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Two release rates from monolithic carboxymethyl starch tablets: formulation, characterization, and in vitro/in vivo evaluation

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Abstract

Most of non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen at more than 1200 mg/day may generate gastrointestinal and cardiovascular side effects. Bilayer or multiparticulate devices have been developed for controlled release in order to prevent undesired side effects. A new “two release rate (2RR) monolithic tablets” approach is now proposed for controlled release of poorly soluble drugs, particularly NSAIDs. Ibuprofen was used as model drug. This concept is based on a calcium carboxymethyl-starch (CaCMS) complex as a novel, low-cost excipient for monolithic dosage forms easy to manufacture by direct compaction. The in vitro dissolution from CaCMS formulations (tablets containing 400 or 600 mg active principle) showed two distinct release rates: (i) an initial fast release (for 30 min in simulated gastric fluid) of about 200 mg ibuprofen, an amount similar to the dosage of conventional immediate-release form (Motrin® 200 mg), and (ii) a slow release of remaining about 200 or 400 mg for a period of 12 h. A preliminary in vivo study (beagle dogs) showed pharmacokinetic parameters of one single controlled-release dosage of ibuprofen (400 mg) formulated with CaCMS, near equivalence with multiple doses (three tablets of 200 mg ibuprofen) of conventional Motrin®. A marked reduction (with 33%) of administered dose (400 instead 600 mg) was achieved by the new formulation with equivalent therapeutic effects. This dose reduction may be beneficial and is expected to minimize side damage risks. Although the present study was limited to NSAIDs, the 2RR concept can be applied for other drugs, particularly for subjects unable to follow frequent administrations.

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Abbreviations

2RR:

Two release rates

API:

Active pharmaceutical ingredient

CMS:

Carboxymethyl-starch

CaCMS:

Calcium carboxymethyl-starch

DS:

Degree of substitution

NaCMS:

Sodium carboxymethyl-starch

NSAID:

Non-steroidal anti-inflammatory drugs

OTC:

Over the counter

SGF:

Simulated gastric fluid

SIF:

Simulated intestinal fluid

References

  1. *** Canadian Compendium of Pharmaceuticals and Specialties (CPS 2013) #4 Analgesic Products. Canadian Pharmacists Association-Association des pharmaciens du Canada. Ottawa, ON, Canada.

  2. Moore RA, Derry S, Wiffen PJ, Straube S, Aldington DJ. Overview review: comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions. Eur J Pain. 2015;19:1213–23.

    Article  CAS  PubMed  Google Scholar 

  3. Devrim B, Canefe K. Preparation and evaluation of modified release ibuprofen microspheres with acrylic polymers (Eudragit) by quasi emulsion solvent diffusion method: effect of variables

  4. Earl RT, Jenkins R, Munro AJ. A double-masked comparison of the efficacy of once-daily sustained-release ibuprofen and once-daily piroxicam for 24-hour control of arthralgia due to osteoarthritis in the elderly. Curr Ther Res. 1996;57:811–21.

    Article  CAS  Google Scholar 

  5. Henry D, Drew A, Beuzeville S. Gastrointestinal adverse drug reactions attributed to ibuprofen. In: Rainsford KD, editor. Ibuprofen: a critical bibliographic review. London: Taylor & Francis; 1999. p. 458–96.

    Google Scholar 

  6. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011;8:e1001098. doi:10.1371/journal.pmed.1001098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miwa LJ, Jones JK. Adverse drug reactions attributed to ibuprofen: effects other than gastrointestinal. In: Rainsford KD, editor. Ibuprofen: a critical bibliographic review. Taylor & Francis; 1999. p. 398–423.

  8. Murtha JL, Ando HY. Synthesis of the cholesteryl ester prodrugs cholesteryl ibuprofen and cholesteryl flufenamate and their formulation into phospholipid microemulsions. J Pharm Sci. 1994;83:1222–8.

    Article  CAS  PubMed  Google Scholar 

  9. Goldstein J, Hochberg M, Fort J, Zhang Y, Hwang C, Sostek M. Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone. Aliment Pharmacol Ther. 2010;32:401–13.

    Article  CAS  PubMed  Google Scholar 

  10. Thapa P, Ghimire M, Mullen AB, Stevens HN. Controlled release oral drug delivery system containing water-insoluble drug. Journal of Engineering Science and Technology. 2005;1:1–10.

    Google Scholar 

  11. Newa M, Bhandari KH, Li DX, Kwon T-H, Kim JA, Yoo BK, et al. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188. Int J Pharm. 2007;343:228–37.

    Article  CAS  PubMed  Google Scholar 

  12. Lopes CM, Lobo JMS, Pinto JF, Costa PC. Compressed matrix core tablet as a quick/slow dual-component delivery system containing ibuprofen. AAPS PharmSciTech. 2007;8:E195–202.

    Article  PubMed Central  Google Scholar 

  13. Mehlisch DR, Ardia A, Pallotta T. A controlled comparative study of ibuprofen arginate versus conventional ibuprofen in the treatment of postoperative dental pain. J Clin Pharmacol. 2002;42:904–11.

    Article  CAS  PubMed  Google Scholar 

  14. Haslam JL, Forbes AE, Rork GS, Pipkin TL, Slade DA, Khossravi D. Tableting of controlled release multiparticulates, the effect of millisphere size and protective overcoating. Int J Pharm. 1998;173:233–42.

    Article  CAS  Google Scholar 

  15. Abbaspour M, Sadeghi F, Garekani HA. Design and study of ibuprofen disintegrating sustained-release tablets comprising coated pellets. Eur J Pharm Biopharm. 2008;68:747–59.

    Article  CAS  PubMed  Google Scholar 

  16. Adeyeye CM, Price JC. Development and evaluation of sustained-release ibuprofen–wax microspheres. II. In vitro dissolution studies. Pharm Res. 1994;11:575–9.

    Article  CAS  PubMed  Google Scholar 

  17. Lopes CM, Lobo JMS, Pinto JF, Costa P. Compressed mini-tablets as a biphasic delivery system. Int J Pharm. 2006;323:93–100.

    Article  CAS  PubMed  Google Scholar 

  18. Horn D, Ditter W. Chromatographic study of interactions between polyvinylpyrrolidone and drugs. J Pharm Sci. 1982;71:1021–6.

    Article  CAS  PubMed  Google Scholar 

  19. Tan SS. Influence of crospovidone on the oral bioavailability of a model drug and toxin. Master’s Thesis. University Sains Malaysia; 2008.

  20. Le-Tien C, Millette M, Mateescu MA, Lacroix M. Modified alginate and chitosan for lactic acid bacteria immobilization. Biotechnol Appl Biochem. 2004;39:347–54.

    Article  CAS  PubMed  Google Scholar 

  21. Davies NM. Sustained release and enteric coated NSAIDs: are they really GI safe? J Pharm Pharmaceut Sci. 1999;2:5–14.

    CAS  Google Scholar 

  22. Friciu MM, Canh Le T, Ispas-Szabo P, Mateescu MA. Carboxymethyl starch and lecithin complex as matrix for targeted drug delivery: I. Monolithic mesalamine forms for colon delivery. Eur J Pharm Biopharm. 2013;85:521–30.

    Article  Google Scholar 

  23. Adams SS, Bough RG, Cliffe EE, Dickinson W, Lessel B, McCullough KF, Mills RF, Nicholson JS, Williams GA. Some aspects of the pharmacology, metabolism, and toxicology of ibuprofen. Rheumatol Phys Med. 1970;11(Suppl):9–22.

    Article  Google Scholar 

  24. Assaad E, Mateescu MA. The influence of protonation ratio on properties of carboxymethyl starch excipient at various substitution degrees: structural insights and drug release kinetics. Int J Pharm. 2010;394:75–84.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Financial support from Matripharm International Inc. is gratefully acknowledged. Thanks are due to Dr. Maximilien Arella for helpful discussions and to Mrs. Lindsay Blemur (M.Sc.) for her valuable assistance.

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Authors and Affiliations

  1. Matripharm International Inc., Laval, Québec, Canada

    Tien Canh Le

  2. Department of Chemistry and Centre Pharmaqam, Université du Québec à Montréal, CP 8888, Branch A, Montréal, Québec, H3C 3P8, Canada

    Mircea Alexandru Mateescu

Authors
  1. Tien Canh Le
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  2. Mircea Alexandru Mateescu
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Corresponding author

Correspondence to Mircea Alexandru Mateescu.

Ethics declarations

The in vivo study on beagle dogs was conducted following the protocol approved by the Animal Care Committee (INRS-Institut Armand-Frappier, Center of Experimental Biology, Laval, Québec, Canada).

Declaration

The study was realized in basis of a university research contract conducted in the university, except the in vivo study that was done by a contract research organization. The authors are coinventors of an US Patent application owned by Matripharm Inc.

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Le, T.C., Mateescu, M.A. Two release rates from monolithic carboxymethyl starch tablets: formulation, characterization, and in vitro/in vivo evaluation. Drug Deliv. and Transl. Res. 7, 516–528 (2017). https://doi.org/10.1007/s13346-017-0375-6

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