Journal of Materials Science: Materials in Medicine

, Volume 21, Issue 12, pp 3141–3150 | Cite as

In vitro characterisation of calcium phosphate biomaterials loaded with lidocaine hydrochloride and morphine hydrochloride

  • H. Gautier
  • V. Chamblain
  • P. Weiss
  • C. Merle
  • J. M. Bouler


Calcium phosphate substitutes drug delivery systems are well known substances used in minor bone void-filling to release their therapeutic agent in situ. Few studies associating anaesthetics and analgesics have been performed to date. The aim of this work was to study the association of the analgesic, morphine, and the local anaesthetic, lidocaine, with a calcium deficient apatite matrix. Three types of biomaterials i.e. powders, granules and blocks, were prepared by isostatic compression, wet granulation and a combination of the two, evaluated and compared. The chemical structure of the associated therapeutic agent was studied and the characteristics of the drug delivery systems were appraised in terms of drug release. The integrity of the lidocaine hydrochloride structure, as determined by RMN 1H, was confirmed regardless of the formulation technique used (isostatic compression or wet granulation). However, analyses of morphine hydrochloride by RMN 1H revealed slight structural modifications. The association and formulation techniques that were used made it possible to obtain an in vitro release time varying from 1 to 4 days for lidocaine hydrochloride and from 1 to 3 days for morphine hydrochloride.


Morphine Lidocaine Drug Delivery System Release Profile Calcium Phosphate 



The authors are grateful to Pr Muriel Duflos from BioCit (UPRES EA 1155), University of Nantes, for NMR analysis; Mrs Anne-Françoise Miegeville from the Laboratoire de Thérapeutiques Cliniques et Expérimentales (EA 3826), University of Nantes, for device assistance. This work was supported by Graftys SA.


  1. 1.
    Vallet-Regi M, Gonzalez-Calbet JM. Calcium phosphates as substitution of bone tissues. Prog Solid State Chem. 2004;32:1–31.CrossRefGoogle Scholar
  2. 2.
    Obadia L, Amador G, Daculsi G, Bouler JM. Calcium-deficient apatite: influence of granule size and consolidation mode on release and in vitro activity of vancomycin. Biomaterials. 2003;24:1265–70.CrossRefPubMedGoogle Scholar
  3. 3.
    Gautier H, Guicheux J, Grimandi G, Faivre-Chauvet A, Daculsi G, Merle C. In vitro influence of apatite granule specific area on human growth hormone loading and release. J Biomed Mater Res. 1998;40:606–61.CrossRefPubMedGoogle Scholar
  4. 4.
    Verron E, khairoun I, Guicheux J, Bouler JM. Calcium phosphate biomaterials as bone drug delivery systems: a review. Drug Discov Today. 2010;15:547–52.CrossRefPubMedGoogle Scholar
  5. 5.
    Jindong Z, Hai T, Junchao G, Bo W, Li B, Qiang WB. Evaluation of a novel osteoporotic drug delivery system in vitro: alendronate-loaded calcium phosphate cement. Orthopedics. 2010;33(8):682–3.Google Scholar
  6. 6.
    El-Ghannam A, Ricci K, Malkawi A, Jahed K, Vedantham K, Wyan H, Allen LD, Dréau D. A ceramic-based anticancer drug delivery system to treat breast cancer. J Mater Sci Mater Med. 2010;21(9):2701–10.CrossRefPubMedGoogle Scholar
  7. 7.
    Bond DM, Rudan J, Kobus SM, Adams MA. Depot local anesthetic in polymethylmethacrylate bone cement. Clin Orthop. 2004;418:242–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Chen PC, Park YJ, Chang LC, Kohane DS, Bartlett RH, Langer R, Yang VC. Injectable microparticle-gel system for prolonged and localized lidocaine release. I. In vitro characterization. J Biomed Mater Res A. 2004;70(3):459–66.CrossRefPubMedGoogle Scholar
  9. 9.
    Verron E, Gauthier O, Janvier P, Le Guen H, Holopherne D, Cavagna R, Bouler JM. Analgesic properties of calcium phosphate apatite loaded with bupivacaine on postoperative pain. J Biomed Mater Res B Appl Biomater. 2010;94(1):89–96.PubMedGoogle Scholar
  10. 10.
    Obadia L, Rouillon T, Bujoli B, Daculsi G, Bouler JM. Calcium deficient apatites synthesized by ammonia hydrolysis of dicalcium phosphate dihydrate: influence of temperature, time and pressure. J Biomed Mater Res B Appl Biomater. 2007;80(1):32–42.PubMedGoogle Scholar
  11. 11.
    Gautier H, Merle C, Auget J-L, Daculsi G. Isostatic compression, a new process for incorporating vancomycin into biphasic calcium phosphate: comparison with a classical method. Biomaterials. 2000;21:243–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Bourgeois B, Laboux O, Obadia L, Gauthier O, Betti E, Aguado E, Dacusi G, Bouler JM. Calcium deficient apatite: a first in vivo study concerning bone ingrowth. J Biomed Mater Res A. 2003;65(3):402–3.CrossRefPubMedGoogle Scholar
  13. 13.
    Kimakhe S, Bohic S, Larrose C, Reynaud A, Pilet P, Giumelli B, Heymann D, Daculsi G. Biological activities of sustained polymyxin B release from calcium phosphate biomaterial prepared by dynamic compaction: an in vitro study. J Biomed Mater Res. 1999;47(1):18–27.CrossRefPubMedGoogle Scholar
  14. 14.
    Chen PC, Kohane DS, Park YJ, Bartlett RH, Langer R, Yang VC. Injectable microparticle-gel system for prolonged and localized lidocaine release. II. In vivo anesthetic effects. J Biomed Mater Res A. 2004;70(3):459–66.CrossRefPubMedGoogle Scholar
  15. 15.
    Al Malyan M, Becchi C, Nikkola L, Viitanen P, Boncinelli S, Chiellini F, Ashammakhi N. Polymer-based biodegradable drug delivery systems in pain management. J Craniofac Surg. 2006;17(2):302–13.CrossRefPubMedGoogle Scholar
  16. 16.
    Paavola A, Yliruusi J, Kajimoto Y, Kalso E, Wahistrom T, Rosenberg P. Controlled release of lidocaïne from injectable gels and efficacy in rat sciatic nerve block. Pharm Res. 1995;12:1997–2000.CrossRefPubMedGoogle Scholar
  17. 17.
    Sato S, Baba Y, Tajima K, Kimura T, Tsuji MH, Kohda Y, Sato Y. Prolongation of epidural anesthesia in the rabbit with the use of a biodegradable copolymer paste containing lidocaïne. Anesth Analg. 1995;80:97–101.CrossRefPubMedGoogle Scholar
  18. 18.
    Reuben SS, Sklar J. Pain management in patients who undergo outpatient arthroscopic surgery of the knee. J Bone Joint Surg Am. 2000;82:1754–66.PubMedGoogle Scholar
  19. 19.
    Arias JL, Gómez-Gallo A, Delgado AV, Ruiz MA, Kollidon SR. Colloidal particles as vehicles for oral morphine delivery in pain treatment. Colloids Surf Biointerfaces. 2009;70(2):207–12.CrossRefGoogle Scholar
  20. 20.
    Nakamura K, Nara E, Akiyama Y. Development of an oral sustained release drug delivery system utilizing pH-dependent swelling of carboxyvinyl polymer. J Control Release. 2006;111(3):309–15.CrossRefPubMedGoogle Scholar
  21. 21.
    Hasirci V, Bonney I, Goudas LC, Shuster L, Carr DB, Wise DL. Antihyperalgesic effect of simultaneously released hydromorphone and bupivacaine from polymer fibers in the rat chronic constriction injury model. Life Sci. 2003;73(26):3323–37.CrossRefPubMedGoogle Scholar
  22. 22.
    Masson P, Tonello C, Balny C. High-pressure biotechnology in medicine and pharmaceutical science. J Biomed Biotechnol. 2001;1(2):85–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Balny C, Hayashi R, Heremans K, Masson P. Eurotext JL, high pressure and biotechnology, vol. 224. London: Colloque INSERM; 1992.Google Scholar
  24. 24.
    Gautier H, Caillon J, Le Ray AM, Daculsi G, Merle C. Influence of isostatic compression on the stability of vancomycin loaded with a calcium phosphate-implantable drug delivery device. J Biomed Mater Res. 2000;52(2):308–14.CrossRefPubMedGoogle Scholar
  25. 25.
    Daculsi G, Weiss P, Bouler J-M, Gauthier O, Millot F, Aguado E. Biphasic calcium phosphate/hydrosoluble polymer composites: a new concept for bone and dental substitution materials. Bone. 1999;25(2):59S–61S.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • H. Gautier
    • 1
    • 2
  • V. Chamblain
    • 1
  • P. Weiss
    • 1
  • C. Merle
    • 1
    • 2
  • J. M. Bouler
    • 1
  1. 1.Laboratoire d’Ingénierie Ostéo-Articulaire et Dentaire, LIOAD, Faculté de Chirurgie DentaireINSERM, U 791NantesFrance
  2. 2.Laboratoire de Pharmacie Galénique, Faculté de PharmacieUniversité de NantesNantesFrance

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