Design of experiment based formulation optimization of chitosan-coated nano-liposomes of progesterone for effective oral delivery

Prachi Dehariya; Reena Soni; Suresh Kumar Paswan; Prakash Kumar Soni

doi:10.7324/JAPS.2023.142351

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Abstract

The aim of this research was to design and develop chitosan-coated nano-liposomes of progesterone for its safe and effective oral delivery through the vesicular system providing sustained drug release, enhanced drug stability in gastro-intestinal (GI) fluid and improved drug absorption leading to better patient compliance. The aqueous solubility of progesterone (poorly soluble drug) was enhanced by hydroxy-propyl-beta-cyclodextrin complexation and the drug-loaded liposomes were prepared by ethanol injection method followed by surface coating with chitosan. Design of experiment-based formulation optimization was performed using Box-Behnken design selecting lipid, cholesterol, and drug content as formulation factors (independent variables) and mean particle size (MPS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), drug loading (DL) and cumulative % drug release (CDR) as evaluation parameters (response variables). The optimized formulation was prepared and evaluated for all preferred critical quality attributes which showed 168.3 nm MPS, 0.307 PDI, 24 mV ZP, 53% EE, 7.2% DL, and 76.4% CDR at 24 hours. In-vitro GI drug stability of chitosan-coated liposomes was studied in simulated gastric fluid and simulated intestinal fluid which exhibited 2.12 and 77.3 fold extended half-life, respectively. The ex-vivo GI-drug absorption study demonstrated two-fold rise in progesterone absorption from liposomal formulation. The chitosan-coated liposomes of progesterone which showed sustained drug release following Higuchi model kinetics was found to be a better alternative for oral delivery of progesterone overcoming drawbacks of conventional dosage forms.

Keyword: Progesterone oral drug delivery liposomes design of experiment (DoE) chitosan-coated Box

Citation:

Dehariya P, Soni R, Paswan SK, Soni PK. Design of experiment based formulation optimization of chitosan-coated nano-liposomes of progesterone for effective oral delivery. J Appl Pharm Sci, 2023; 13(06):256–270. https://doi.org/10.7324/JAPS.2023.142351

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, Samiei M, Kouhi M, Nejati-Koshki K. Liposome: classification, preparation, and applications. Nanoscale Res Lett, 2013; 8:102. https://doi.org/10.1186/1556-276X-8-102
Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ. Advances in oral drug delivery. Front Pharmacol, 2021; 12:618411. https://doi.org/10.3389/fphar.2021.618411
Arafat M, Kirchhoefer C, Mikov M, Sarfraz M, Löbenberg R. Nanosized liposomes containing bile salt: a vesicular nanocarrier for enhancing oral bioavailability of BCS class III drug. J Pharm Sci, 2017; 20:305-18. https://doi.org/10.18433/J3CK88
Babadi D, Dadashzadeh S, Osouli M, Abbasian Z, Daryabari MS, Sadrai S, Haeri A. Biopharmaceutical and pharmacokinetic aspects of nanocarrier-mediated oral delivery of poorly soluble drugs. J Drug Deliv Sci Technol, 2021; 62:102324. https://doi.org/10.1016/j.jddst.2021.102324
Bajka BH, Rigby NM, Cross KL, Macierzanka A, Mackie AR. The influence of small intestinal mucus structure on particle transport ex vivo. Colloids Surf B, 2015; 135:73-80. https://doi.org/10.1016/j.colsurfb.2015.07.038
Braga Emidio N, Tran HNT, Andersson A, Dawson PE, Albericio F, Vetter I, Muttenthaler, M. Improving the gastrointestinal stability of linaclotide. J Med Chem, 2021; 64:8384-90. https://doi.org/10.1021/acs.jmedchem.1c00380
Cagdas M, Sezer, AD, Bucak S. Liposomes as potential drug carrier systems for drug delivery. InTech Open, Paris, France, 2014. https://doi.org/10.5772/58459
Chadha R, Bhandari S. Drug-excipient compatibility screening- role of thermoanalytical and spectroscopic techniques. J Pharm Biomed Anal, 2014; 87:82-97. https://doi.org/10.1016/j.jpba.2013.06.016
Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 2018; 10(2):57. https://doi.org/10.3390/pharmaceutics10020057
Elsayad MK, Mowafy HA, Zaky AA, Samy AM. Chitosan caged liposomes for improving oral bioavailability of rivaroxaban: in vitro and in vivo evaluation. Pharm Dev Technol, 2021; 26:316-27. https://doi.org/10.1080/10837450.2020.1870237
Ghassemi S, Haeri A, Shahhosseini S, Dadashzadeh S. Labrasol-enriched nanoliposomal formulation: novel approach to improve oral absorption of water-insoluble drug, carvedilol. AAPS PharmSciTech, 2018; 19:2961-70. https://doi.org/10.1208/s12249-018-1118-9
Gouda A, Sakr OS, Nasr M, Sammour O. Ethanol injection technique for liposomes formulation: an insight into development, influencing factors, challenges and applications. J Drug Deliv Sci Technol, 2021; 61:102174. https://doi.org/10.1016/j.jddst.2020.102174
Hasan M, Jahan I, Hasan AHM, Zaman M, Hamiduzzaman M. Formulation development, characterization and in-vitro evaluation of tamoxifen loaded liposomes. J Pharm Res Int, 2020; 32:64-82. https://doi.org/10.9734/jpri/2020/v32i630449
He H, Lu Y, Qi J, Zhu Q, Chen Z, Wu W. Adapting liposomes for oral drug delivery. Acta Pharm Sin B, 2019; 9:36-48. https://doi.org/10.1016/j.apsb.2018.06.005
Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics, 2019; 11:129. https://doi.org/10.3390/pharmaceutics11030129
Jaafar-Maalej C, Diab R, Andrieu V, Elaissari A, Fessi H. Ethanol injection method for hydrophilic and lipophilic drug-loaded liposome preparation. J Liposome Res, 2010; 20:228-43. https://doi.org/10.3109/08982100903347923
Jansook P, Loftsson T. CDs as solubilizers: effects of excipients and competing drugs. Int J Pharm, 2009; 379:32-40. https://doi.org/10.1016/j.ijpharm.2009.06.005
Jin Y, Wen J, Garg S, Liu D, Zhou Y, Teng L, Zhang W. Development of a novel niosomal system for oral delivery of ginkgo biloba extract. Int J Nanomed, 2013; 8:421-30. https://doi.org/10.2147/IJN.S37984
Kulkarni SB, Betageri GV, Singh, M. Factors affecting microencapsulation of drugs in liposomes. J Microencapsul, 1995; 12: 229-46. https://doi.org/10.3109/02652049509010292
Lahiani-Skiba M, Barbot C, Bounoure F, Joudieh S, Skiba M. Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems. Drug Dev Ind Pharm, 2006; 32:1043-58. https://doi.org/10.1080/03639040600897093
Large DE, Abdelmessih RG, Fink EA, Auguste DT. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Adv Drug Deliv Rev, 2021; 176:113851. https://doi.org/10.1016/j.addr.2021.113851
Lee MK. Liposomes for enhanced bioavailability of water-insoluble drugs: in vivo evidence and recent approaches. Pharmaceutics, 2020; 12:264. https://doi.org/10.3390/pharmaceutics12030264
Liu W, Ye A, Han F, Han J. Advances and challenges in liposome digestion: surface interaction, biological fate, and GIT modeling. Adv Colloid Interface Sci, 2019; 263:52-67. https://doi.org/10.1016/j.cis.2018.11.007
Loftsson T, Jarho P, Másson M, Järvinen T. Cyclodextrins in drug delivery. Expert Opin Drug Deliv, 2005; 2:335-51. https://doi.org/10.1517/17425247.2.1.335
Lombardo D, Kiselev MA. Methods of liposomes preparation: formation and control factors of versatile nanocarriers for biomedical and nanomedicine application. Pharmaceutics, 2022; 14:543. https://doi.org/10.3390/pharmaceutics14030543
Luo Z, Paunovi? N, Leroux JC. Physical methods for enhancing drug absorption from the gastrointestinal tract. Adv Drug Deliv Rev, 2021; 175:113814. https://doi.org/10.1016/j.addr.2021.05.024
Ma B, Wang J, Sun J, Li M, Xu H, Sun G, Sun X. Permeability of rhynchophylline across human intestinal cell in vitro. Int J Clin Exp Pathol, 2014; 7:1957-66.
Nguyen TX, Huang L, Gauthier M, Yang G, Wang Q. Recent advances in liposome surface modification for oral drug delivery. Nanomedicine, 2016; 11:1169-85. https://doi.org/10.2217/nnm.16.9
Nguyen TX, Huang L, Liu L, Elamin Abdalla AM, Gauthier M, Yang G. Chitosan-coated nano-liposomes for the oral delivery of berberine hydrochloride. J Mater Chem B, 2014; 2:7149-59. https://doi.org/10.1039/C4TB00876F
Panwar P, Pandey B, Lakhera PC, Singh KP. Preparation, characterization, and in vitro release study of albendazole-encapsulated nanosize liposomes. Int J Nanomed, 2010; 5:101-8. https://doi.org/10.2147/IJN.S8030
Schwendener RA, Schott H. Liposome formulations of hydrophobic drugs. Mçethods Mol Biol, 2010; 605:129-38. https://doi.org/10.1007/978-1-60327-360-2_8
Sharma S, Diwan A, Kalra R, Arora V. Physico-chemical characterization, analytical method development and solubility studies for progesterone. Indian J Pharm Biol Res, 2017; 5(2):29-35. https://doi.org/10.30750/ijpbr.5.2.6
Shimpi S, Chauhan B, Shimpi P. Cyclodextrins: application in different routes of drug administration. Acta Pharm, 2005; 55:139-56.
Simon JA, Robinson DE, Andrews MC, Hildebrand JR 3rd, Rocci ML Jr, Blake RE, Hodgen GD. The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone. Fertil Steril, 1993; 60:26-33. https://doi.org/10.1016/S0015-0282(16)56031-2
Soni PK, Saini TR. Development and evaluation of HP-β-CD complexation based novel ophthalmic gel formulation of nepafenac. Int J Pharm Sci, 2019; 10(12):5707-14.
Soni PK, Saini TR. Formulation design and optimization of cationic-charged liposomes of brimonidine tartrate for effective ocular drug delivery by design of experiment (DoE) approach. Drug Dev Ind Pharm, 2021a; 47:1847-66. https://doi.org/10.1080/03639045.2022.2070198
Soni PK, Saini TR. Purification of drug loaded liposomal formulations by a novel stirred cell ultrafiltration technique. Pharm Nanotechnol, 2021b; 9:347-360. https://doi.org/10.2174/2211738509666211124145848
Stanczyk FZ, Hapgood J, Winer S, Mishell DRJr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev, 2013; 34:171-208. https://doi.org/10.1210/er.2012-1008
Sur S, Fries AC, Kinzler KW, Zhou S, Vogelstein, B. Remote loading of preencapsulated drugs into stealth liposomes. Proc Natl Acad Sci USA, 2014; 111:2283-8. https://doi.org/10.1073/pnas.1324135111
Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov, 2005; 4:145-60. https://doi.org/10.1038/nrd1632
Vemuri S, Rhodes CT. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv, 1995; 70:95-111. https://doi.org/10.1016/0031-6865(95)00010-7
Wang M, Liu M, Xie T, Zhang BF, Gao XL. Chitosan-modified cholesterol-free liposomes for improving the oral bioavailability of progesterone. Colloids Surf B, 2017; 159:580-5. https://doi.org/10.1016/j.colsurfb.2017.08.028
Weng J, Tong HHY. In vitro release study of the polymeric drug nanoparticles: development and validation of a novel method. Pharmaceutics, 2020; 12(8):732. https://doi.org/10.3390/pharmaceutics12080732
Zafar A, Alruwaili NK, Imam SS. Formulation of genistein-hp β cyclodextrin-poloxamer 188 ternary inclusion complex: solubility to cytotoxicity assessment. Pharmaceutics, 2021; 13:1997. https://doi.org/10.3390/pharmaceutics13121997

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Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, Samiei M, Kouhi M, Nejati-Koshki K. Liposome: classification, preparation, and applications. Nanoscale Res Lett, 2013; 8:102. https://doi.org/10.1186/1556-276X-8-102

Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ. Advances in oral drug delivery. Front Pharmacol, 2021; 12:618411. https://doi.org/10.3389/fphar.2021.618411

Arafat M, Kirchhoefer C, Mikov M, Sarfraz M, Löbenberg R. Nanosized liposomes containing bile salt: a vesicular nanocarrier for enhancing oral bioavailability of BCS class III drug. J Pharm Sci, 2017; 20:305-18. https://doi.org/10.18433/J3CK88

Babadi D, Dadashzadeh S, Osouli M, Abbasian Z, Daryabari MS, Sadrai S, Haeri A. Biopharmaceutical and pharmacokinetic aspects of nanocarrier-mediated oral delivery of poorly soluble drugs. J Drug Deliv Sci Technol, 2021; 62:102324. https://doi.org/10.1016/j.jddst.2021.102324

Bajka BH, Rigby NM, Cross KL, Macierzanka A, Mackie AR. The influence of small intestinal mucus structure on particle transport ex vivo. Colloids Surf B, 2015; 135:73-80. https://doi.org/10.1016/j.colsurfb.2015.07.038

Braga Emidio N, Tran HNT, Andersson A, Dawson PE, Albericio F, Vetter I, Muttenthaler, M. Improving the gastrointestinal stability of linaclotide. J Med Chem, 2021; 64:8384-90. https://doi.org/10.1021/acs.jmedchem.1c00380

Cagdas M, Sezer, AD, Bucak S. Liposomes as potential drug carrier systems for drug delivery. InTech Open, Paris, France, 2014. https://doi.org/10.5772/58459

Chadha R, Bhandari S. Drug-excipient compatibility screening- role of thermoanalytical and spectroscopic techniques. J Pharm Biomed Anal, 2014; 87:82-97. https://doi.org/10.1016/j.jpba.2013.06.016

Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 2018; 10(2):57. https://doi.org/10.3390/pharmaceutics10020057

Elsayad MK, Mowafy HA, Zaky AA, Samy AM. Chitosan caged liposomes for improving oral bioavailability of rivaroxaban: in vitro and in vivo evaluation. Pharm Dev Technol, 2021; 26:316-27. https://doi.org/10.1080/10837450.2020.1870237

Ghassemi S, Haeri A, Shahhosseini S, Dadashzadeh S. Labrasol-enriched nanoliposomal formulation: novel approach to improve oral absorption of water-insoluble drug, carvedilol. AAPS PharmSciTech, 2018; 19:2961-70. https://doi.org/10.1208/s12249-018-1118-9

Gouda A, Sakr OS, Nasr M, Sammour O. Ethanol injection technique for liposomes formulation: an insight into development, influencing factors, challenges and applications. J Drug Deliv Sci Technol, 2021; 61:102174. https://doi.org/10.1016/j.jddst.2020.102174

Hasan M, Jahan I, Hasan AHM, Zaman M, Hamiduzzaman M. Formulation development, characterization and in-vitro evaluation of tamoxifen loaded liposomes. J Pharm Res Int, 2020; 32:64-82. https://doi.org/10.9734/jpri/2020/v32i630449

He H, Lu Y, Qi J, Zhu Q, Chen Z, Wu W. Adapting liposomes for oral drug delivery. Acta Pharm Sin B, 2019; 9:36-48. https://doi.org/10.1016/j.apsb.2018.06.005

Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics, 2019; 11:129. https://doi.org/10.3390/pharmaceutics11030129

Jaafar-Maalej C, Diab R, Andrieu V, Elaissari A, Fessi H. Ethanol injection method for hydrophilic and lipophilic drug-loaded liposome preparation. J Liposome Res, 2010; 20:228-43. https://doi.org/10.3109/08982100903347923

Jansook P, Loftsson T. CDs as solubilizers: effects of excipients and competing drugs. Int J Pharm, 2009; 379:32-40. https://doi.org/10.1016/j.ijpharm.2009.06.005

Jin Y, Wen J, Garg S, Liu D, Zhou Y, Teng L, Zhang W. Development of a novel niosomal system for oral delivery of ginkgo biloba extract. Int J Nanomed, 2013; 8:421-30. https://doi.org/10.2147/IJN.S37984

Kulkarni SB, Betageri GV, Singh, M. Factors affecting microencapsulation of drugs in liposomes. J Microencapsul, 1995; 12: 229-46. https://doi.org/10.3109/02652049509010292

Lahiani-Skiba M, Barbot C, Bounoure F, Joudieh S, Skiba M. Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems. Drug Dev Ind Pharm, 2006; 32:1043-58. https://doi.org/10.1080/03639040600897093

Large DE, Abdelmessih RG, Fink EA, Auguste DT. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Adv Drug Deliv Rev, 2021; 176:113851. https://doi.org/10.1016/j.addr.2021.113851

Lee MK. Liposomes for enhanced bioavailability of water-insoluble drugs: in vivo evidence and recent approaches. Pharmaceutics, 2020; 12:264. https://doi.org/10.3390/pharmaceutics12030264

Liu W, Ye A, Han F, Han J. Advances and challenges in liposome digestion: surface interaction, biological fate, and GIT modeling. Adv Colloid Interface Sci, 2019; 263:52-67. https://doi.org/10.1016/j.cis.2018.11.007

Loftsson T, Jarho P, Másson M, Järvinen T. Cyclodextrins in drug delivery. Expert Opin Drug Deliv, 2005; 2:335-51. https://doi.org/10.1517/17425247.2.1.335

Lombardo D, Kiselev MA. Methods of liposomes preparation: formation and control factors of versatile nanocarriers for biomedical and nanomedicine application. Pharmaceutics, 2022; 14:543. https://doi.org/10.3390/pharmaceutics14030543

Luo Z, Paunovi? N, Leroux JC. Physical methods for enhancing drug absorption from the gastrointestinal tract. Adv Drug Deliv Rev, 2021; 175:113814. https://doi.org/10.1016/j.addr.2021.05.024

Ma B, Wang J, Sun J, Li M, Xu H, Sun G, Sun X. Permeability of rhynchophylline across human intestinal cell in vitro. Int J Clin Exp Pathol, 2014; 7:1957-66.

Nguyen TX, Huang L, Gauthier M, Yang G, Wang Q. Recent advances in liposome surface modification for oral drug delivery. Nanomedicine, 2016; 11:1169-85. https://doi.org/10.2217/nnm.16.9

Nguyen TX, Huang L, Liu L, Elamin Abdalla AM, Gauthier M, Yang G. Chitosan-coated nano-liposomes for the oral delivery of berberine hydrochloride. J Mater Chem B, 2014; 2:7149-59. https://doi.org/10.1039/C4TB00876F

Panwar P, Pandey B, Lakhera PC, Singh KP. Preparation, characterization, and in vitro release study of albendazole-encapsulated nanosize liposomes. Int J Nanomed, 2010; 5:101-8. https://doi.org/10.2147/IJN.S8030

Schwendener RA, Schott H. Liposome formulations of hydrophobic drugs. Mçethods Mol Biol, 2010; 605:129-38. https://doi.org/10.1007/978-1-60327-360-2_8

Sharma S, Diwan A, Kalra R, Arora V. Physico-chemical characterization, analytical method development and solubility studies for progesterone. Indian J Pharm Biol Res, 2017; 5(2):29-35. https://doi.org/10.30750/ijpbr.5.2.6

Shimpi S, Chauhan B, Shimpi P. Cyclodextrins: application in different routes of drug administration. Acta Pharm, 2005; 55:139-56.

Simon JA, Robinson DE, Andrews MC, Hildebrand JR 3rd, Rocci ML Jr, Blake RE, Hodgen GD. The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone. Fertil Steril, 1993; 60:26-33. https://doi.org/10.1016/S0015-0282(16)56031-2

Soni PK, Saini TR. Development and evaluation of HP-β-CD complexation based novel ophthalmic gel formulation of nepafenac. Int J Pharm Sci, 2019; 10(12):5707-14.

Soni PK, Saini TR. Formulation design and optimization of cationic-charged liposomes of brimonidine tartrate for effective ocular drug delivery by design of experiment (DoE) approach. Drug Dev Ind Pharm, 2021a; 47:1847-66. https://doi.org/10.1080/03639045.2022.2070198

Soni PK, Saini TR. Purification of drug loaded liposomal formulations by a novel stirred cell ultrafiltration technique. Pharm Nanotechnol, 2021b; 9:347-360. https://doi.org/10.2174/2211738509666211124145848

Stanczyk FZ, Hapgood J, Winer S, Mishell DRJr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev, 2013; 34:171-208. https://doi.org/10.1210/er.2012-1008

Sur S, Fries AC, Kinzler KW, Zhou S, Vogelstein, B. Remote loading of preencapsulated drugs into stealth liposomes. Proc Natl Acad Sci USA, 2014; 111:2283-8. https://doi.org/10.1073/pnas.1324135111

Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov, 2005; 4:145-60. https://doi.org/10.1038/nrd1632

Vemuri S, Rhodes CT. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv, 1995; 70:95-111. https://doi.org/10.1016/0031-6865(95)00010-7

Wang M, Liu M, Xie T, Zhang BF, Gao XL. Chitosan-modified cholesterol-free liposomes for improving the oral bioavailability of progesterone. Colloids Surf B, 2017; 159:580-5. https://doi.org/10.1016/j.colsurfb.2017.08.028

Weng J, Tong HHY. In vitro release study of the polymeric drug nanoparticles: development and validation of a novel method. Pharmaceutics, 2020; 12(8):732. https://doi.org/10.3390/pharmaceutics12080732

Zafar A, Alruwaili NK, Imam SS. Formulation of genistein-hp β cyclodextrin-poloxamer 188 ternary inclusion complex: solubility to cytotoxicity assessment. Pharmaceutics, 2021; 13:1997. https://doi.org/10.3390/pharmaceutics13121997