Subcutaneous drug implants are convenient systems for the long-term delivery of drugs in animals. Lipid carriers are logical tools because they generally allow for higher doses and low toxicity. The present study used an US Food and Drug Administration Target Animal Safety test system to evaluate the safety of a subcutaneous implant of a cholesterol-triglyceride-buprenorphine powder in 120 BALB/c mice. Mice were evaluated in 4- and 12-day trials with 1- and 5-fold doses of the intended 3？mg/kg dose of drug. One male mouse treated with three 3？mg/kg doses and surgery on days 0, 4, and 8 died on day 9. The cause of death was not determined. In the surviving 119 mice there was no evidence of skin reaction at the site of the implant. Compared to control animals treated with saline, weight measurements, clinical pathology, histopathology, and clinical observations were unremarkable. These results demonstrate that the lipid carrier is substantially safe. Cholesterol-triglyceride-drug powders may provide a valuable research tool for studies of analgesic and inflammatory drug implants in veterinary medicine. 1. Introduction Guidelines for the care and use of laboratory animals uniformly recommend the use of analgesia in any procedure with a potential for pain [1]. Yet, the use of analgesics in research remains low [2, 3]. One factor that may account for the modest utilization of analgesia is the management challenge involved with intraperitoneal (IP) and subcutaneous (SC) injections of mice and rats at the 6–8-hour intervals necessary to maintain effective blood concentrations of drug [4]. In addition, it has been considered that repeated IP or SC injections in surgically traumatized rodents may induce stress responses and depress weight gain [5, 6]. Several strategies are being investigated to address this problem. The practicality and duration of slow-release oral preparations for 11-hour morphine therapy in laboratory rats have been described [7]. Food- and water-based analgesia has been explored by several investigators [8–10]. Grant and colleagues demonstrated that liposomal morphine implants could deliver long-acting analgesia to mice [11]. More recently, Smith, Krugner-Higby, and colleagues have published a series of studies demonstrating the 2-3-day activity of lipid encapsulated morphine derivatives in laboratory animal models of pain [12–14]. Foley and colleagues described the 2-3-day efficacy of a proprietary sustained release polymer-based buprenorphine preparation in rats [15]. Carbone and coworkers described the efficacy of a similar formulation
References
[1]
Institute for Laboratory Animal Research, Guide for the Care and Use of Laboratory Animals, National Academy Press, Washington, DC, USA, 2011.
[2]
T. W. Adamson, L. V. Kendall, S. Goss et al., “Assessment of carprofen and buprenorphine on recovery of mice after surgical removal of the mammary fat pad,” Journal of the American Association for Laboratory Animal Science, vol. 49, no. 5, pp. 610–616, 2010.
[3]
E. L. Stokes, P. A. Flecknell, and C. A. Richardson, “Reported analgesic and anaesthetic administration to rodents undergoing experimental surgical procedures,” Laboratory Animals, vol. 43, no. 2, pp. 149–154, 2009.
[4]
N. M. Gades, P. J. Danneman, S. K. Wixson, and E. A. Tolley, “The magnitude and duration of the analgesic effect of morphine, butorphanol , and buprenorphine in rats and mice,” Contemporary Topics in Laboratory Animal Science, vol. 39, no. 2, pp. 8–13, 2000.
[5]
A. Bomzon, “Are repeated doses of buprenorphine detrimental to postoperative recovery after laparotomy in rats?” Comparative Medicine, vol. 56, no. 2, pp. 114–118, 2006.
[6]
M. W. H. Schaap, J. J. Uilenreef, M. D. Mitsogiannis, J. G. Van't Klooster, S. S. Arndt, and L. J. Hellebrekers, “Optimizing the dosing interval of buprenorphine in a multimodal postoperative analgesic strategy in the rat: minimizing side-effects without affecting weight gain and food intake,” Laboratory Animals, vol. 46, no. 4, pp. 287–292, 2012.
[7]
M. C. Leach, H. E. Bailey, A. L. Dickinson, J. V. Roughan, and P. A. Flecknell, “A preliminary investigation into the practicality of use and duration of action of slow-release preparations of morphine and hydromorphone in laboratory rats,” Laboratory Animals, vol. 44, no. 1, pp. 59–65, 2010.
[8]
M. C. Leach, A. R. Forrester, and P. A. Flecknell, “Influence of preferred foodstuffs on the antinociceptive effects of orally administered buprenorphine in laboratory rats,” Laboratory Animals, vol. 44, no. 1, pp. 54–58, 2010.
[9]
O. Kalliokoski, K. R. Jacobsen, J. Hau, and K. S. P. Abelson, “Serum concentrations of buprenorphine after oral and parenteral administration in male mice,” Veterinary Journal, vol. 187, no. 2, pp. 251–254, 2011.
[10]
A. C. Thompson, M. B. Kristal, A. Sallaj, A. Acheson, L. B. Martin, and T. Martin, “Analgesic efficacy of orally administered buprenorphine in rats: methodologic considerations,” Comparative Medicine, vol. 54, no. 3, pp. 293–300, 2004.
[11]
G. J. Grant, K. Vermeulen, M. I. Zakowski, M. Stenner, H. Turndorf, and L. Langerman, “Prolonged analgesia and decreased toxicity with liposomal morphine in a mouse model,” Anesthesia & Analgesia, vol. 79, no. 4, pp. 706–709, 1994.
[12]
M. D. Clark, L. Krugner-Higby, L. J. Smith, T. D. Heath, K. L. Clark, and D. Olson, “Evaluation of liposome-encapsulated oxymorphone hydrochloride in mice after splenectomy,” Comparative Medicine, vol. 54, no. 5, pp. 558–563, 2004.
[13]
J. R. Schmidt, L. Krugner-Higby, T. D. Heath, R. Sullivan, and L. J. Smith, “Epidural administration of liposome-encapsulated hydromorphone provides extended analgesia in a rodent model of stifle arthritis,” Journal of the American Association for Laboratory Animal Science, vol. 50, no. 4, pp. 507–512, 2011.
[14]
L. J. Smith, J. R. Valenzuela, L. A. Krugner-Higby, C. Brown, and T. D. Heath, “A single dose of liposome-encapsulated hydromorphone provides extended analgesia in a rat model of neuropathic pain,” Comparative Medicine, vol. 56, no. 6, pp. 487–492, 2006.
[15]
P. L. Foley, H. Liang, and A. R. Crichlow, “Evaluation of a sustained-release formulation of buprenorphine for analgesia in rats,” Journal of the American Association for Laboratory Animal Science, vol. 50, no. 2, pp. 198–204, 2011.
[16]
E. T. Carbone, K. E. Lindstrom, S. Diep, and L. Carbone, “Duration of action of sustained-release buprenorphine in 2 strains of mice,” Journal of the American Association for Laboratory Animal Science: JAALAS, vol. 51, no. 6, pp. 815–819, 2012.
[17]
J. V. Roughan and P. A. Flecknell, “Buprenorphine: a reappraisal of its antinociceptive effects and therapeutic use in alleviating post-operative pain in animals,” Laboratory Animals, vol. 36, no. 3, pp. 322–343, 2002.
[18]
M. Guarnieri, C. Brayton, L. Detolla, N. Forbes-Mcbean, R. Sarabia-Estrada, and P. Zadnik, “Safety and efficacy of buprenorphine for analgesia in laboratory mice and rats,” Lab Animal, vol. 41, no. 11, pp. 337–343, 2012.
[19]
A. Cowan, J. C. Doxey, and E. J. R. Harry, “The animal pharmacology of buprenorphine, an oripavine analgesic agent,” British Journal of Pharmacology, vol. 60, no. 4, pp. 547–554, 1977.
[20]
A. Cowan, “Buprenorphine: the basic pharmacology revisited,” Journal of Addiction Medicine, vol. 1, no. 2, pp. 68–72, 2007.
[21]
C. R. Bethune, C. M. Bernards, T. Bui-Nguyen, D. D. Shen, and R. J. Y. Ho, “The role of drug-lipid interactions on the disposition of liposome-formulated opioid analgesics in vitro and in vivo,” Anesthesia and Analgesia, vol. 93, no. 4, pp. 928–933, 2001.
[22]
D. K. Mishra, V. Dhote, P. Bhatnagar, and P. K. Mishra, “Engineering solid lipid nanoparticles for improved drug delivery: promises and challenges of translational research,” Drug Delivery and Translational Research, vol. 2, no. 4, pp. 238–253, 2012.
[23]
R. B. Pontani and A. L. Misra, “A long-acting buprenorphine delivery system,” Pharmacology Biochemistry and Behavior, vol. 18, no. 3, pp. 471–474, 1983.
[24]
A. L. Misra and R. B. Pontani, “An improved long-acting delivery system for narcotic antagonists,” Journal of Pharmacy and Pharmacology, vol. 30, no. 5, pp. 325–326, 1978.
[25]
Guidance for Industry (GFI#61), “FDA Approval of Animal Drugs for Minor Uses and for Minor Species, Target Animal Safety and Effectiveness Protocol Development and Submission,” May 2008, http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM241787.pdf.
[26]
European Medicines Agency Veterinary Medicines and Inspections, “Guidelines of target animal safety for pharmaceuticals,” VICH Topic GL43, European Medicines Agency Veterinary Medicines and Inspections, 2006.
[27]
M. Guarnieri, B. Tyler, L. Detolla, M. Zhao, and B. Kobrin, “Subcutaneous implants for long-acting drug therapy in laboratory animals may generate unintended drug reservoirs,” Journal of Pharmacy and Bioallied Sciences, vol. 6, no. 1, pp. 38–42, 2014.
[28]
Guidance for Industry 185, Target Animal Safety for Veterinary Pharmaceutical Products, VICH GL43, US Department of Health and Human Services Food and Drug Administration Center for Veterinary Medicine, 2009.
[29]
I. Park, D. Kim, J. Song, et al., “Buprederm, a new transdermal delivery system of buprenorphine: pharmacokinetic, efficacy and skin irritancy studies,” Pharmaceutical Research, vol. 25, no. 5, pp. 1052–1062, 2008.
[30]
K. Pieper, T. Schuster, O. Levionnois, U. Matis, and A. Bergadano, “Antinociceptive efficacy and plasma concentrations of transdermal buprenorphine in dogs,” Veterinary Journal, vol. 187, no. 3, pp. 335–341, 2011.
[31]
S. C. Sigmon, D. E. Moody, E. S. Nuwayser, and G. E. Bigelow, “An injection depot formulation of buprenorphine: extended biodelivery and effects,” Addiction, vol. 101, no. 3, pp. 420–432, 2006.
[32]
N. Forbes, C. Brayton, S. Grindle, S. Shepherd, B. Tyler, and M. Guarnieri, “Serial bleeding in mice: morbidity and mortality rates with superficial temporal vein phlebotomy,” Lab Animal, vol. 39, pp. 236–240, 2010.
N. Schildhaus, E. Trink, C. Polson et al., “Thermal latency studies in opiate-treated mice,” Journal of Pharmacy and Bioallied Sciences, vol. 6, no. 1, pp. 43–47, 2014.
[36]
J. V. Roughan and P. A. Flecknell, “Effects of surgery and analgesic administration on spontaneous behaviour in singly housed rats,” Research in Veterinary Science, vol. 69, no. 3, pp. 283–288, 2000.
[37]
M. C. Leach, K. Klaus, A. L. Miller, M. S. di Perrotolo, S. G. Sotocinal, and P. A. Flecknell, “The assessment of post-vasectomy pain in mice using behaviour and the mouse grimace scale,” PloS ONE, vol. 7, no. 4, Article ID e35656, 2012.
[38]
L. C. Matsumiya, R. E. Sorge, S. G. Sotocinal et al., “Using the mouse grimace scale to reevaluate the efficacy of postoperative analgesics in laboratory mice,” Journal of the American Association for Laboratory Animal Science, vol. 51, no. 1, pp. 42–49, 2012.
[39]
S. R. Kleppner, R. Patel, J. McDonough, and L. C. Costantini, “In-vitro and in-vivo characterization of a buprenorphine delivery system,” Journal of Pharmacy and Pharmacology, vol. 58, no. 3, pp. 295–302, 2006.
[40]
R. Dinarvand, M. M. Alimorad, M. Amanlou, and H. Akbari, “In vitro release of clomipramine HCL and buprenorphine HCL from poly adipic anhydride (PAA) and poly trimethylene carbonate (PTMC) blends,” Journal of Biomedical Materials Research A, vol. 75, no. 1, pp. 185–191, 2005.
[41]
A. Della Puppa, M. Rossetto, P. Ciccarino et al., “The first 3 months after BCNU wafers implantation in high-grade glioma patients: clinical and radiological considerations on a clinical series,” Acta Neurochirurgica, vol. 152, no. 11, pp. 1923–1931, 2010.
[42]
C. C. Horn, B. A. Kimball, H. Wang et al., “Why can't rodents vomit? A comparative behavioral, anatomical, and physiological study,” PLoS ONE, vol. 8, no. 6, pp. 1–16, 2013.
[43]
L. St A Stewart and W. J. Martin, “Evaluation of postoperative analgesia in a rat model of incisional pain,” Contemporary Topics in Laboratory Animal Science, vol. 42, no. 1, pp. 28–34, 2003.
[44]
J. Clark J.A., P. H. Myers, M. F. Goelz, J. E. Thigpen, and D. B. Forsythe, “Pica behavior associated with buprenorphine administration in the rat,” Laboratory Animal Science, vol. 47, no. 3, pp. 300–303, 1997.
[45]
P. Jablonski, B. O. Howden, and K. Baxter, “Influence of buprenorphine analgesia on post-operative recovery in two strains of rats,” Laboratory Animals, vol. 35, no. 3, pp. 213–222, 2001.
