Abstract
The aim of the proposed work was to develop robust hot-melt extrusion (HME) process for fabricating sustained-release mini-matrices (pellets) of a highly water-soluble drug, tramadol hydrochloride. The current work was designed to identify a formulation window with target functional performances such as streamlined processability and sustained-release profile with alcohol-resistant properties. HME was used to perform screening tests of various drug loadings and excipients to determine the acceptable limit of each independent component (critical material attributes, CMAs) in the Design of Experiment (DoE). It was observed that the ratio of hydrophobic (ethyl cellulose, EC; Compritol® ATO 888, C888) to hydrophilic (hydroxypropyl cellulose, HPC) components were critical factors evaluated using DoE. The processing temperature (105–175 °C) was identified as a critical process parameter. FTIR chemical imaging was used to assess the drug-matrix interaction, confirming a homogeneous drug distribution inside the polymer-lipid matrix system. SEM analysis and FTIR results were also in close agreement. Finally, a feasible formulation window containing EC, C888, and HPC in the ratios of 40:20:10 with the desired quality target product profile was successfully developed. Hydroalcoholic dissolution studies revealed safe and sustained-release of tramadol that resisted drug release variations for the first few hours in alcohol. The developed mini-matrices followed the Peppas–Sahlin model indicating a combination of Fickian diffusion and swelling mechanisms. Herein we conclude, a successful blueprint technology for the development of alcohol-resistant mini-matrices of tramadol hydrochloride via HME to provide once-a-day therapy for pain management, consequently reducing the dosing frequency.
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References
Altunkaya H, Ozer Y, Kargi E, Ozkocak I, Hosnuter M, Demirel CB, Babuccu O (2004) The postoperative analgesic effect of tramadol when used as subcutaneous local anesthetic. Anesth Analg. https://doi.org/10.1213/01.ANE.0000135640.21229.A0
Anseth KS, Bowman CN, Brannon-Peppas L (1996) Mechanical properties of hydrogels and their experimental determination. Biomaterials 17(17):1647–1657. https://doi.org/10.1016/0142-9612(96)87644-7
Banakar UV (1991) Pharmaceutical dissolution testing. CRC Press. https://doi.org/10.1201/b14198
Borujeni SH, Mirdamadian SZ, Varshosaz J, Taheri A (2020) Three-dimensional (3D) printed tablets using ethyl cellulose and hydroxypropyl cellulose to achieve zero order sustained release profile. Cellulose 27(3):1573–1589. https://doi.org/10.1007/s10570-019-02881-4
Butreddy A, Sarabu S, Dumpa N, Bandari S, Repka MA (2020) Extended release pellets prepared by hot melt extrusion technique for abuse deterrent potential: category-1 in-vitro evaluation. Int J Pharm 587:119624. https://doi.org/10.1016/j.ijpharm.2020.119624
Cepeda MS, Camargo F, Zea C, Valencia L (2007) Tramadol for osteoarthritis: a systematic review and metaanalysis. J Rheumatol 34(3):543
Chen L, Yang G, Chu X et al (2019) Polymer distribution and mechanism conversion in multiple media of phase-separated controlled-release film-coating. Pharmaceutics 11(2):80. https://doi.org/10.3390/pharmaceutics11020080
Chime S, Onunkwo G, Onyishi I (2013) Kinetics and mechanisms of drug release from swellable and non swellable matrices: a review. Res J Pharm Biol Chem Sci 4(2):97–103. https://doi.org/10.1517/17425241003602259
Costa P, Sousa Lobo JM (2001) Modeling and comparison of dissolution profiles. Eur J Pharm Sci 13(2):123–133. https://doi.org/10.1016/S0928-0987(01)00095-1
Crowley MM, Schroeder B, Fredersdorf A et al (2004) Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion. Int J Pharm 269(2):509–522. https://doi.org/10.1016/j.ijpharm.2003.09.037
Draft guidance on tramadol, center for drug evaluation and research (CDER) (2007). In: US Food and Drug Administration, New Hampshire
Duhmke RM, Cornblath DD, Hollingshead JR (2004) Tramadol for neuropathic pain. Cochrane Datab Syst Rev. https://doi.org/10.1002/14651858.cd003726.pub2
Follonier N, Doelker E, Cole ET (1994) Evaluation of hot-melt extrusion as a new technique for the production of polymer-based pellets for sustained release capsules containing high loadings of freely soluble drugs. Drug Dev Ind Pharm 20(8):1323–1339. https://doi.org/10.3109/03639049409038373
Follonier N, Doelker E, Cole ET (1995) Various ways of modulating the release of diltiazem hydrochloride from hot-melt extruded sustained release pellets prepared using polymeric materials. J Control Release 36(3):243–250. https://doi.org/10.1016/0168-3659(95)00041-6
Friuli V, Bruni G, Musitelli G, Conte U, Maggi L (2018) Influence of dissolution media and presence of alcohol on the in vitro performance of pharmaceutical products containing an insoluble drug. J Pharm Sci 107(1):507–511. https://doi.org/10.1016/j.xphs.2017.06.001
Fuenmayor E, Forde M, Healy AV, Devine DM, Lyons JG, McConville C, Major I (2018) Material considerations for fused-filament fabrication of solid dosage forms. Pharmaceutics 10(2):44. https://doi.org/10.3390/pharmaceutics10020044
Goldberg DS, McGee SJ (2011) Pain as a global public health priority. BMC Public Health 11(1):770. https://doi.org/10.1186/1471-2458-11-770
Goodhart FW, Jan S (1989) Dry powder layering. In: Sellassie IG (ed) Pharmaceutical pelletization technology, 1st edn. Marcel Dekker Inc, New York, pp 165–186
He M (1986) Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the international association for the study of pain. Subcomm Taxon Pain Suppl 3:S1-226
Higuchi T (1961) Rate of release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci 50(10):874–875. https://doi.org/10.1002/jps.2600501018
Hörmann TR, Jäger N, Funke A, Mürb RK, Khinast JG, Paudel A (2018) Formulation performance and processability window for manufacturing a dual-polymer amorphous solid dispersion via hot-melt extrusion and strand pelletization. Int J Pharm 553(1–2):408–421. https://doi.org/10.1016/j.ijpharm.2018.10.035
Hörmann TR, Rehrl J, Scheibelhofer O, Schaden LM, Funke A, Makert C, Khinast JG (2019) Sensitivity of a continuous hot-melt extrusion and strand pelletization line to control actions and composition variation. Int J Pharm 566:239–253. https://doi.org/10.1016/j.ijpharm.2019.05.046
Kang S, He Y, Yu DG, Li W, Wang K (2021) Drug–zein@ lipid hybrid nanoparticles: electrospraying preparation and drug extended release application. Colloids Surf B 201:111629. https://doi.org/10.1016/j.colsurfb.2021.111629
Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA (1983) Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 15(1):25–35. https://doi.org/10.1016/0378-5173(83)90064-9
Kugelmann H (2008) Drug preparation of tramadol and acetaminophen. WO2008064854A1
Lao LL, Peppas NA, Boey FY, Venkatraman SS (2011) Modeling of drug release from bulk-degrading polymers. Int J Pharm 418(1):28–41. https://doi.org/10.1016/j.ijpharm.2010.12.020
Leppert W, Łuczak J (2005) The role of tramadol in cancer pain treatment—a review. Support Care Cancer 13(1):5–17. https://doi.org/10.1007/s00520-004-0720-4
Liu J, Zhang F, McGinity JW (2001) Properties of lipophilic matrix tablets containing phenylpropanolamine hydrochloride prepared by hot-melt extrusion. Eur J Pharm Biopharm 52(2):181–190. https://doi.org/10.1016/S0939-6411(01)00162-X
Mamidi HK, Palekar S, Nukala PK et al (2021) Process optimization of twin-screw melt granulation of fenofibrate using design of experiment (DoE). Int J Pharm 593:120101. https://doi.org/10.1016/j.ijpharm.2020.120101
Maniruzzaman M, Boateng JS, Snowden MJ, Douroumis D (2012) A review of hot-melt extrusion: process technology to pharmaceutical products. Int Sch Res Notices. https://doi.org/10.5402/2012/436763
Martin C (2013) Twin screw extrusion for pharmaceutical processes. In: Repka MA, Langley N, DiNunzio J (eds) Melt extrusion: materials, technology and drug product design. Springe, New York, pp 47–79
Moore JW, Flanner HH (1996) Mathematical comparison of dissolution profiles. Pharm Technol 20(6):64–74
Moriguchi R, Kogure K, Akita H, Futaki S, Miyagishi M, Taira K, Harashima H (2005) A multifunctional envelope-type nano device for novel gene delivery of siRNA plasmids. Int J Pharm 301(1):277–285. https://doi.org/10.1016/j.ijpharm.2005.05.021
Mortelmans LJ, Desruelles D, Baert JA, Hente KR, Tailly GG (2006) Use of tramadol drip in controlling renal colic pain. J Endourol 20(12):1010–1015. https://doi.org/10.1089/end.2006.20.1010
Natarajan JV, Nugraha C, Ng XW, Venkatraman S (2014) Sustained-release from nanocarriers: a review. J Control Release 193:122–138. https://doi.org/10.1016/j.jconrel.2014.05.029
Nukala PK, Palekar S, Patki M, Fu Y, Patel K (2019) Multi-dose oral abuse deterrent formulation of loperamide using hot melt extrusion. Int J Pharm 569:118629. https://doi.org/10.1016/j.ijpharm.2019.118629
Ozturk AG, Ozturk SS, Palsson BO, Wheatley TA, Dressman JB (1990) Mechanism of release from pellets coated with an ethylcellulose-based film. J Control Release 14(3):203–213. https://doi.org/10.1016/0168-3659(90)90160-U
Palekar S, Nukala PK, Mishra SM, Kipping T, Patel K (2019) Application of 3D printing technology and quality by design approach for development of age-appropriate pediatric formulation of baclofen. Int J Pharm 556:106–116. https://doi.org/10.1016/j.ijpharm.2018.11.062
Palem CR, Dudhipala N, Battu SK, Goda S, Repka MA, Yamsani MR (2015) Combined dosage form of pioglitazone and felodipine as mucoadhesive pellets via hot melt extrusion for improved buccal delivery with application of quality by design approach. J Drug Deliv Sci Technol 30:209–219. https://doi.org/10.1016/j.jddst.2015.10.017
Patki M, Palekar S, Nukala PK, Vartak R, Patel K (2020) Overdose and alcohol sensitive immediate release system (OASIS) for deterring accidental overdose or abuse of drugs. AAPS PharmSciTech 22(1):9. https://doi.org/10.1208/s12249-020-01879-7
Peppas NA (2010) Biomedical applications of hydrogels handbook. Springer Science & Business Media
Plumb K (2005) Continuous processing in the pharmaceutical industry: changing the mind set. Chem Eng Res Des 83(6):730–738. https://doi.org/10.1205/cherd.04359
Pozos AJ, Martínez R, Aguirre P, Pérez J (2007) Tramadol administered in a combination of routes for reducing pain after removal of an impacted mandibular third molar. J Oral Maxillofac Surg 65(8):1633–1639. https://doi.org/10.1016/j.joms.2006.06.267
Quadir MA, Rahman MS, Karim MZ, Akter S, Awkat M, Reza MS (2003) Evaluation of hydrophobic materials as matrices for controlled-release drug delivery. Pak J Pharm Sci 16(2):17–28
Quinten T, Beer TD, Vervaet C, Remon JP (2009) Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets. Eur J Pharm Biopharm 71(1):145–154. https://doi.org/10.1016/j.ejpb.2008.02.025
Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, Martin C, McGinity JW (2007) Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm 33(10):1043–1057. https://doi.org/10.1080/03639040701525627
Ritger PL, Peppas NA (1987) A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J Control Release 5(1):37–42. https://doi.org/10.1016/0168-3659(87)90035-6
Roblegg E, Jäger E, Hodzic A, Koscher G, Mohr S, Zimmer A, Khinast J (2011) Development of sustained-release lipophilic calcium stearate pellets via hot melt extrusion. Eur J Pharm Biopharm 79(3):635–645. https://doi.org/10.1016/j.ejpb.2011.07.004
Rosiaux Y, Velghe C, Muschert S, Chokshi R, Leclercq B, Siepmann F, Siepmann J (2014) Mechanisms controlling theophylline release from ethanol-resistant coated pellets. Pharm Res 31(3):731–741. https://doi.org/10.1007/s11095-013-1194-1
Sahutoglu C, Kocabas S, Askar FZ (2018) Tramadol use in a patient with Brugada syndrome and morphine allergy: a case report. J Pain Res 11:191–194. https://doi.org/10.2147/JPR.S150905
Shah VP, Tsong Y, Sathe P, Liu JP (1998) In vitro dissolution profile comparison—statistics and analysis of the similarity factor, f2. Pharm Res 15(6):889–896. https://doi.org/10.1023/A:1011976615750
Siepmann J, Göpferich A (2001) Mathematical modeling of bioerodible, polymeric drug delivery systems. Adv Drug Deliv Rev 48(2):229–247. https://doi.org/10.1016/S0169-409X(01)00116-8
Siepmann J, Peppas NA (2012) Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev 64:163–174. https://doi.org/10.1016/j.addr.2012.09.028
Siepmann J, Siegel RA, Rathbone MJ (2011) Fundamentals and applications of controlled release drug delivery: Springer Science & Business Media
Smith DM, Kapoor Y, Klinzing GR, Procopio AT (2018) Pharmaceutical 3D printing: design and qualification of a single step print and fill capsule. Int J Pharm 544(1):21–30. https://doi.org/10.1016/j.ijpharm.2018.03.056
Subedi M, Bajaj S, Kumar MS, Yc M (2019) An overview of tramadol and its usage in pain management and future perspective. Biomed Pharmacother 111:443–451. https://doi.org/10.1016/j.biopha.2018.12.085
Tambe S, Jain D, Agarwal Y, Amin P (2021) Hot-melt extrusion: highlighting recent advances in pharmaceutical applications. J Drug Deliv Sci Technol 63:102452. https://doi.org/10.1016/j.jddst.2021.102452
Tanaka N, Imai K, Okimoto K, Ueda S, Tokunaga Y, Ibuki R, Higaki K, Kimura T (2006) Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine (II): In vivo evaluation. J Control Release 112(1):51–56. https://doi.org/10.1016/j.jconrel.2006.01.020
Traynor MJ, Brown MB, Pannala A, Beck P, Martin GP (2008) Influence of alcohol on the release of tramadol from 24-h controlled-release formulations during in vitro dissolution experiments. Drug Dev Ind Pharm 34(8):885–889. https://doi.org/10.1080/03639040801929240
Verhoeven E, De Beer TR, Van den Mooter G, Remon JP, Vervaet C (2008) Influence of formulation and process parameters on the release characteristics of ethylcellulose sustained-release mini-matrices produced by hot-melt extrusion. Eur J Pharm Biopharm 69(1):312–319. https://doi.org/10.1016/j.ejpb.2007.10.007
Vithani K, Douroumis D (2019) Hot-melt extruded lipidic pellets for pediatric applications: an investigation of the effects and stability on drug dissolution. J Drug Deliv Sci Technol 49:43–49. https://doi.org/10.1016/j.jddst.2018.10.033
Vo AQ, Feng X, Morott JT, Pimparade MB, Tiwari RV, Zhang F, Repka MA (2016) A novel floating controlled release drug delivery system prepared by hot-melt extrusion. Eur J Pharm Biopharm 98:108–121. https://doi.org/10.1016/j.ejpb.2015.11.015
Vo AQ, Kutz G, He H, Narala S, Bandari S, Repka MA (2020) Continuous manufacturing of ketoprofen delayed release pellets using melt extrusion technology: application of QbD design space, inline near infrared, and inline pellet size analysis. J Pharm Sci 109(12):3598–3607. https://doi.org/10.1016/j.xphs.2020.09.007
WHO Expert Committee on Drug Dependence (2016) World Health Organization technical report series (998), 1–34
Won DG, Park G, Ngo HV, Jin G, Park C, Lee BJ (2021) Evaluation of the impact of abuse deterring agents on the physicochemical factors of tramadol-loaded tablet and the definition of new abuse deterrent index. Int J Pharm 605:120726. https://doi.org/10.1016/j.ijpharm.2021.120726
Xu H, Xu X, Li S, Song WL, Yu DG, Annie Bligh SW (2021) The effect of drug heterogeneous distributions within core-sheath nanostructures on its sustained release profiles. Biomolecules 11(9):1330. https://doi.org/10.3390/biom11091330
Yao J, Zhang Y, Hu Q, Zeng D, Hua F, Meng W, Wang W, Bao GH (2017) Optimization of paeonol-loaded poly (butyl-2-cyanoacrylate) nanocapsules by central composite design with response surface methodology together with the antibacterial properties. Eur J Pharm Sci 101:189–199. https://doi.org/10.1016/j.ejps.2017.01.028
Young CR, Koleng JJ, McGinity JW (2002) Production of spherical pellets by a hot-melt extrusion and spheronization process. Int J Pharm 242(1):87–92. https://doi.org/10.1016/S0378-5173(02)00152-7
Yu LX (2008) Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res 25(4):781–791. https://doi.org/10.1007/s11095-007-9511-1
Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, Woodcock J (2014) Understanding Pharmaceutical Quality by Design. AAPS J 16(4):771–783. https://doi.org/10.1208/s12248-014-9598-3
Zhang YE, Tchao R, Schwartz JB (2001) Effect of processing methods and heat treatment on the formation of wax matrix tablets for sustained drug release. Pharm Dev Technol 6(2):131–144. https://doi.org/10.1081/PDT-100000736
Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, Xie S (2010) DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J 12(3):263–271. https://doi.org/10.1208/s12248-010-9185-1
Zhang J, Feng X, Patil H, Tiwari RV, Repka MA (2017) Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. Int J Pharm 519(1):186–197. https://doi.org/10.1016/j.ijpharm.2016.12.049
Acknowledgments
The authors would like to thank Lifescient Inc., USA for sponsoring the project. The authors would also like to thank Colorcon Asia Pvt. Ltd., Ashland India Pvt. Ltd., and Gattefossé India Pvt. Ltd. for kindly supplying the excipients used in the study.
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This work was funded by Lifescient Inc., USA.
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DDJ: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing—original draft, review and editing, Visualization, Data curation. SMT—Validation, Writing—original draft, review and editing, Data curation. PDA—Conceptualization, Writing—review and editing, Supervision, Resources, Funding acquisition.
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Jain, D.D., Tambe, S.M. & Amin, P.D. Formulation performance window for manufacturing cellulose-based sustained-release mini-matrices of highly water-soluble drug via hot-melt extrusion technology. Cellulose 29, 3323–3350 (2022). https://doi.org/10.1007/s10570-022-04458-0
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DOI: https://doi.org/10.1007/s10570-022-04458-0