Butorphanol is a κ-opioid receptor agonist, μ-opioid receptor antagonist drug used routinely in avian medicine for pain management. On the basis of a limited number of studies of psittacine birds, butorphanol appears to be the most effective opioid analgesic for members of the family Psittacidae; however, a very short period of antinociception (2 to 3 hours in Amazon parrots [Amazona spp]) limits its clinical use.1,2 Moreover, butorphanol has poor oral bioavailability and thus is usually administered parenterally (SC, IM, or IV as a continuous rate infusion).1 Repeated handling is stressful to birds, multiple injections may induce pain and cause repeated local muscle trauma, and placement of an IV catheter is not practical in all situations. Hence, there is a need for a sustained-release butorphanol formulation for use in psittacine birds.
Poloxamer copolymers, also known as poly(ethylene oxide-b-propylene oxide-b-ethylene oxide), are thermosensitive hydrogels.3 This group of copolymers consists of PEO and PPO blocks arranged in a triblock structure (ie, PEO-PPO-PEO), with a chemical formula of HO [CH2-CH2O]x [CH(CH3)-CH2O]y [CH2-CH2O]x OH.4 Gelation of poloxamer copolymers occurs by dehydration of PPO blocks. The PEO blocks remain hydrophilic between 0° and 100°C, whereas water solubility of PPO blocks decreases dramatically as the temperature increases above 15°C.5 Increasing dehydration of PPO blocks results in aggregation of the copolymer molecules into micelles. Above the Tsol-gel, micellar packing occurs and the compound becomes a gel; this phenomenon is perfectly reversible.4 Micellar packing is responsible for the high viscosity, partial rigidity, and slow dissolution of a gel, which make poloxamer copolymers highly effective sustained-release systems for both hydrophilic and hydrophobic drugs.4
Poloxamer 407 is composed of approximately 70% PEO and 30% PPO. The Tsol-gel of P407 ranges from 15° to 35°C and is influenced by a number of factors. The Tsol-gel increases as P407 concentration decreases.4,5 Moreover, Tsol-gel of P407 can be influenced by the addition of drugs or other chemical agents. For example, sodium chloride, dimethyl sulfoxide, and vitamin B12 have been found to decrease Tsol-gel, whereas diclofenac, ethanol, and hydrochloric acid increase it.6 Other drugs, including morphine and lidocaine, apparently have no effect on Tsol-gel.4
Poloxamer 407 is frequently used as a sustained drug delivery system for medicinal agents because it has low toxicity, high solubility, and good drugrelease capacity. It has been incorporated in a variety of formulations (oral, ophthalmologic, injectable, rectal, topical, and nasal) for use in humans7–26 and has been used for sustained-release drugs in numerous other species including rats,7–14,19 cattle,15–17 dogs,18–22 and rabbits.23–26 To the authors’ knowledge, only 1 study27 has been conducted with birds. In that study,27 pharmacokinetics of P407-doxycycline administered IM to broiler chickens was compared with that of orally administered doxycycline (0.5% aqueous solution of doxycycline hyclate).
The objectives of the study reported here were to assess the ease and reliability for compounding of P407 and identify the best concentration of P407 for use as the base for a sustained-release formulation of butorphanol, ensure that adequate gelation of P407 and of But-P407 occurs between 38° and 40°C (an approximation of avian core body temperature), compare rheological properties of But-P407 with those of P407 alone to ensure that the addition of butorphanol does not substantially alter gelation properties, determine whether sterilization of P407 via microfiltration affects Tsol-gel or viscosity, and determine the rate of butorphanol diffusion from P407 in vitro. We hypothesized that it would be possible to reliably compound P407, P407 compounds would have a higher viscosity at avian body temperature than at mammalian body temperature, in vitro viscosity and gelation properties of P407 and But-P407 would be similar, microfiltration would not alter the viscosity profile of P407, and in vitro diffusion of butorphanol from the gel would be slower than diffusion from a solution of butorphanol tartrate.
This manuscript represents part of a dissertation submitted by Dr. Laniesse to the Department of Pathobiology at the University of Guelph as partial fulfillment of the requirements for a Doctor of Veterinary Science degree.
Supported by grants from the Ontario Veterinary College Pet Trust and the Campbell Center for the Study of Animal Welfare. Dr. Laniesse was supported by a stipend provided by the Tasha Award.
Presented in abstract form at the Exoticscon Conference, San Antonio, Texas, September 2015.
The authors thank Dr. Tracy Drazenovich for assistance with the laboratory materials, Dr. Fernanda Svaikauskas for assistance with the rheological equipment, and Dan McKemie and Sandy Yim for assistance with the liquid chromatography-tandem mass spectrometry analysis.
Butorphanol in poloxamer 407
Temperature at which there is a transition between the 2 states (solution and gel) of a poloxamer
BASF Corp, Sigma-Aldrich, Oakville, ON, Canada.
Torbugesic, Wyeth, Markham, ON, Canada.
BenchMixer, Benchmark, Edison, NJ.
Millex GP filter unit, 0.22-μm, Millipore Express PES membrane, Merck Millipore Ltd, Cork, Ireland.
AR 2000, TA Instruments, Mississauga, ON, Canada.
SnakeSkin dialysis tubing, 3.5K MWCO, 22 mm, ThermoFisher Scientific, Rockford, Ill.
Amresco, Solon, Ohio.
ThermoFisher Scientific Inc, Waltham, Mass.
Toronto Research Chemicals, Toronto, ON, Canada.
R version 3.0.1, The R Foundation for Statistical Computing, Vienna, Austria.
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