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In Vivo Evaluation of a Novel Chitosan-Polycaprolactone Based Mucoadhesive Gastro-Retentive Sustained Release Drug Delivery System for Milnacipran HCl

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Abstract

The study was aimed to develop a gastro-retentive mucoadhesive sustained release matrix formulation for milnacipran HCl (MCN) by using the design of experiment (DoE). The gastro-retentive swellable mucoadhesive matrix tablets were prepared by modified solvent-based wet granulation through mixing milnacipran (MCN), chitosan low molecular weight (CH-LM), chitosan medium molecular weight (CH-MM), and polycaprolactone (PCL). Optimization of the formulation was carried out via DoE. Formulations were characterized by DSC, FTIR, and in vitro drug release testing. In vitro mucoadhesive studies were performed on rabbit’s intestinal mucosa. In vivo drug release studies were performed on dogs. Optimized matrix formulations showed no significant interaction among the polymers and MCN, confirmed by DSC and FTIR, and were characterized as swellable controlled release matrix systems. The optimized formulations MOPT3 and MOPT4 showed significantly improved adhesion time of 12 h on the gastric mucosa. Based on the in vivo analysis, the elimination half-life of MCN was increased that proved the matrix formulation to be sustained release DDS. The Tmax was extended from 2 to 12 ± 1.63 h for MOPT4. Cmax of matrix was reduced to 121.60 ± 9.496 ng/ml as compared to 149.22 ± 9.942 ng/ml of solution. The bioavailability of the matrix formulation was significantly improved as compared to the MCN solution by 272.20 ± 48.11%. The controlled drug release and strong mucoadhesive properties of the gastro-retentive matrix formulations suggested the potential application of the formulations for the extended oral delivery of MCN.

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References

  1. Malik R, Garg T, Goyal AK, Rath G. Polymeric nanofibers: targeted gastro-retentive drug delivery systems. J Drug Target. 2015;23(2):109–24.

    Article  CAS  Google Scholar 

  2. Kaur R, Garg T, Malik B, Gupta UD, Gupta P, Rath G, et al. Development and characterization of spray-dried porous nanoaggregates for pulmonary delivery of anti-tubercular drugs. Drug Delivery. 2016;23(3):872–7.

    Article  CAS  Google Scholar 

  3. Kulkarni S, Kulkarni R, Jadhav P. Tiwari A. Google Patents: Controlled release pharmaceutical compositions of milnacipran; 2014.

    Google Scholar 

  4. English C, Rey JA, Rufin C. Milnacipran (Savella), a treatment option for fibromyalgia. Pharm Ther. 2010;35(5):261.

    Google Scholar 

  5. Kyle JA, Dugan BD, Testerman KK. New drug approvals: milnacipran for treatment of fibromyalgia. Ann Pharmacother. 2010;44(9):1422–9.

    Article  CAS  Google Scholar 

  6. Ratnakar NC, Gohel MC. Formulation and eveluation of milnacipran HCl controlled release osmotic tablets. Pharma Sci Monit. 2018;9(1).

  7. Luo Y, Teng Z, Li Y, Wang Q. Solid lipid nanoparticles for oral drug delivery: chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake. Carbohydr Polym. 2015;122:221–9.

    Article  CAS  Google Scholar 

  8. Hussain T, Shahzad MK, Hayat K, Hussain K, Bukhari NI. Simple and sensitive colorimetric method for the determination of milnacipran in bulk and swellable matrix tablets. Pharm Chem J. 2016;50(5):346–52.

    Article  CAS  Google Scholar 

  9. Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010;12(3):263–71.

    Article  Google Scholar 

  10. Luppi B, Bigucci F, Abruzzo A, Corace G, Cerchiara T, Zecchi V. Freeze-dried chitosan/pectin nasal inserts for antipsychotic drug delivery. Eur J Pharm Biopharm. 2010;75(3):381–7.

    Article  CAS  Google Scholar 

  11. Puozzo C, Filaquier C, Zorza G. Determination of milnacipran, a serotonin and noradrenaline reuptake inhibitor, in human plasma using liquid chromatography with spectrofluorimetric detection. J Chromatogr B Anal Technol Biomed Life Sci. 2004;806(2):221–8.

    Article  CAS  Google Scholar 

  12. Parejiya PB, Movaliya VR, Barot BS, Modi D, Shelat PK, Shukla A. Quantitative determination of milnacipran HCl in rabbit plasma by HPLC and its application to pharmacokinetics study. J Liq Chromatogr Relat Technol. 2014;37(1):99–111.

    Article  CAS  Google Scholar 

  13. Allen P, Bennett K, Heritage B (2018) SPSS statistics: a practical guide with student resource access 12 months: Cengage AU

  14. USP. The United States Pharmacopeia. US Pharmacopeial Convention Inc., Rockville, MD,USA: 2748–27512005

  15. Hussain T, Saeed T, Mumtaz AM, Javaid Z, Abbas K, Awais A, et al. Effect of two hydrophobic polymers on the release of gliclazide from their matrix tablets. Acta Pol Pharm. 2013;70(4):749–57.

    CAS  PubMed  Google Scholar 

  16. Pickering G, Macian N, Delage N, Picard P, Cardot J-M, Sickout-Arondo S, et al. Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study. Drug Des Devel Ther. 2018;12:2485.

    Article  CAS  Google Scholar 

  17. Parejiya PB, Barot BS, Patel HK, Chorawala MR, Shelat PK, Shukla A. In vivo performance evaluation and establishment of IVIVC for osmotic pump based extended release formulation of milnacipran HCl. Biopharm Drug Dispos. 2013;34(4):227–35.

    Article  CAS  Google Scholar 

  18. Gaspar MC, Grégoire N, Sousa JJ, Pais AA, Lamarche I, Gobin P, et al. Pulmonary pharmacokinetics of levofloxacin in rats after aerosolization of immediate-release chitosan or sustained-release PLGA microspheres. Eur J Pharm Sci. 2016;93:184–91.

    Article  CAS  Google Scholar 

  19. Gopal PR, Prabakar AC, Chandrashekar E, Somaiah PV. Synthesis and characterization of process related impurities of (±)-milnacipran. J Chin Chem Soc. 2013;60(6):639–44.

    Article  CAS  Google Scholar 

  20. Wu C-S. A comparison of the structure, thermal properties, and biodegradability of polycaprolactone/chitosan and acrylic acid grafted polycaprolactone/chitosan. Polymer. 2005;46(1):147–55.

    Article  CAS  Google Scholar 

  21. Abdolmohammadi S, Siyamak S, Ibrahim NA, Yunus WMZW, Rahman MZA, Azizi S, et al. Enhancement of mechanical and thermal properties of polycaprolactone/chitosan blend by calcium carbonate nanoparticles. Int J Mol Sci. 2012;13(4):4508–22.

    Article  CAS  Google Scholar 

  22. Bauer M, Megret C, Lamure A, Lacabanne C, Fauran-Clavel MJ. Differential scanning calorimetry study of the interaction of antidepressant drugs, noradrenaline, and 5-hydroxytryptamine with a membrane model. J Pharm Sci. 1990;79(10):897–901.

    Article  CAS  Google Scholar 

  23. Senda T, He Y, Inoue Y. Biodegradable blends of poly (ε-caprolactone) with α-chitin and chitosan: specific interactions, thermal properties and crystallization behavior. Polym Int. 2002;51(1):33–9.

    Article  CAS  Google Scholar 

  24. Sun Y, Cui F, Shi K, Wang J, Niu M, Ma R. The effect of chitosan molecular weight on the characteristics of spray-dried methotrexate-loaded chitosan microspheres for nasal administration. Drug Dev Ind Pharm. 2009;35(3):379–86.

    Article  CAS  Google Scholar 

  25. Siepmann J, Peppas N. Hydrophilic matrices for controlled drug delivery: an improved mathematical model to predict the resulting drug release kinetics (the “sequential layer” model). Pharm Res. 2000;17(10):1290–8.

    Article  CAS  Google Scholar 

  26. Peppas NA, Narasimhan B. Mathematical models in drug delivery: how modeling has shaped the way we design new drug delivery systems. J Control Release. 2014;190:75–81.

    Article  CAS  Google Scholar 

  27. Omwancha WS, Mallipeddi R, Valle BL, Neau SH. Chitosan as a pore former in coated beads for colon specific drug delivery of 5-ASA. Int J Pharm. 2013;441(1):343–51.

    Article  CAS  Google Scholar 

  28. Sahoo S, Sasmal A, Nanda R, Phani A, Nayak P. Synthesis of chitosan–polycaprolactone blend for control delivery of ofloxacin drug. Carbohydr Polym. 2010;79(1):106–13.

    Article  CAS  Google Scholar 

  29. Abruzzo A, Bigucci F, Cerchiara T, Cruciani F, Vitali B, Luppi B. Mucoadhesive chitosan/gelatin films for buccal delivery of propranolol hydrochloride. Carbohydr Polym. 2012;87(1):581–8.

    Article  CAS  Google Scholar 

  30. Vemula SK, Veerareddy PR, Devadasu VR. Pharmacokinetics of colon-specific pH and time-dependent flurbiprofen tablets. Eur J Drug Metab Pharmacokinet. 2015;40(3):301–11.

    Article  CAS  Google Scholar 

  31. Tang M, Hu P, Huang S, Zheng Q, Yu H, He Y. Development of an extended-release formulation for apremilast and a level A in vitro–in vivo correlation study in beagle dogs. Chem Pharm Bull. 2016;64(11):1607–15.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors are thankful to Pharmedic Laboratories for providing analytical facilities. The authors also extend their gratitude to Mr. Ahmad Aqib and Miss Sehar for cooperating in arranging and managing the data for the research article.

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Authors and Affiliations

  1. University College of Pharmacy, University of the Punjab, Lahore, 54000, Pakistan

    Talib Hussain, Rahat Shamim, Khalid Hussain, Nasir Abbas, Amjad Hussain & Nadeem Irfan Bukhari

  2. Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan

    Talib Hussain

  3. Faculty of Pharmacy, COMSATS University of Islamabad, Lahore campus, Lahore, Pakistan

    Muhammad Ijaz

  4. Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria

    Julia Anita Griessinger

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  1. Talib Hussain
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  2. Muhammad Ijaz
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  3. Rahat Shamim
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  4. Khalid Hussain
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  5. Nasir Abbas
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  6. Amjad Hussain
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  8. Nadeem Irfan Bukhari
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Correspondence to Nadeem Irfan Bukhari.

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Hussain, T., Ijaz, M., Shamim, R. et al. In Vivo Evaluation of a Novel Chitosan-Polycaprolactone Based Mucoadhesive Gastro-Retentive Sustained Release Drug Delivery System for Milnacipran HCl. AAPS PharmSciTech 21, 58 (2020). https://doi.org/10.1208/s12249-019-1606-6

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