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Multiparticulate Systems for Paediatric Drug Delivery

  • Affiong Iyire
  • Afzal R. MohammedEmail author
Chapter
Part of the Advances in Delivery Science and Technology book series (ADST)

Abstract

This chapter explores the feasibility of formulating drugs as multiparticulates for children. The paediatric population is diverse and ranges from preterm infants to teenagers between 16 and 18 years of age. Salient physiological differences exist within this population as compared with adults which translate to significant changes in pharmacokinetic characteristics of administered drugs. Thus paediatrics should not be treated as ‘miniature’ adults requiring simple dose reduction during drug therapy administration. Factors such as physiology/drug pharmacokinetics, child capability, duration and frequency of therapy, convenience and acceptability as well as impact on caregivers must be considered during choice and design of paediatric dosage forms. Multiparticulates are solid dosage forms containing small discrete spherical subunits <2.5 mm in size, with each unit displaying characteristic functionalities that are independent of other subunits. Multiparticulates present a versatile and convenient dosage form with multiple applications such that they can be sprinkled on semisolid meals for younger children, or compressed into fast disintegrating tablets for older children. Major considerations during paediatric multiparticulate drug development include palatability and taste masking since these are oral dosage forms that release the drug in close proximity of the taste buds, robustness of coatings that give each subunit its individualised functionality, safe use of excipients as well as the ease of extemporaneous preparations where individual dose titration may be required. The World Health Organization (WHO) has proposed a paradigm shift from the use of liquids to age-appropriate solid dosage forms for paediatrics, and this may result in an increased number of approved multiparticulate paediatric formulations in the market.

Keywords

Paediatric Preterm Infants Children Multiparticulates Paediatric considerations Paediatric dosage forms Sprinkles Dispersible powders Versatile dosage forms 

References

  1. 1.
    Dey N, Majumdar S, Rao M. Multiparticulate drug delivery systems for controlled release. Trop J Pharm Res. 2008;7(3):1067–75.CrossRefGoogle Scholar
  2. 2.
    Gandhi B, Baheti J. Multiparticulates drug delivery systems: a review. Int J Pharm Chem Sci. 2013;2(3):1620–6.Google Scholar
  3. 3.
    Cram A, Bartlett JA, Heimlich J. Oral multiparticulates as a flexible solid dosage form approach for paediatric use. Bio Pharma Asia. 2013. https://biopharma-asia.com/magazine-articles/oral-multiparticulates-as-a-flexible-solid-dosage-form-approach-for-paediatric-use/.
  4. 4.
    Varum FJ, Merchant HA, Basit AW. Oral modified-release formulations in motion: the relationship between gastrointestinal transit and drug absorption. Int J Pharm. 2010;395(1):26–36.CrossRefPubMedGoogle Scholar
  5. 5.
    Patwekar SL, Baramade MK. Controlled release approach to novel multiparticulate drug delivery system. Int J Pharm Pharm Sci. 2012;4(3):757–63.Google Scholar
  6. 6.
    EMA. Reflection paper: Formulations of choice for the paediatric population. 2006. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003782.pdf. Accessed 14 Apr 2014.
  7. 7.
    Wood AJ, Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. New Engl J Med. 2003;349(12):1157–67.CrossRefGoogle Scholar
  8. 8.
    Milsap RL, Jusko WJ. Pharmacokinetics in the infant. Environ Health Perspect. 1994;102(Suppl 11):107.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kaye JL. Review of paediatric gastrointestinal physiology data relevant to oral drug delivery. Int J Clin Pharm. 2011;33(1):20–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Strolin Benedetti M, Baltes E. Drug metabolism and disposition in children. Fund Clin Pharm. 2003;17(3):281–99.CrossRefGoogle Scholar
  11. 11.
    Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45(11):1077–97.CrossRefPubMedGoogle Scholar
  12. 12.
    Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv. 2007;4(1):37–45.CrossRefPubMedGoogle Scholar
  13. 13.
    Cram A, Breitkreutz J, Desset-Brèthes S, Nunn T, Tuleu C. Challenges of developing palatable oral paediatric formulations. Int J Pharm. 2009;365(1):1–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Stoltenberg I, Breitkreutz J. Orally disintegrating mini-tablets (odmts) - a novel solid oral dosage form for paediatric use. Eur J Pharm Biopharm. 2011;78(3):462–9. doi: 10.1016/j.ejpb.2011.02.005.CrossRefPubMedGoogle Scholar
  15. 15.
    Thomson SA, Tuleu C, Wong IC, Keady S, Pitt KG, Sutcliffe AG. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics. 2009;123(2):e235–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Kayumba P, Huyghebaert N, Cordella C, Ntawukuliryayo J, Vervaet C, Remon JP. Quinine sulphate pellets for flexible pediatric drug dosing: formulation development and evaluation of taste-masking efficiency using the electronic tongue. Eur J Pharm Biopharm. 2007;66(3):460–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Clarke G, Newton J, Short M. Comparative gastrointestinal transit of pellet systems of varying density. Int J Pharm. 1995;114(1):1–11.CrossRefGoogle Scholar
  18. 18.
    Basit AW, Podczeck F, Michael Newton J, Waddington WA, Ell PJ, Lacey LF. The use of formulation technology to assess regional gastrointestinal drug absorption in humans. EurJ Pharm Sci. 2004;21(2):179–89.CrossRefGoogle Scholar
  19. 19.
    Wilding IR, Hardy JG, Sparrow RA, Davis SS, Daly PB, English JR. In vivo evaluation of enteric-coated naproxen tablets using gamma scintigraphy. Pharm Res. 1992;9(11):1436–41.CrossRefPubMedGoogle Scholar
  20. 20.
    Davis S, Hardy J, Taylor M, Whalley D, Wilson C. A comparative study of the gastrointestinal transit of a pellet and tablet formulation. Int J Pharm. 1984;21(2):167–77.CrossRefGoogle Scholar
  21. 21.
    Abrahamsson B, Alpsten M, Jonsson UE, Lundberg P, Sandberg A, Sundgren M, Svenheden A, Tölli J. Gastro-intestinal transit of a multiple-unit formulation (metoprolol cr/zok) and a non-disintegrating tablet with the emphasis on colon. Int J Pharm. 1996;140(2):229–35.CrossRefGoogle Scholar
  22. 22.
    Abdul S, Chandewar AV, Jaiswal SB. A flexible technology for modified-release drugs: multiple-unit pellet system (mups). J Control Release. 2010;147(1):2–16.CrossRefPubMedGoogle Scholar
  23. 23.
    Roy J. Pharmaceutical impurities—a mini-review. AAPs Pharm Sci Tech. 2002;3(2):1–8.CrossRefGoogle Scholar
  24. 24.
    Tegeli V, Gajeli G, Chougule G, Thorat Y, Shivsharan U, Kumbhar S. Significance of impurity profiling: a review. Int J Drug Formul Res. 2011;2(4):174–95.Google Scholar
  25. 25.
    Roy P, Shahiwala A. Multiparticulate formulation approach to pulsatile drug delivery: Current perspectives. J Control Release. 2009;134(2):74–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M. Delivery devices for the administration of paediatric formulations: Overview of current practice, challenges and recent developments. Int J Pharm. 2011;415(1):221–31.CrossRefPubMedGoogle Scholar
  27. 27.
    Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol. 2007;59(8):1043–55. doi: 10.1211/jpp.59.8.0001.CrossRefPubMedGoogle Scholar
  28. 28.
    Sohi H, Sultana Y, Khar RK. Taste masking technologies in oral pharmaceuticals: recent developments and approaches. Drug Dev Ind Pharm. 2004;30(5):429–48.CrossRefPubMedGoogle Scholar
  29. 29.
    Kaushik D, Dureja H. Recent patents and patented technology platforms for pharmaceutical taste masking. Recent Pat Drug Deliv Formul. 2014;8(1):37–45.CrossRefPubMedGoogle Scholar
  30. 30.
    Heer D, Aggarwal G, Kumar SH. Recent trends of fast dissolving drug delivery system-an overview of formulation technology. Pharmacophore. 2013;4(1):1–9.Google Scholar
  31. 31.
    Walsh J, Cram A, Woertz K, Breitkreutz J, Winzenburg G, Turner R, Tuleu C. Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients. Adv Drug Deliv Rev. 2014;73:14–33. http://dx.doi.org/10.1016/j.addr.2014.02.012 CrossRefPubMedGoogle Scholar
  32. 32.
    Sharma V, Chopra H. Role of taste and taste masking of bitter drugs in pharmaceutical industries an overview. Int J Pharm Pharm Sci. 2010;2(4):123–5.Google Scholar
  33. 33.
    Slavkova M, Breitkreutz J. Orodispersible drug formulations for children and elderly. Eur J Pharm Sci. 2015;75:2–9. http://dx.doi.org/10.1016/j.ejps.2015.02.015 CrossRefPubMedGoogle Scholar
  34. 34.
    Eby GA. Flavor stable zinc acetate compositions for oral absorption. Google Patents. 1992.Google Scholar
  35. 35.
    Paradissis GN. Sachet drug delivery system. Google Patents. 1988.Google Scholar
  36. 36.
    Ley JP. Masking bitter taste by molecules. Chemosens Percept. 2008;1(1):58–77.CrossRefGoogle Scholar
  37. 37.
    Zyck DJ, Greenberg MJ, Barkalow DG, Marske SW, Urnezis PW, Mazzone P. Antacid chewing gum products coated with high viscosity materials. Google Patents. 2003.Google Scholar
  38. 38.
    Toraishi K, Nakamura N, Yuizono Y, Mori M, Kurokawa M. Application of a rapid–jelly form confectionery for improving children’s compliance in taking bitter medicines. Jpn J Hosp Pharm. 1988;24(5):479–83.CrossRefGoogle Scholar
  39. 39.
    Morott JT, Pimparade M, Park JB, Worley CP, Majumdar S, Lian Z, Pinto E, Bi Y, Durig T, Repka MA. The effects of screw configuration and polymeric carriers on hot-melt extruded taste-masked formulations incorporated into orally disintegrating tablets. J Pharm Sci. 2015;104(1):124–34.CrossRefPubMedGoogle Scholar
  40. 40.
    Puttewar T, Kshirsagar M, Chandewar A, Chikhale R. Formulation and evaluation of orodispersible tablet of taste masked doxylamine succinate using ion exchange resin. J King Saud Uni-Sci. 2010;22(4):229–40.CrossRefGoogle Scholar
  41. 41.
    Shah PP, Mashru RC. Palatable reconstitutable dry suspension of artemether for flexible pediatric dosing using cyclodextrin inclusion complexation. Pharm Dev Technol. 2010;15(3):276–85.CrossRefPubMedGoogle Scholar
  42. 42.
    Karaman R. Prodrugs for masking bitter taste of antibacterial drugs—a computational approach. J Mol Model. 2013;19(6):2399–412.CrossRefPubMedGoogle Scholar
  43. 43.
    Cerea M, Zheng W, Young CR, McGinity JW. A novel powder coating process for attaining taste masking and moisture protective films applied to tablets. Int J Pharm. 2004;279(1):127–39.CrossRefPubMedGoogle Scholar
  44. 44.
    Shirai Y, Sogo K, Yamamoto K, Kojima K, Fujioka H, Makita H, Nakamura Y. A novel fine granule system for masking bitter taste. Biol Pharm Bull. 1993;16(2):172.CrossRefPubMedGoogle Scholar
  45. 45.
    Witzleb R, Kanikanti V-R, Hamann H-J, Kleinebudde P. Solid lipid extrusion with small die diameters–electrostatic charging, taste masking and continuous production. Eur J Pharm Biopharm. 2011;77(1):170–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Mohammed A. Coating apparatus and method. UK Patent. 2014. 1419308.0.Google Scholar
  47. 47.
    Schiffter H, Condliffe J, Vonhoff S. Spray-freeze-drying of nanosuspensions: The manufacture of insulin particles for needle-free ballistic powder delivery. J R Soc Interface. 2010;7:S483–500. doi: 10.1098/rsif.2010.0114.focus.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Woertz K, Tissen C, Kleinebudde P, Breitkreutz J. Rational development of taste masked oral liquids guided by an electronic tongue. Int J Pharm. 2010;400(1):114–23.CrossRefPubMedGoogle Scholar
  49. 49.
    Al-Khattawi A, Iyire A, Dennison T, Dahmash E, Bailey C, Smith J, Rue P, Mohammed A. Systematic screening of compressed odt excipients: cellulosic versus non-cellulosic. Curr Drug Deliv. 2014;11:486–500.CrossRefPubMedGoogle Scholar
  50. 50.
    Al-Khattawi A, Alyami H, Townsend B, Ma X, Mohammed AR. Evidence-based nanoscopic and molecular framework for excipient functionality in compressed orally disintegrating tablets. PLoS One. 2014;9(7):e101369.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Stoltenberg I, Winzenburg G, Breitkreutz J. Solid oral dosage forms for children–formulations, excipients and acceptance issues. Eur Ind Pharm. 2011;8:4–7.Google Scholar
  52. 52.
    Al-khattawi A, Mohammed A. Excipients in medicines for children: scientific and regulatory paradigms. Eur Pharm Rev. 2014;19:67–70.Google Scholar
  53. 53.
    Pifferi G, Restani P. The safety of pharmaceutical excipients. Il Farmaco. 2003;58(8):541–50.CrossRefPubMedGoogle Scholar
  54. 54.
    Nahata MC. Pediatric drug formulations: challenges and potential solutions. Ann Pharm. 1999;33(2):247–9.Google Scholar
  55. 55.
    Guidance for industry, bioavailability and bioequivalence studies for orally-administered drug products—general considerations. Us department of health and human services food and drug administration center for drug evaluation and research. 2003. https://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf.
  56. 56.
    Nunn T, Williams J. Formulation of medicines for children. Br J Clin Pharmacol. 2005;59(6):674–6.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Takon I. Clinical use of a modified release methylphenidate in the treatment of childhood attention deficit hyperactivity disorder. Ann Gen Psychiatry. 2011;10:25.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Amrutkar P, Chaudhari P, Patil S. Design and in vitro evaluation of multiparticulate floating drug delivery system of zolpidem tartarate. Colloids Surf B Biointerfaces. 2012;89:182–7.CrossRefPubMedGoogle Scholar
  59. 59.
    Dhole A, Gaikwad P, Bankar V, Pawar S. A review on floating multiparticulate drug delivery system--a novel approach to gastric retention. Int J Pharm Sci Rev Res. 2011;6(2):205–11.Google Scholar
  60. 60.
    Patel PB, Dhake AS. Multiparticulate approach: an emerging trend in colon specific drug delivery for chronotherapy. J Appl Pharm Sci. 2011;1(05):59–63.Google Scholar
  61. 61.
    Shukla D, Chakraborty S, Singh S, Mishra B. Lipid-based oral multiparticulate formulations-advantages, technological advances and industrial applications. Expert Opin Drug Deliv. 2011;8(2):207–24.CrossRefPubMedGoogle Scholar

Copyright information

© Controlled Release Society 2017

Authors and Affiliations

  1. 1.Aston School of Pharmacy, Aston UniversityBirminghamUK

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