Skip to main content

Advertisement

SpringerLink
Log in

Assessment of Age-Related Changes in Pediatric Gastrointestinal Solubility

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Compound solubility serves as a surrogate indicator of oral biopharmaceutical performance. Between infancy and adulthood, marked compositional changes in gastrointestinal (GI) fluids occur. This study serves to assess how developmental changes in GI fluid composition affects compound solubility.

Methods

Solubility assessments were conducted in vitro using biorelevant media reflective of age-specific pediatric cohorts (i.e., neonates and infants). Previously published adult media (i.e., FaSSGF, FeSSGF, FaSSIF.v2, and FeSSIF.v2) were employed as references for pediatric media development. Investigations assessing age-specific changes in GI fluid parameters (i.e., pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of neonatal and infant media. Solubility assessments at 37°C were conducted for seven BCS Class II compounds within the developed pediatric and reference adult media.

Results

For six of the seven compounds investigated, solubility fell outside an 80–125% range from adult values in at least one of the developed pediatric media. This result indicates a potential for age-related alterations in oral drug performance, especially for compounds whose absorption is delimited by solubility (i.e., BCS Class II).

Conclusion

Developmental changes in GI fluid composition can result in relevant discrepancies in luminal compound solubility between children and adults.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

BCS:

Biopharmaceutics classification systems

FaSSGF:

Fasted-state simulated gastric fluid

FaSSIF:

Fasted-state simulated intestinal fluid

FeSSGF:

Fed-state simulated gastric fluid

FeSSIF:

Fed-state simulated intestinal fluid

FFA:

Free fatty acids

GA:

Gestational age

GI:

Gastrointestinal

IVIVC:

In vitro–in vivo correlations

NaTc:

Sodium taurocholate

NEC:

Necrotizing enterocolitis

P-BCS:

Pediatric biopharmaceutics classification systems

PNA:

Postnatal age

US-FDA:

United States Food and Drug Administration

REFERENCES

  1. Galia E, Nicolaides E, Horter D, Lobenberg R, Reppas C, Dressman JB. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res. 1998;15(5):698–705.

    Article  PubMed  CAS  Google Scholar 

  2. Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 2008;25(7):1663–76.

    Article  PubMed  CAS  Google Scholar 

  3. Vertzoni M, Dressman J, Butler J, Hempenstall J, Reppas C. Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Pharm Verfahr. 2005;60(3):413–7.

    Article  CAS  Google Scholar 

  4. Shono Y, Jantratid E, Janssen N, Kesisoglou F, Mao Y, Vertzoni M, et al. Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling. Eur J Pharm Biopharm. 2009;73(1):107–14.

    Article  PubMed  CAS  Google Scholar 

  5. Dressman JB, Reppas C. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2000;11 Suppl 2:S73–80.

    CAS  Google Scholar 

  6. Kaye JL. Review of paediatric gastrointestinal physiology data relevant to oral drug delivery. Int J Clin Pharm. 2011;33(1):20–4.

    Article  PubMed  Google Scholar 

  7. Mooij MG, de Koning BA, Huijsman ML, de Wildt SN. Ontogeny of oral drug absorption processes in children. Exp Opin Drug Metab Toxicol. 2012;8(10):1293–303.

    Article  CAS  Google Scholar 

  8. Abdel-Rahman SM, Amidon GL, Kaul A, Lukacova V, Vinks AA, Knipp GT. Summary of the National Institute of Child Health and Human Development-best pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System Working Group. Clin Ther. 2012;34(11):S11–24.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Amidon GL, Lennernas H, Shah VP, Crison JR. 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):413–20.

    Article  PubMed  CAS  Google Scholar 

  10. Khadra I, Zhou Z, Dunn C, Wilson CG, Halbert G. Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2015;67:65–75.

    CAS  Google Scholar 

  11. Hentges DJ, Marsh WW, Petschow BW, Thai WR, Carter MK. Influence of infant diets on the ecology of the intestinal tract of human flora-associated mice. J Pediatr Gastroenterol Nutr. 1992;14(2):146–52.

    Article  PubMed  CAS  Google Scholar 

  12. Van Slyke DD. On the measurement of buffer values on the relationship of buffer values to the dissociation constant of the buffer and the concentration and reaction of the buffer solution. J Biol Chem. 1922;52:525–70.

    Google Scholar 

  13. Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, et al. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 2014;42(Database issue):D1091–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Granero GE, Ramachandran C, Amidon GL. Dissolution and solubility behavior of fenofibrate in sodium lauryl sulfate solutions. Drug Dev Ind Pharm. 2005;31(9):917–22.

    Article  PubMed  CAS  Google Scholar 

  15. Vogt M, Kunath K, Dressman JB. Dissolution enhancement of fenofibrate by micronization, cogrinding and spray-drying: comparison with commercial preparations. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Pharm Verfahr . 2008;68(2):283–8.

    Article  CAS  Google Scholar 

  16. Vertzoni MV, Reppas C, Archontaki HA. Sensitive and simple liquid chromatographic method with ultraviolet detection for the determination of nifedipine in canine plasma. Anal Chim Acta. 2006;573-574:298–304.

    Article  PubMed  CAS  Google Scholar 

  17. Parkin JE, Boddy MR. Development of a chromatographic method of analysis for glucosyl-amines formed from dapsone. J Liq Chromatogr Relat Technol. 1998;21(14):2131–42.

    Article  CAS  Google Scholar 

  18. Jain N, Raghuwanshi R, Jain D. Development and validation of RP-HPLC method for simultaneous estimation of atorvastatin calcium and fenofibrate in tablet dosage forms. Indian J Pharm Sci. 2008;70(2):263–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Trotta M, Gallarate M, Carlotti ME, Morel S. Preparation of griseofulvin nanoparticles from water-dilutable microemulsions. Int J Pharm. 2003;254(2):235–42.

    Article  PubMed  CAS  Google Scholar 

  20. Al Za’abi MA, Dehghanzadeh GH, Norris RL, Charles BG. A rapid and sensitive microscale HPLC method for the determination of indomethacin in plasma of premature neonates with patent ductus arteriousus. J Chromatogr B Anal Technol Biomed Life Sci. 2006;830(2):364–7.

    Article  CAS  Google Scholar 

  21. Sanches C, Lopez KV, Omosako CE, Bertoline MA, Pereira MD, Santos S. Micromethod for quantification of carbamazepine, phenobartital and phenytoin in human plasma by HPLC-UV detection for therapeutic drug monitoring application. Lat Am J Pharm. 2008;27(4):485–91.

    CAS  Google Scholar 

  22. Jain D, Laxman R, Acharya A, Jain V, Bhardwaj S. Development and validation of RP-HPLC and ultraviolet spectrophotometric methods for simultaneous determination of sprinolactone and torsemide in pharmaceutical dosage form. IJRAP. 2010;1(2):459–67.

    Google Scholar 

  23. Juenemann D, Bohets H, Ozdemir M, de Maesschalck R, Vanhoutte K, Peeters K, et al. Online monitoring of dissolution tests using dedicated potentiometric sensors in biorelevant media. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Pharm Verfahr. 2011;78(1):158–65.

    Article  CAS  Google Scholar 

  24. Guidance for industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research; 2003.

  25. Mithani SD, Bakatselou V, TenHoor CN, Dressman JB. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm Res. 1996;13(1):163–7.

    Article  PubMed  CAS  Google Scholar 

  26. James LP, Marotti T, Stowe CD, Farrar HC, Taylor BJ, Kearns GL. Pharmacokinetics and pharmacodynamics of famotidine in infants. J Clin Pharmacol. 1998;38(12):1089–95.

    PubMed  CAS  Google Scholar 

  27. James LP, Marshall JD, Heulitt MJ, Wells TG, Letzig L, Kearns GL. Pharmacokinetics and pharmacodynamics of famotidine in children. J Clin Pharmacol. 1996;36(1):48–54.

    Article  PubMed  CAS  Google Scholar 

  28. Krafte-Jacobs B, Persinger M, Carver J, Moore L, Brilli R. Rapid placement of transpyloric feeding tubes: a comparison of pH-assisted and standard insertion techniques in children. Pediatrics. 1996;98(2 Pt 1):242–8.

    PubMed  CAS  Google Scholar 

  29. Gharpure V, Meert KL, Sarnaik AP, Metheny NA. Indicators of postpyloric feeding tube placement in children. Crit Care Med. 2000;28(8):2962–6.

    Article  PubMed  CAS  Google Scholar 

  30. Westhus N. Methods to test feeding tube placement in children. MCN Am J Matern Child Nurs. 2004;29(5):282–7; quiz 90-1.

  31. Metheny NA, Stewart BJ, Smith L, Yan H, Diebold M, Clouse RE. pH and concentrations of pepsin and trypsin in feeding tube aspirates as predictors of tube placement. JPEN J Parenter Enteral Nutr. 1997;21(5):279–85.

    Article  PubMed  CAS  Google Scholar 

  32. Arvedson JC. Swallowing and feeding in infants and young children. Goyal and Shaker’s GI motility online. New York: Nature Publishing Group; 2006.

    Google Scholar 

  33. Agunod M, Yamaguchi N, Lopez R, Luhby AL, Glass GB. Correlative study of hydrochloric acid, pepsin, and intrinsic factor secretion in newborns and infants. Am J Dig Dis. 1969;14(6):400–14.

    Article  PubMed  CAS  Google Scholar 

  34. Armand M, Hamosh M, Mehta NR, Angelus PA, Philpott JR, Henderson TR, et al. Effect of human milk or formula on gastric function and fat digestion in the premature infant. Pediatr Res. 1996;40(3):429–37.

    Article  PubMed  CAS  Google Scholar 

  35. Armand M, Hamosh M, DiPalma JS, Gallagher J, Benjamin SB, Philpott JR, et al. Dietary fat modulates gastric lipase activity in healthy humans. Am J Clin Nutr. 1995;62(1):74–80.

    PubMed  CAS  Google Scholar 

  36. Wakayama Y, Wilkins S, Kimura K. Is 5% dextrose in water a proper choice for initial postoperative feeding in infants? J Pediatr Surg. 1988;23(7):644–6.

    Article  PubMed  CAS  Google Scholar 

  37. Miller BR, Tharp JA, Issacs WB. Gastric residual volume in infants and children following a 3-hour fast. J Clin Anesth. 1990;2(5):301–5.

    Article  PubMed  CAS  Google Scholar 

  38. Avery GB, Randolph JG, Weaver T. Gastric acidity in the first day of life. Pediatrics. 1966;37(6):1005–7.

    PubMed  CAS  Google Scholar 

  39. Cote CJ, Goudsouzian NG, Liu LM, Dedrick DF, Szyfelbein SK. Assessment of risk factors related to the acid aspiration syndrome in pediatric patients-gastric ph and residual volume. Anesthesiology. 1982;56(1):70–2.

    Article  PubMed  CAS  Google Scholar 

  40. Datta S, Houle GL, Fox GS. Concentration of lidocaine hydrochloride in newborn gastric fluid after elective caesarean section and vaginal delivery with epidural analgesia. Can Anaesth Soc J. 1975;22(1):79–83.

    Article  PubMed  CAS  Google Scholar 

  41. Ebers DW, Gibbs GE, Smith DI. Gastric acidity on the first day of life. Pediatrics. 1956;18(5):800–2.

    PubMed  CAS  Google Scholar 

  42. Euler AR, Byrne WJ, Meis PJ, Leake RD, Ament ME. Basal and pentagastrin-stimulated acid secretion in newborn human infants. Pediatr Res. 1979;13(1):36–7.

    Article  PubMed  CAS  Google Scholar 

  43. Goresky GV, Finley GA, Bissonnette B, Shaffer EA. Efficacy, duration, and absorption of a paediatric oral liquid preparation of ranitidine hydrochloride. Can J Anaesth. 1992;39(8):791–8.

    Article  PubMed  CAS  Google Scholar 

  44. Griswold CC, Shohl AT. GAstric digestion in new-born infants. Am J Dis Child. 1925;30(4):541–9.

    Google Scholar 

  45. Jahr JS, Burckart G, Smith SS, Shapiro J, Cook DR. Effects of famotidine on gastric pH and residual volume in pediatric surgery. Acta Anaesthesiol Scand. 1991;35(5):457–60.

    Article  PubMed  CAS  Google Scholar 

  46. Maekawa N, Mikawa K, Yaku H, Nishina K, Obara H. Effects of 2-, 4- and 12-hour fasting intervals on preoperative gastric fluid pH and volume, and plasma glucose and lipid homeostasis in children. Acta Anaesthesiol Scand. 1993;37(8):783–7.

    Article  PubMed  CAS  Google Scholar 

  47. Maffei HV, Nobrega FJ. Gastric pH and microflora of normal and diarrhoeic infants. Gut. 1975;16(9):719–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Meakin G, Dingwall AE, Addison GM. Effects of fasting and oral premedication on the pH and volume of gastric aspirate in children. Br J Anaesth. 1987;59(6):678–82.

    Article  PubMed  CAS  Google Scholar 

  49. Miclat NN, Hodgkinson R, Marx GF. Neonatal gastric pH. Anesth Analg. 1978;57(1):98–101.

    Article  PubMed  CAS  Google Scholar 

  50. Mikawa K, Nishina K, Maekawa N, Asano M, Obara H. Lansoprazole reduces preoperative gastric fluid acidity and volume in children. Can J Anaesth. 1995;42(6):467–72.

    Article  PubMed  CAS  Google Scholar 

  51. Nishina K, Mikawa K, Maekawa N, Tamada M, Obara H. Omeprazole reduces preoperative gastric fluid acidity and volume in children. Can J Anaesth. 1994;41(10):925–9.

    Article  PubMed  CAS  Google Scholar 

  52. Omari TI, Davidson GP. Multipoint measurement of intragastric pH in healthy preterm infants. Arch Dis Child Fetal Neonatal Ed. 2003;88(6):F517–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Rogers IM, Drainer IK, Moore MR, Buchanan KD. Plasma gastrin in congenitial hypertrophic pyloric stenosis. A hypothesis disproved. Arch Dis Child. 1975;50(6):467–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Sandhar BK, Goresky GV, Maltby JR, Shaffer EA. Effect of oral liquids and ranitidine on gastric fluid volume and pH in children undergoing outpatient surgery. Anesthesiology. 1989;71(3):327–30.

    Article  PubMed  CAS  Google Scholar 

  55. Splinter WM, Stewart JA, Muir JG. Large volumes of apple juice preoperatively do not affect gastric pH and volume in children. Can J Anaesth. 1990;37(1):36–9.

    Article  PubMed  CAS  Google Scholar 

  56. Di Maio S, Carrier RL. Gastrointestinal contents in fasted state and post-lipid ingestion: in vivo measurements and in vitro models for studying oral drug delivery. J Control Release. 2011;151(2):110–22.

    Article  PubMed  CAS  Google Scholar 

  57. Muller-Lissner SA, Fimmel CJ, Sonnenberg A, Will N, Muller-Duysing W, Heinzel F, et al. Novel approach to quantify duodenogastric reflux in healthy volunteers and in patients with type I gastric ulcer. Gut. 1983;24(6):510–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Rees WD, Go VL, Malagelada JR. Simultaneous measurement of antroduodenal motility, gastric emptying, and duodenogastric reflux in man. Gut. 1979;20(11):963–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J. 2010;12(3):397–406.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Klein S, Butler J, Hempenstall JM, Reppas C, Dressman JB. Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts. J Pharm Pharmacol. 2004;56(5):605–10.

    Article  PubMed  CAS  Google Scholar 

  61. Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res. 1998;15(1):11–22.

    Article  PubMed  CAS  Google Scholar 

  62. Kalantzi L, Goumas K, Kalioras V, Abrahamsson B, Dressman JB, Reppas C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm Res. 2006;23(1):165–76.

    Article  PubMed  CAS  Google Scholar 

  63. Dressman JB, Berardi RR, Dermentzoglou LC, Russell TL, Schmaltz SP, Barnett JL, et al. Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm Res. 1990;7(7):756–61.

    Article  PubMed  CAS  Google Scholar 

  64. Sondheimer JM, Clark DA, Gervaise EP. Continuous gastric pH measurement in young and older healthy preterm infants receiving formula and clear liquid feedings. J Pediatr Gastroenterol Nutr. 1985;4(3):352–5.

    Article  PubMed  CAS  Google Scholar 

  65. Billeaud C, Senterre J, Rigo J. Osmolality of the gastric and duodenal contents in low birth weight infants fed human milk or various formulae. Acta Paediatr Scand. 1982;71(5):799–803.

    Article  PubMed  CAS  Google Scholar 

  66. Thatrimontrichai A, Janjindamai W. Postprandial osmolality of gastric contents in very low-birth-weight infants fed expressed breast milk with additives. Southeast Asian J Trop Med Public Health. 2009;40(5):1080–6.

    PubMed  CAS  Google Scholar 

  67. Fallingborg J, Christensen LA, Ingeman-Nielsen M, Jacobsen BA, Abildgaard K, Rasmussen HH, et al. Measurement of gastrointestinal pH and regional transit times in normal children. J Pediatr Gastroenterol Nutr. 1990;11(2):211–4.

    Article  PubMed  CAS  Google Scholar 

  68. Fredrikzon B, Olivecrona T. Decrease of lipase and esterase activities in intestinal contents of newborn infants during test meals. Pediatr Res. 1978;12(5):631–4.

    Article  PubMed  CAS  Google Scholar 

  69. Gilbertson HR, Rogers EJ, Ukoumunne OC. Determination of a practical pH cutoff level for reliable confirmation of nasogastric tube placement. JPEN J Parenter Enteral Nutr. 2011;35(4):540–4.

    Article  PubMed  Google Scholar 

  70. Metheny NA, Eikov R, Rountree V, Lengettie E. Clinical research: indicators of feeding-tube placement in neonates. Nutr Clin Pract. 1999;14(6):307–14.

    Article  Google Scholar 

  71. Fuchs A, Dressman JB. Composition and physicochemical properties of fasted-state human duodenal and jejunal fluid: a critical evaluation of the available data. J Pharm Sci. 2014;103(11):3398–411.

    Article  PubMed  CAS  Google Scholar 

  72. Jarvenpaa AL. Feeding the low-birth-weight infant. IV. Fat absorption as a function of diet and duodenal bile acids. Pediatrics. 1983;72(5):684–9.

    PubMed  CAS  Google Scholar 

  73. Signer E, Murphy GM, Edkins S, Anderson CM. Role of bile salts in fat malabsorption of premature infants. Arch Dis Child. 1974;49(3):174–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Boehm G, Bierbach U, Senger H, Jakobsson I, Minoli I, Moro G, et al. Activities of lipase and trypsin in duodenal juice of infants small for gestational age. J Pediatr Gastroenterol Nutr. 1991;12(3):324–7.

    Article  PubMed  CAS  Google Scholar 

  75. Boehm G, Braun W, Moro G, Minoli I. Bile acid concentrations in serum and duodenal aspirates of healthy preterm infants: effects of gestational and postnatal age. Biol Neonate. 1997;71(4):207–14.

    Article  PubMed  CAS  Google Scholar 

  76. Brueton MJ, Berger HM, Brown GA, Ablitt L, Iyngkaran N, Wharton BA. Duodenal bile acid conjugation patterns and dietary sulphur amino acids in the newborn. Gut. 1978;19(2):95–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Challacombe DN, Edkins S, Brown GA. Duodenal bile acids in infancy. Arch Dis Child. 1975;50(11):837–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Encrantz JC, Sjovall J. On the bile acids in duodenal contents of infants and children. Bile acids and steroids 72. Clin Chim Acta Int J Clin Chem. 1959;4:793–9.

    Article  CAS  Google Scholar 

  79. Glasgow JF, Dinsmore H, Molla A, Macfarlane T. A comprehensive study of duodenal bile salts in newborn infants and their relationship to fat absorption. Ir J Med Sci. 1980;149(9):346–56.

    Article  PubMed  CAS  Google Scholar 

  80. Norman A, Strandvik B, Ojamae O. Bile acids and pancreatic enzymes during absorption in the newborn. Acta Paediatr Scand. 1972;61(5):571–6.

    Article  PubMed  CAS  Google Scholar 

  81. Poley JR, Dower JC, Owen Jr CA, Stickler GB. Bile acids in infants and children. J Lab Clin Med. 1964;63:838–46.

    PubMed  CAS  Google Scholar 

  82. Lavy U, Silverberg M, Davidson M. Role of bile acids in fat absorption in low birth weights infants. Pediatr Res. 1971;5(8):387.

    Article  Google Scholar 

  83. Barbero GJ, Runge G, Fischer D, Crawford MN, Torres FE, Gyorgy P. Investigations on the bacterial flora, pH, and sugar content in the intestinal tract of infants. J Pediatr. 1952;40(2):152–63.

    Article  PubMed  CAS  Google Scholar 

  84. Boehm G, Bierbach U, Senger H, Jakobsson I, Minoli I, Moro G, et al. Postnatal adaptation of lipase- and trypsin-activities in duodenal juice of premature infants appropriate for gestational age. Biomed Biochim Acta. 1990;49(5):369–73.

    PubMed  CAS  Google Scholar 

  85. Robinson PJ, Smith AL, Sly PD. Duodenal pH in cystic fibrosis and its relationship to fat malabsorption. Dig Dis Sci. 1990;35(10):1299–304.

    Article  PubMed  CAS  Google Scholar 

  86. Clarysse S, Tack J, Lammert F, Duchateau G, Reppas C, Augustijns P. Postprandial evolution in composition and characteristics of human duodenal fluids in different nutritional states. J Pharm Sci. 2009;98(3):1177–92.

    Article  PubMed  CAS  Google Scholar 

  87. Rune SJ, Viskum K. Duodenal pH values in normal controls and in patients with duodenal ulcer. Gut. 1969;10(7):569–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Challacombe DN, Brown GA, Edkins S. Duodenal bile acids in infants with protracted diarrhoea. Arch Dis Child. 1979;54(2):131–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Harries JT, Muller DP, McCollum JP, Lipson A, Roma E, Norman AP. Intestinal bile salts in cystic fibrosis: studies in the patient and experimental animal. Arch Dis Child. 1979;54(1):19–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Armand M, Borel P, Pasquier B, Dubois C, Senft M, Andre M, et al. Physicochemical characteristics of emulsions during fat digestion in human stomach and duodenum. Am J Physiol. 1996;271(1 Pt 1):G172–83.

    PubMed  CAS  Google Scholar 

  91. Hernell O, Staggers JE, Carey MC. Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings. Biochemistry. 1990;29(8):2041–56.

    Article  PubMed  CAS  Google Scholar 

  92. Srinivasan L, Bokiniec R, King C, Weaver G, Edwards AD. Increased osmolality of breast milk with therapeutic additives. Arch Dis Child Fetal Neonatal Ed. 2004;89(6):F514–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Lindquist S, Hernell O. Lipid digestion and absorption in early life: an update. Curr Opin Clin Nutr Metab Care. 2010;13(3):314–20.

    Article  PubMed  CAS  Google Scholar 

  94. Lambert DK, Christensen RD, Henry E, Besner GE, Baer VL, Wiedmeier SE, et al. Necrotizing enterocolitis in term neonates: data from a multihospital health-care system. J Perinat Off J Calif Perinatal Assoc. 2007;27(7):437–43.

    Article  CAS  Google Scholar 

  95. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet. 1990;336(8730):1519–23.

    Article  PubMed  CAS  Google Scholar 

  96. Penn AH, Altshuler AE, Small JW, Taylor SF, Dobkins KR, Schmid-Schonbein GW. Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis. Pediatr Res. 2012;72(6):560–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Clarysse S, Brouwers J, Tack J, Annaert P, Augustijns P. Intestinal drug solubility estimation based on simulated intestinal fluids: comparison with solubility in human intestinal fluids. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2011;43(4):260–9.

    CAS  Google Scholar 

  98. Augustijns P, Wuyts B, Hens B, Annaert P, Butler J, Brouwers J. A review of drug solubility in human intestinal fluids: implications for the prediction of oral absorption. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2014;57:322–32.

    CAS  Google Scholar 

  99. Hibberd CM, Brooke OG, Carter ND, Haug M, Harzer G. Variation in the composition of breast milk during the first 5 weeks of lactation: implications for the feeding of preterm infants. Arch Dis Child. 1982;57(9):658–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Smith JD, Clinard V, Barnes CL. Pharmacists’ guide to infant formulas for term infants. J Am Pharm Ass: JAPhA. 2011;51(3):e28–35; quiz e6–7.

  101. Macheras PE, Reppas CI. Studies on drug-milk freeze-dried formulations. I: bioavailability of sulfamethizole and dicumarol formulations. J Pharm Sci. 1986;75(7):692–6.

    Article  PubMed  CAS  Google Scholar 

  102. Juni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ. 2001;323(7303):42–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Chapman MJ. Pharmacology of fenofibrate. Am J Med. 1987;83(5B):21–5.

    Article  PubMed  CAS  Google Scholar 

  104. Desager JP, Costermans J, Verberckmoes R, Harvengt C. Effect of hemodialysis on plasma kinetics of fenofibrate in chronic renal failure. Nephron. 1982;31(1):51–4.

    Article  PubMed  CAS  Google Scholar 

  105. Kesisoglou F, Wu Y. Understanding the effect of API properties on bioavailability through absorption modeling. AAPS J. 2008;10(4):516–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Fotaki NV, Vertzoni M. Biorelevant dissolution methods and their applications in in vitro- in vivo correlations for oral formulations. Open Drug Deliv J. 2010;4:2–13.

    Article  CAS  Google Scholar 

  107. Horter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev. 2001;46(1-3):75–87.

    Article  PubMed  CAS  Google Scholar 

  108. Marques MR. Enzymes in the dissolution testing of gelatin capsules. AAPS PharmSciTech. 2014;15(6):1410–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This work was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC). The authors would also like to express their gratitude to Sarah Cordery for her guidance within the laboratory and Fotios Baxevanis for his assistance with the analysis.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada

    Anil R. Maharaj & Andrea N. Edginton

  2. Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK

    Nikoletta Fotaki

Authors
  1. Anil R. Maharaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea N. Edginton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nikoletta Fotaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nikoletta Fotaki.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maharaj, A.R., Edginton, A.N. & Fotaki, N. Assessment of Age-Related Changes in Pediatric Gastrointestinal Solubility. Pharm Res 33, 52–71 (2016). https://doi.org/10.1007/s11095-015-1762-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-015-1762-7

KEY WORDS

Search

Navigation