Controlled release of insulin through hydrogels of (acrylic acid)/trimethylolpropane triacrylate

Abstract

Hydrogels of poly(acrylic acid) crosslinked with trimethylolpropane triacrylate (TMPTA) were produced through solution polymerization. After these hydrogels were loaded with insulin solution, they evidenced swelling. Experiments of controlled release of insulin through the hydrogels were performed in acidic and basic media in order to evaluate the rates of release of this protein provided by the referred copolymer. Additionally, a mathematical description of the system based on differential mass balance was made and simulated in MATLAB. The model consists of a system of differential equations which was solved numerically. As expected, the values of swelling index at the equilibrium and the rates of insulin release were inversely proportional to the degree of crosslinking. The mathematical model provided reliable predictions of release profiles with fitted values of diffusivity of insulin through the hydrogels in the range of 6.0 × 10−7–1.3 × 10−6 cm2/s. The fitted and experimental values of partition coefficients of insulin between the hydrogel and the medium were lower for basic media, pointing out good affinity of insulin for these media in comparison to the acidic solutions.

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Abbreviations

av :

Surface area of the hydrogel per unit of volume (cm−1)

\( C_{A}^{I} \) :

Insulin concentration inside the hydrogel (phase I) (IU/cm3)

\( C_{A,eq}^{II} \) :

Concentration of insulin in phase II in equilibrium with \( \left. {C_{A}^{I} } \right|_{r = R} \)

\( C_{A,i}^{I} \) :

Concentration of insulin in ‘i’ position inside the hydrogel (IU/cm3)

\( C_{A,initial}^{I} \) :

Initial insulin concentration inside the hydrogel (phase I) (IU/cm3)

\( C_{A}^{II} \) :

Insulin concentration in the receiving medium (phase II) (IU/cm3)

DA :

Diffusion coefficient of insulin inside the swollen hydrogel (cm2/s)

IU:

Insulin units

kc :

Mass transfer coefficient of insulin in the receiving solution (cm/s)

K P :

Partition coefficient of insulin between phases I and II

N:

Number of points used in the method of lines

r:

Radial direction (cm)

R:

Radius of the hydrogel (cm)

Sw:

Swelling index

t:

Time of release (s)

VI :

Volume of phase I (cm3)

VII :

Volume of phase II (cm3)

wd :

Weight of dried hydrogel (g)

wsw :

Weight of swollen hydrogel (g)

References

  1. 1.

    American Diabetes Association (2012) Diagnosis and classification of diabetes mellitus. Diabetes Care 35(1):564–571

    Google Scholar 

  2. 2.

    Sajeesh S, Sharma CP (2006) Cyclodextrin–insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery. Int J Pharm 325:147–154

    Article  Google Scholar 

  3. 3.

    Langer R (1998) Drug delivery and targeting. Nature 392:5

    Google Scholar 

  4. 4.

    Ratner BD, Hoffman AS (1976) Synthetic hydrogels for biomedical applications. Hydrogels for medical and related applications, ACS Symposium Series, No. 31, American Chemical Society, Washington, DC 136

  5. 5.

    Peppas NA, Langer R (1994) New challenges in biomaterials. Science 263:1715–1720

    Article  Google Scholar 

  6. 6.

    Peppas NA (1997) Hydrogels and drug delivery. Curr Opin Colloid Interface Sci 2:531–537

    Article  Google Scholar 

  7. 7.

    Dagani R (1997) Inteligent gels. Chem Eng News 75:26–36

    Google Scholar 

  8. 8.

    Kost J (1999) Intelligent drug delivery systems. In: Mathiowitz E (ed) Encyclopedia of controlled drug delivery. Wiley, Hoboken, pp 445–459

    Google Scholar 

  9. 9.

    Zhu YJ, Chen F (2015) pH-responsive drug-delivery systems. Chem An Asian J 10:284–305

    Article  Google Scholar 

  10. 10.

    Buwalda SJ, Boere KWM, Dijkstra PJ, Feijen J, Vermonden T, Hennink WE (2015) Hydrogels in a historical perspective: from simple networks to smart materials. J Control Release 190:254–273

    Article  Google Scholar 

  11. 11.

    Vashist A, Gupta YK, Ahmad S (2014) Recent advances in hydrogel based drug delivery systems for the human body. J Mat Chem B 2(2):147–166

    Article  Google Scholar 

  12. 12.

    Roskos KV, Tefft JA, Fritzinger BK, Heller J (1992) Development of a morphine-triggered naltrexone delivery system. J Control Release 19:145–160

    Article  Google Scholar 

  13. 13.

    Gutowska A, Bae YH, Feijen J, Kim SW (1992) Heparin release from thermosensitive hydrogels. J Control Release 22:95–104

    Article  Google Scholar 

  14. 14.

    Yang K, Wan S, Chen B, Gao W, Chen J, Liu M, He B, Wu H (2015) Dual pH and temperature responsive hydrogels based on β-cyclodextrin derivatives for atorvastatin delivery. Carbohydr Polym 136:300–306

    Article  Google Scholar 

  15. 15.

    Patel VR, Amiji MM (1996) Preparation and characterization of freeze-dried chitosan-poly(ethylene oxide) hydrogels for site-specific antibiotic delivery in the stomach. Pharm Res 13:588–593

    Article  Google Scholar 

  16. 16.

    Ninni L, Ermatchkov V, Hasse H, Maurer G (2014) Swelling behavior of chemically cross-linked poly(N-IPAAm-allylglycine) hydrogels: effects of NaCl and pH. Fluid Ph Equilib 361(15):257–265

    Article  Google Scholar 

  17. 17.

    Hu X, Wei W, Qi X, Yu H, Feng L, Li J, Wang S, Zhang J, Dong W (2015) Preparation and characterization of a novel pH-sensitive Salecan-g-poly(acrylic acid) hydrogel for controlled release of doxorubicin. J Mat Chem B 3:2685–2697

    Article  Google Scholar 

  18. 18.

    Bilia A, Carelli V, Di Colo G, Nannipieri E (1996) In vitro evaluation of a pH-sensitive hydrogel for control of GI drug delivery from silicone-based matrices. Int J Pharm 130:83–92

    Article  Google Scholar 

  19. 19.

    Huo D, Yang J, Hou C, Yang M (2010) Macroporous Poly(N-isopropylamide-co-acrylamide) Hydrogels prepared by two-step polymerization for drug delivery applications. Chem Eng Technol 33:1943–1949

    Article  Google Scholar 

  20. 20.

    Galdi I, Lamberti G (2012) Drug release from matrix systems: analysis by finite element methods. Heat Mass Transf 48:519–528

    Article  Google Scholar 

  21. 21.

    Muria MD, Lamberti G, Titomanlio G (2009) Modeling the pharmacokinetics of extended release pharmaceutical systems. Heat Mass Transf 45:579–589

    Article  Google Scholar 

  22. 22.

    Liu Y, Zhang H, Zhang J, Zheng Y (2015) Constitutive modeling for polymer hydrogels: a new perspective and applications to anisotropic hydrogels in free swelling. Eur J Mech-A/Solids 54:171–186

    MathSciNet  Article  Google Scholar 

  23. 23.

    Ende MT, Peppas NA (1997) Transport of ionizable drugs and proteins in crosslinked poly(acrylic acid) and poly(acrylic acid-co-2-hydroxyethyl methacrylate) hydrogels. II. Diffusion and release studies. J Control Release 48:47–56

    Article  Google Scholar 

  24. 24.

    Ramkissoon-Ganorkar C, Liu F, Baudys M, Kim SW (1999) Modulating insulin-release profile from pH/thermosensitive polymeric beads through polymer molecular weight. J Control Release 59:287–298

    Article  Google Scholar 

  25. 25.

    Rasool N, Yasin T, Heng JYY, Akhter Z (2010) Synthesis and characterization of novel pH-, ionic strength and temperature- sensitive hydrogel for insulin delivery. Polymer 51:1687–1693

    Article  Google Scholar 

  26. 26.

    Taleb MFA (2013) Radiation synthesis of multifunctional polymer hydrogels for oral delivery of insulin. Int J Biol Macromol 62:341–347

    Article  Google Scholar 

  27. 27.

    Gao X, Cao Y, Song X, Zhang Z, Zhuang X, He C, Chen X (2014) Biodegradable pH-responsive carboxymethyl cellulose/poly (acrylic acid) hydrogels for oral insulin delivery. Macromol Biosci 14:565–575

    Article  Google Scholar 

  28. 28.

    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    Google Scholar 

  29. 29.

    Bird RB, Stewart WE, Lightfoot EN (2007) Transport Phenomena, 2nd edn. Wiley, Hoboken

    Google Scholar 

Download references

Acknowledgments

The authors wish to thank FAPESP (Grant Number 2012/11532-0), CNPq (Grant Number 304321/2011-7) and CAPES for the support.

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Correspondence to Leandro G. Aguiar.

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Raymundi, V.C., Aguiar, L.G., Souza, E.F. et al. Controlled release of insulin through hydrogels of (acrylic acid)/trimethylolpropane triacrylate. Heat Mass Transfer 52, 2193–2201 (2016). https://doi.org/10.1007/s00231-015-1732-y

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Keywords

  • Acrylic Acid
  • Control Release
  • Naltrexone
  • Methacrylic Acid
  • Cupric Sulfate