Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

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

Preparation, Characterization and Prevention of Auto-oxidation of Amorphous Sirolimus by Encapsulation in Polymeric Films Using Hot Melt Extrusion

Author(s): Parijat Kanaujia*, Ponnammal Poovizhi, Wai Kiong Ng and Reginald B. H. Tan

Volume 16, Issue 7, 2019

Page: [663 - 671] Pages: 9

DOI: 10.2174/1567201816666190416123939

Price: $65

Abstract

Background: Sirolimus (SIR) is a macrocyclic lactone antibiotic and used therapeutically as a potent immunosuppressant for prophylaxis of kidney transplant rejection. The development of an oral dosage form is challenging because of very poor aqueous solubility (2.6µg/ml). The oral bioavailability of SIR is only 15-20 % and is affected by food and other drugs. The main reasons for low bioavailability are intestinal degradation by enzymes especially by cytochrome P4503A4, efflux by P-glycoprotein and hepatic first-pass metabolism.

Objective: The main objective was to prepare a mouth dissolving film dosage form of amorphous SIR to improve dissolution.

Methods: Crystalline SIR was transformed to its form amorphous by milling for 2 h at room temperature. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) were used for characterisation. The stability of amorphous SIR was studied at 4°C and 40°C/75% RH. Amorphous SIR was formulated as oral films by melt extrusion with polyvinylpyrrolidone- vinyl acetate (PVP-VA), Soluplus® and hydroxypropyl cellulose (HPC) as carriers. The films were characterized for drug content, physical state, dissolution profile and stability at 4°C and 40°C/75% RH.

Results: The PRXD and DSC confirmed the conversion of crystalline SIR to amorphous form by milling. The solubility of amorphous SIR was several folds higher than its crystalline form, but amorphous SIR was highly unstable at all tested temperatures (4° and 40°C). The extruded films exhibited higher dissolution and stability compared to milled SIR powder alone, but the process of extrusion had some detrimental effect on the chemical stability of amorphous SIR.

Conclusion: The film formulations showed a significant improvement in the storage stability of the amorphous form of SIR and the solubility advantage of the amorphous form was evident in the dissolution testing. The oral films can potentially improve the bioavailability of SIR by absorption through the buccal mucosa.

Keywords: Amorphous sirolimus, melt extrusion, dissolution enhancement, mouth dissolving film, polymeric films, oxidation.

« Previous Next »
Graphical Abstract

[1]
Amidon, G.L.; Lennernäs, H.; Shah, V.P.; Crison, J.R. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 1995, 12(3), 413-420.
[http://dx.doi.org/10.1023/A:1016212804288] [PMID: 7617530]
[2]
Kanaujia, P.; Poovizhi, P.; Ng, W.K.; Tan, R.B.H. Amorphous formulations for dissolution and bioavailability enhancement of poorly soluble APIs. Powder Technol., 2015, 285, 2-15.
[http://dx.doi.org/10.1016/j.powtec.2015.05.012]
[3]
Breitenbach, J. Melt extrusion: from process to drug delivery technology. Eur. J. Pharm. Biopharm., 2002, 54(2), 107-117.
[http://dx.doi.org/10.1016/S0939-6411(02)00061-9] [PMID: 12191680]
[4]
Simamora, P.; Alvarez, J.M.; Yalkowsky, S.H. Solubilization of rapamycin. Int. J. Pharm., 2001, 213(1-2), 25-29.
[http://dx.doi.org/10.1016/S0378-5173(00)00617-7] [PMID: 11165091]
[5]
Wu, C.Y.; Benet, L.Z. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm. Res., 2005, 22(1), 11-23.
[http://dx.doi.org/10.1007/s11095-004-9004-4] [PMID: 15771225]
[6]
Shen, L.J.; Wu, F.L. Nanomedicines in renal transplant rejection--focus on sirolimus. Int. J. Nanomed, 2007, 2(1), 25-32.
[http://dx.doi.org/10.2147/nano.2007.2.1.25] [PMID: 17722509]
[7]
Sehgal, S.N. Rapamune (RAPA, rapamycin, sirolimus): Mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin. Biochem., 1998, 31(5), 335-340.
[http://dx.doi.org/10.1016/S0009-9120(98)00045-9] [PMID: 9721431]
[8]
Paine, M.F.; Leung, L.Y.; Lim, H.K.; Liao, K.; Oganesian, A.; Zhang, M.Y.; Thummel, K.E.; Watkins, P.B. Identification of a novel route of extraction of sirolimus in human small intestine: Roles of metabolism and secretion. J. Pharmacol. Exp. Ther., 2002, 301(1), 174-186.
[http://dx.doi.org/10.1124/jpet.301.1.174] [PMID: 11907172]
[9]
MacDonald, A.; Scarola, J.; Burke, J.T.; Zimmerman, J.J. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin. Ther. , 2000(22 Suppl B,), B101-121.
[http://dx.doi.org/10.1016/S0149-2918(00)89027-X]
[10]
Meier-Kriesche, H.U.; Kaplan, B. Toxicity and efficacy of sirolimus: Relationship to whole-blood concentrations. Clin. Ther. , 2000(22 Suppl B,), B93-100.
[http://dx.doi.org/10.1016/S0149-2918(00)89026-8]
[11]
Onyesom, I.; Lamprou, D.A.; Sygellou, L.; Owusu-Ware, S.K.; Antonijevic, M.; Chowdhry, B.Z.; Douroumis, D. Sirolimus encapsulated liposomes for cancer therapy: Physicochemical and mechanical characterization of sirolimus distribution within liposome bilayers. Mol. Pharm., 2013, 10(11), 4281-4293.
[http://dx.doi.org/10.1021/mp400362v] [PMID: 24099044]
[12]
Kim, M.S.; Kim, J.S.; Cho, W.K.; Hwang, S.J. Enhanced solubility and oral absorption of sirolimus using D-α-tocopheryl polyethylene glycol succinate micelles. Artif. Cells Nanomed. Biotechnol., 2013, 41(2), 85-91.
[http://dx.doi.org/10.3109/21691401.2012.742100] [PMID: 23305536]
[13]
Abdur, R.M.; Imran, V.; Erem, B.; Dilek, D.E. Rapamycin cyclodextrin complexation: Improved solubility and dissolution rate. J. Incl. Phenom. Macro., 2011, 70, 167-175.
[http://dx.doi.org/10.1007/s10847-010-9885-2]
[14]
Hu, X.; Lin, C.; Chen, D.; Zhang, J.; Liu, Z.; Wu, W.; Song, H. Sirolimus solid self-microemulsifying pellets: Formulation development, characterization and bioavailability evaluation. Int. J. Pharm., 2012, 438(1-2), 123-133.
[http://dx.doi.org/10.1016/j.ijpharm.2012.07.055] [PMID: 22850296]
[15]
Nieto, A.; Hou, H.; Moon, S.W.; Sailor, M.J.; Freeman, W.R.; Cheng, L. Surface engineering of porous silicon microparticles for intravitreal sustained delivery of rapamycin. Invest. Ophthalmol. Vis. Sci., 2015, 56(2), 1070-1080.
[http://dx.doi.org/10.1167/iovs.14-15997] [PMID: 25613937]
[16]
Shen, Y.; Li, X.; Le, Y. Amorphous nanoparticulate formulation of sirolimus and its tablets. Pharmaceutics, 2018, 10(3), 155-167.
[http://dx.doi.org/10.3390/pharmaceutics10030155] [PMID: 30208637]
[17]
Emami, S.; Valizadeh, H.; Islambulchilar, Z.; Zakeri-Milani, P. Development and physicochemical characterization of sirolimus solid dispersions prepared by solvent evaporation method. Adv. Pharm. Bull., 2014, 4(4), 369-374.
[PMID: 25436193]
[18]
Cho, Y.; Ha, E.S.; Baek, I.H.; Kim, M.S.; Cho, C.W.; Hwang, S.J. Enhanced supersaturation and oral absorption of sirolimus using an amorphous solid dispersion based on Eudragit® e. Molecules, 2015, 20(6), 9496-9509.
[http://dx.doi.org/10.3390/molecules20069496] [PMID: 26020699]
[19]
Kim, M.S.; Kim, J.S.; Cho, W.; Cha, K.H.; Park, H.J.; Park, J.; Hwang, S.J. Supersaturatable formulations for the enhanced oral absorption of sirolimus. Int. J. Pharm., 2013, 445(1-2), 108-116.
[http://dx.doi.org/10.1016/j.ijpharm.2013.01.067] [PMID: 23396259]
[20]
Kim, M.S.; Kim, J.S.; Park, H.J.; Cho, W.K.; Cha, K.H.; Hwang, S.J. Enhanced bioavailability of sirolimus via preparation of solid dispersion nanoparticles using a supercritical antisolvent process. Int. J. Nanomedicine, 2011, 6, 2997-3009.
[PMID: 22162657]
[21]
Sun, H.; Gu, X.; Liu, K.; Fang, C.; Tang, M. Applicability of electrospun polypropylene carbonate polymers as a drug carrier for sirolimus. Mol. Med. Rep., 2017, 15(6), 4253-4258.
[http://dx.doi.org/10.3892/mmr.2017.6540] [PMID: 28487969]
[22]
Nudelman, Z.; Friedman, M.; Barasch, D.; Nemirovski, A.; Findler, M.; Pikovsky, A.; Gutkind, J.; Czerninski, R. Levels of sirolimus in saliva and blood following mouthwash application. Oral Dis., 2014, 20(8), 768-772.
[http://dx.doi.org/10.1111/odi.12229] [PMID: 24548545]
[23]
Nudelman, Z.; Findler, M.; Barasch, D.; Nemirovski, A.; Pikovsky, A.; Kirmayer, D.; Basheer, M.; Gutkind, J.S.; Friedman, M.; Czerninski, R. Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application. Cancer Chemother. Pharmacol., 2015, 75(5), 969-974.
[http://dx.doi.org/10.1007/s00280-015-2721-z] [PMID: 25757961]
[24]
Clark, A.B.; Chandrasekar, I.; Nickleson, J. Novel route of sirolimus administration in a neonate. J. Pharm. Pract., 2018, 31(2), 167-168.
[http://dx.doi.org/10.1177/0897190017705811] [PMID: 28441898]
[25]
Carvalho, S.R.; Watts, A.B.; Peters, J.I.; Liu, S.; Hengsawas, S.; Escotet-Espinoza, M.S.; Williams, R.O., III Characterization and pharmacokinetic analysis of crystalline versus amorphous rapamycin dry powder via pulmonary administration in rats. Eur. J. Pharm. Biopharm., 2014, 88(1), 136-147.
[http://dx.doi.org/10.1016/j.ejpb.2014.05.008] [PMID: 24859653]
[26]
Oyler, A.R.; Armstrong, B.L.; Dunphy, R.; Alquier, L.; Maryanoff, C.A.; Cohen, J.H.; Merciadez, M.; Khublall, A.; Mehta, R.; Patel, A.; Il’ichev, Y.V. Mass balance in rapamycin autoxidation. J. Pharm. Biomed. Anal., 2008, 48(5), 1368-1374.
[http://dx.doi.org/10.1016/j.jpba.2008.09.030] [PMID: 19019612]
[27]
Oyler, A.R.; Segmuller, B.E.; Sun, Y.; Polshyna, A.; Dunphy, R.; Armstrong, B.L.; Achord, P.; Maryanoff, C.A.; Alquier, L.; Il’ichev, Y.V. Forced degradation studies of rapamycin: Identification of autoxidation products. J. Pharm. Biomed. Anal., 2012, 59, 194-200.
[http://dx.doi.org/10.1016/j.jpba.2011.10.017] [PMID: 22088479]
[28]
Il’ichev, Y.V.; Alquier, L.; Maryanoff, C.A. Degradation of rapamycin and its ring-opened isomer: Role of base catalysis. ARKIVOC, 2007, 2007, 110-131.
[http://dx.doi.org/10.3998/ark.5550190.0008.c09]
[29]
Okamoto, P.; Lam, N. Physics of crystal-to-glass transformations.Solid State Physics; Ehrenreich, H; Spaepen, F., Ed.; Elsevier Science Publishing Co. Inc., 1999, Vol. 52, pp. 1-135.
[30]
Descamps, M.; Willart, J.F.; Dudognon, E.; Caron, V. Transformation of pharmaceutical compounds upon milling and comilling: the role of T(g). J. Pharm. Sci., 2007, 96(5), 1398-1407.
[http://dx.doi.org/10.1002/jps.20939] [PMID: 17455353]
[31]
Trasi, N.S.; Byrn, S.R. Mechanically induced amorphization of drugs: a study of the thermal behavior of cryomilled compounds. AAPS PharmSciTech, 2012, 13(3), 772-784.
[http://dx.doi.org/10.1208/s12249-012-9801-8] [PMID: 22585375]
[32]
Maryanoff, C.A.; Six, K.; Vandecruys, R. Solvent free amorphous rapamycin. US 7,393,952 B2,, 2008.
[33]
Cho, Y.; Ha, E.S.; Baek, I.H.; Kim, M.S.; Cho, C.W.; Hwang, S.J. Enhanced supersaturation and oral absorption of sirolimus using an amorphous solid dispersion based on Eudragit® e. Molecules, 2015, 20(6), 9496-9509.
[http://dx.doi.org/10.3390/molecules20069496] [PMID: 26020699]
[34]
Craig, D.Q.M. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int. J. Pharm., 2002, 231(2), 131-144.
[http://dx.doi.org/10.1016/S0378-5173(01)00891-2] [PMID: 11755266]

Rights & Permissions Print Cite
Article Metrics
33
3
1
© 2024 Bentham Science Publishers | Privacy Policy