Skip to main content

Investigation into the Emerging Role of the Basic Amino Acid L-Lysine in Enhancing Solubility and Permeability of BCS Class II and BCS Class IV Drugs

Pharmaceutical Research volume 35, Article number: 160 (2018) Cite this article

Abstract

Background

The search for a simple and scalable approach that can improve the two key biopharmaceutical processes (solubility and permeability) for BCS Class II and BCS Class IV has still been unmet need.

Purpose

In this study, L-lysine was investigated as a potential excipient to tackle problems with solubility and permeability. Bendazac (Class II); quercetin and rutin (Class IV) were employed.

Methods

Drugs-lysine complexes in 1:1 M ratios were prepared by co-precipitation and co-grinding; characterized for solubility, partition coefficient, DSC, FTIR, SEM, dissolution rate and permeability. Chemical stability of quercetin-lysine and rutin-lysine was studied by assessing antioxidant capacity using Trolox and CUPRAC assays.

Results and Conclusion

Drugs-lysine salt/complexes were confirmed. Solubility enhancement factors ranged from 68- to 433-fold increases and dissolution rates were also significantly enhanced by up to 6-times, compared with drugs alone. With the exception of rutin-lysine, Papp for bendazac-lysine and quercetin-lysine enhanced by 2.3- to 4-fold. Papp for quercetin (Class IV) benefited more than bendazac (Class II) when complexed with lysine. This study warrants the use of L-lysine as a promising excipient for enhanced solubility and permeability of Class II and Class IV, providing that the solubility of the drug is ensured at ‘the door step’ of absorption sites.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16

Abbreviations

BCS:

Biopharmaceutics classification system

CUPRAC:

Cupric ion reducing antioxidant capacity

DSC:

Differential scanning calorimetry

FTIR:

Fourier transform infrared spectroscopy

Papp :

Apparent permeability coefficient

SEM:

Scanning electron microscopy

References

  1. 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;12:413–20.

    CAS  Article  Google Scholar 

  2. Ghadi R, Dand N. BCS class IV drugs: highly notorious candidates for formulation development. J Control Release. 2017;248:71–95.

    CAS  Article  Google Scholar 

  3. Giliyar C, Fikstad DT, Tyavanagimatt S. Challenges and opportunities in oral delivery of poorly water-soluble drugs. Drug Deliv Technol. 2006;6:57–63.

    CAS  Google Scholar 

  4. Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world's top oral drugs. AAPS J. 2009;11:740–6.

    CAS  Article  Google Scholar 

  5. Loftsson T. Drug solubilization by complexation. Int J Pharm. 2017;531:276–80.

    CAS  Article  Google Scholar 

  6. ElShaer A, Hanson P, Mohammed A. A novel concentration dependent amino acid ion pair strategy to mediate drug permeation using indomethacin as a model insoluble drug. Eur J Pharm Sci. 2014;62:124–31.

    CAS  Article  Google Scholar 

  7. Khoder M, Abdelkader H, ElShaera A, Karam A, Najlahd M, Alany R. Efficient approach to enhance drug solubility by particle engineering of bovine serum albumin. Int J Pharm. 2016;515:740–8.

    CAS  Article  Google Scholar 

  8. Ahuja M, Dhake AS, Sharma SK, Majumdar DK. Topical ocular delivery of NSAIDs. AAPS J. 2008;10:229–41.

    CAS  Article  Google Scholar 

  9. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal. 2013;2013:162750.

    PubMed  PubMed Central  Google Scholar 

  10. Rich GT, Buchweitz M, Winterbone MS, Kroon PA, Wilde PJ. Towards an understanding of the low bioavailability of quercetin: a study of its interaction with intestinal lipids. Nutrients. 2017;9:111.

    Article  Google Scholar 

  11. Majumdar S, Srirangam R. Potential of the bioflavonoids in the prevention/treatment of ocular disorders. J Pharm Pharmacol. 2010;62:951–65.

    CAS  Article  Google Scholar 

  12. Balfour JA, Clissold SP. Bendazac lysine. A review of its pharmacological properties and therapeutic potential in the management of cataracts. Drugs. 1990;39:575–96.

    CAS  Article  Google Scholar 

  13. Lewis BS, Harding J. The major metabolite of bendazac inhibits the glycosylation of soluble proteins: a possible mechanism for a delay in cataractogenesis. Exp Eye Res. 1988;47:217–25.

    CAS  Article  Google Scholar 

  14. Lewis BS, Rixon KC, Harding JJ. Bendazac prevents cyanate binding to soluble lens protiens and cyanate-induced phase separation opacities in vitro: a possible mechanism by which bendazac could delay cataract. Exp Eye Res. 1986;43:973–9.

    CAS  Article  Google Scholar 

  15. Abdelkader H, Alany RG, Pierscionek B. Age-related cataract and drug therapy: opportunities and challenges for topical antioxidant delivery to the lens. J Pharm Pharmacol. 2014; In Press

  16. Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol. 2010;55:109–33.

    Article  Google Scholar 

  17. Abdelkader H, Longman M, Alany R, Piescionek B. Phytosome-hyaluronic acid systems for ocular delivery of L-carnosine. Int J Nanomedicine. 2016;(11):2815–27.

  18. Huang HS, Schoenwald RD, Lach JL. Corneal penetration behavior of Beta blocking agents II: assessment of barrier contributions. J Pharm Sci. 1983;72:1272–9.

    CAS  Article  Google Scholar 

  19. Schoenwald RD, Huang HS. Corneal penetration behavior of beta blocking agents I: physichochemical factors. J Pharm Sci. 1983;72:1266–72.

    CAS  Article  Google Scholar 

  20. Piel G, Pirotte B, Delneuville I, Neven P, Llabres G, Delarge J, et al. Study of the influence of both cyclodextrins and l-lysine on the aqueous solubility of nimesulide; isolation and characterization of nimesulide-l-lysine-cyclodextrin complexes. J Pharm Sci. 1997;86:475–80.

    CAS  Article  Google Scholar 

  21. Abdelkader H, Wu Z, Al-Kassas R, Brown J, Alany R. Preformulation characteristics of the opioid growth factor antagonist-naltrexone hydrochloride: stability and lipophilicity studies. J Drug Delivery Sci Technol. 2011;21:157–63.

    CAS  Article  Google Scholar 

  22. Florence AT, Attwood D. The solubility of drugs. In: Florence AT, Attwood D, editors. Physichochemical principles of pharmacy. London: McMillan Press Ltd; 1998. p. 152–97.

    Chapter  Google Scholar 

  23. Wu Z, Tucker IG, Razzak M, Medlicott N. Physichochemical characterisation of ricobendazole: I. Solubility, lipophilicity and ionization charactersitics. J Pharm Sci. 2005;94:983–93.

    CAS  Article  Google Scholar 

  24. Abdelkader H, Longman M, Alany R, Pierscionek B. On the anti-cataractogenic effects of L-carnosine: is it best described as an antioxidant, metal chelating agent or glycation inhibitor? Oxid Med Cell Longev. 2016;2016:1–11.

    Article  Google Scholar 

  25. Apak R, Güçlü K, Özyürek M, Çelik SE. Mechanism of antioxidant capacity assays and the CUPRAC (cupric ion reducing antioxidant capacity) assay. Microchimica Acta. 2008;160:413–9.

    CAS  Article  Google Scholar 

  26. Nikghalb L, Singh G, Singh G, Kahkeshan KF. Solid dispersion: methods and polymers to increase the solubility of poorly soluble drugs. Journal of Applied Pharmaceutical Science. 2012;2:170–5.

    Google Scholar 

  27. Nokhodchi A, Talari R, Valizadeh H, Jalali M. An investigation on the solid dispersions of Chlordiazepoxide. Int J Biomed Sci. 2007;3:211–6.

    PubMed  PubMed Central  Google Scholar 

  28. Shore PA, Brodie BB, Hogben CAM. The gastric secretion of drugs: a pH partition hypothesis. J Pharmacol Exp Ther. 1957;119:61–369.

    Google Scholar 

  29. Li B, Konecke S, Harich K, Wegiel L, Taylor L, Edgar K. Solid dispersion of quercetin in cellulose derivative matrices influences both solubility and stability. Carbohydr Polym. 2013;92:2033–40.

    CAS  Article  Google Scholar 

  30. Abdelkader H, Abdallah OY, Salem H. Comparison of the effect of tromethamine and polyvinylpyrrolidone on dissolution properties and analgesic effect of nimesulide. AAPS PharmSciTech. 2007;8(3):E1–8.

    Article  Google Scholar 

  31. Hamishehkar H, Emami S, Lamei B, Valizadeh H, .Jouyban A. Evaluation of solubility and dissolution profile of itraconazole after cogrinding with various hydrophilic carriers. J Drug Delivery Sci Technol 2014;24:653–658.

    CAS  Article  Google Scholar 

  32. Pietta P-G. Flavonoids as antioxidants. J Nat Prod. 2000;63:1035–42.

    CAS  Article  Google Scholar 

  33. Ashrafa O, Nasr M, Nebsen M, Said A, Sammour O. In vitro stabilization and in vivo improvement of ocular pharmacokinetics of the multi-therapeutic agent baicalin: delineating the most suitable vesicular systems. Int J Pharm. 2018;539:83–94.

    Article  Google Scholar 

  34. Gowthamarajan K, Singh S. Dissolution testing for poorly soluble drugs: a continuing perspective. Dissolut Technol. 2010;8:24–32.

    Article  Google Scholar 

  35. Abdelkader H, Alany R. Controlled and continuous release ocular drug delivery systems: pros and cons. Curr Drug Deliv. 2012;9:421–30.

    CAS  Article  Google Scholar 

  36. Jarvinen K, Jarvinen T, Urtti A. Ocular absorption following topical delivery. Adv Drug Deliv Rev. 1995;16:3–19.

    Article  Google Scholar 

  37. Kaur IP, Kanwar M. Ocular preparations:the formulation approach. Drug Dev Ind Pharm. 2002;28:473–93.

    CAS  Article  Google Scholar 

  38. Lang JC. Ocular drug delivery conventional ocular formulations. Adv Drug Deliv Rev. 1995;16:39–43.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

  1. Pharmaceutics Department, Faculty of Pharmacy, Minia University, Minia, Egypt

    Hamdy Abdelkader & Zeinab Fathalla

Authors
  1. Hamdy Abdelkader
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeinab Fathalla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hamdy Abdelkader.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Abdelkader, H., Fathalla, Z. Investigation into the Emerging Role of the Basic Amino Acid L-Lysine in Enhancing Solubility and Permeability of BCS Class II and BCS Class IV Drugs. Pharm Res 35, 160 (2018). https://doi.org/10.1007/s11095-018-2443-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-018-2443-0

Key Words

  • bendazac
  • bioflavonoids
  • co-grinding
  • L-lysine
  • partitioning
  • quercetin
  • rutin
  • solid dispersion