of size and charge of chitosan/polyglutamic acid hollow spheres on cellular internalization, viability and blood compatibility. Biomaterials, 2010, 31(32), 8188-8197.
[http://dx.doi.org/10.1016/j.biomaterials.2010.07.067] [PMID: 20701967]
[32]
Verma, A.; Stellacci, F. Effect of surface properties on nanoparticle cell interactions. Small, 2010, 6(1), 12-21.
[http://dx.doi.org/10.1002/smll.200901158] [PMID: 19844908]
[33]
Stern, M.B. Contemporary approaches to the pharmacotherapeutic management of Parkinson’s disease: An overview. Neurology, 1997, 49(Suppl. 1), S2-S9.
[http://dx.doi.org/10.1212/WNL.49.1_Suppl_1.S2] [PMID: 9222270]
[34]
Müller, T. Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease. Expert Opin. Drug Metab. Toxicol., 2020, 16(5), 403-414.
[http://dx.doi.org/10.1080/17425255.2020.1750596] [PMID: 32238065]

Rights & Permissions Print Cite
Article Metrics
17
2
© 2024 Bentham Science Publishers | Privacy Policy