Anesth Analg 2006;102:1445-1451
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000205747.05693.30
ANESTHETIC PHARMACOLOGY
Novel Depots of Buprenorphine Prodrugs Have a Long-Acting Antinociceptive Effect
Kuo-Sheng Liu, MS* 
,
Jann-Inn Tzeng, MD, MS*,
Yu-Wen Chen, MS*,
Kuo-Lun Huang, MS*,
Chun-Hsiung Kuei, PhD, and
Jhi-Joung Wang, MD, PhD*
*Departments of Anesthesiology and Medical Research, Chi-Mei Medical Center; Department of Chemistry, National Cheng-Kung University, Tainan, Taiwan
Address correspondence and reprint requests to Jhi-Joung Wang, MD, PhD, Departments of Anesthesiology and Medical Research, Chi-Mei Medical Center, or Chun-Hsiung Kuei, PhD, Department of Chemistry, National Cheng-Kung University, Tainan, Taiwan. Address e-mail to 400002{at}mail.chimei.org.tw or kuei{at}mail.ncku.edu.tw
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Abstract
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An analgesic with a prolonged duration may be desirable in patients with long-lasting pain. In this study, we evaluated the antinociceptive effects and durations of action of three novel depots of buprenorphine esters buprenorphine propionate, enanthate, and decanoate given by IM injection, in rats. The pharmacokinetic profiles of buprenorphine in blood after IM injection of these depots were also evaluated. Antinociception was evaluated using the plantar test. Buprenorphine concentrations in blood were assayed using high-performance liquid chromatography. We found that the traditional form of buprenorphine HCl (in saline) produced a dose-related antinociceptive effect. A dose of 0.6 µmol/kg buprenorphine HCl (in saline) produced a significant antinociceptive effect lasting 5 h. The same dose of buprenorphine base, propionate, enanthate, and decanoate (in oil) also produced a significant antinociceptive effect with longer durations of action of 26, 28, 52, and 70 h, respectively. The pharmacokinetic studies demonstrated that all the buprenorphine esters were prodrugs of buprenorphine. We conclude that the novel depots of buprenorphine prodrugs: buprenorphine propionate, enanthate, and decanoate produced a long-acting antinociceptive effect after IM injection in rats.
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Introduction
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Patients with acute pain, such as postoperative pain, posttraumatic pain, and burn pain, often require analgesics in the first 3 days after injury. An analgesic with a potent and long-acting effect of approximately 3 days after a single dose administration may be particularly valuable for this purpose. Currently, no such analgesic is available for the clinical treatment of acute pain. Buprenorphine (Fig. 1), a derivative of the morphine alkaloid thebaine, is a potent analgesic with a potency 25 to 50 times higher than that of morphine (1,2) and has been used in the treatment of acute and chronic pain (1,2). Its main advantages over morphine are a ceiling effect for respiratory depression, low tolerance liability, and a lack of significant withdrawal symptoms (1,2). Buprenorphine is available as an injection for IV and IM administration and as sublingual tablets, with usual recommended dosages of 0.2 to 0.6 mg (0.4 to 1.2 µmol) (1,2). Although buprenorphine has a potent analgesic effect, the duration of action of the traditional form is only 6 to 8 h after IV, IM, or sublingual administration (1,2). Prolonging its duration would make buprenorphine more valuable for the treatment of pain. A transdermal buprenorphine formulation has recently been developed (2). Although it provides a long-duration of action of 3 days, the onset is relatively slow (12 to 24 h). It was designed primarily for the treatment of chronic pain (2).
Depot formulations with prodrug design is one method used to increase the duration of a short-acting drug (3,4). They can be produced by esterifying a drug to form a bioconvertable prodrug-type ester and then formulating it in an injectable oily formulation that forms a drug reservoir at the site of injection (3–6). After IM injection, a long duration of action will occur as the result of a slow release of drug from the reservoir (3–6). By using this design, several depots of buprenorphine esters (Fig. 1), buprenorphine propionate, enanthate, and decanoate, were synthesized and formulated in our laboratory. The aim of the study was to evaluate the antinociceptive effect and duration of action of these oily formulations and to see whether they had a long-acting effect. Pharmacokinetic studies were also performed to evaluate the pharmacokinetic profiles of these dosage forms and to see whether the buprenorphine esters were prodrugs of buprenorphine.
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Methods
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Male Sprague-Dawley rats, purchased from the National Laboratory Animal Center, Taipei, Taiwan, weighing 200–250 g, were used. They were housed in groups of 3 for at least 1 wk before the experiments in a climate-controlled room maintained at 21°C with approximately 50% relative humidity. Lighting was on a 12-h light/dark cycle (lights on at 6:00 am), with food and water available ad libitum except during the time of each testing (10 min on average). All tests were performed in accordance with the recommendations and policies of the International Association for the Study of Pain and the protocol was approved by the animal investigation committee of Chi-Mei Medical Center.
Buprenorphine HCl was purchased from Macfarlan Smith (Edinburgh, UK). Buprenorphine base was obtained using a method of precipitation. After a saturated solution of Na2CO3 (1.4 g/mL) (Riedel-de Haën, Seelze, Germany) added drop by drop into a buprenorphine HCl solution, buprenorphine base was precipitated. The precipitate was then filtered and washed several times with cold deionized water to remove excess Na2CO3. After drying the white residue, buprenorphine base (Fig. 1) was obtained.
Three buprenorphine esters (Fig. 1), buprenorphine propionate, enanthate, and decanoate, were synthesized using the method reported previously (7,8). In brief, the buprenorphine base was reacted with the respective aliphatic acid chloride (i.e., propionyl chloride, enanthic chloride, and decanoyl chloride; Fluka, Buchs, Switzerland) in the presence of dimethylaminopyridine (Riedel-de Haën, Seelze, Germany). Purities of the esters were assured through elemental analysis, nuclear magnetic resonance spectroscopy, and gas chromatography with mass detector (9). Buprenorphine HCl was prepared either in 0.9% saline or in an injectable sesame oil (Sigma, St. Louis, MO). Buprenorphine base and esters were prepared in sesame oil. The lipophilicities of buprenorphine HCl, base, and esters in sesame oil in ambient temperature (21°C) were also determined.
We performed 2 pharmacodynamic studies. In study 1, we evaluated the antinociceptive effect of the traditional form of buprenorphine HCl (in saline) with doses of 0.02, 0.06, 0.2, and 0.6 µmol/kg. The vehicle (saline) was used as control. In study 2, we evaluated the antinociceptive effect of buprenorphine HCl, base, propionate, enanthate, and decanoate (in sesame oil), all with a dose of 0.6 µmol/kg. The vehicle (sesame oil) was used as control. In study 1, the antinociceptive effects were measured at 15 min before medication (time 0) and 0.5, 1, 2, 3, 4, 5, 6, 7 h after medications. In study 2, the antinociceptive effects were measured at 15 min before medication and 2, 4, 6, 8 h after medication on day 1 and every 2 h during daytime for the following 4 days. All medications were injected IM into the left hind leg (biceps femoris and semitendinosus). Six rats were tested for each different treatment (i.e., different drugs or doses). Each rat received only one injection. The injection volume was 1 mL/kg.
The antinociceptive effects were measured using the plantar test (7370; Ugo Basil, Italy) (10,11). In the test, an infrared source located under the glass floor of the cage was positioned by the operator directly beneath the hindpaw of rats. Latency from the time of infrared stimulus to paw withdrawal was assigned as response latency. To prevent tissue damage, a 20-s cut-off time was set. The sensitivity of the test was 0.1 s. The onset time was defined as the first time point of testing in the medication groups that got a significant difference from the vehicle group. The duration of effect was defined as the time interval between the onset time and the last time point of significant effect. The efficacy was defined as the maximum value of antinociceptive effect in each treatment.
We performed 2 pharmacokinetic studies. In study 1, we evaluated the pharmacokinetic profile of IM buprenorphine HCl (in saline) in rats with doses of 0.02, 0.06, 0.2, and 0.6 µmol/kg. In study 2, we evaluated the pharmacokinetic profiles of IM buprenorphine HCl, base, propionate, enanthate, and decanoate (in sesame oil) in rats with a dose of 0.6 µmol/kg. In study 1, 2 mL blood was collected at 0.02, 0.05, 0.08, 0.25, 0.5, 1, 2, 3, 4, 5, 6, and 7 h after medications. In study 2, 2 mL blood was collected at 0.02, 0.5, 2, 4, 6, 8, 24, 26, 28, 30, 48, 50, 52, 54, 72, 74, 76, and 78 h after medications. The time points of blood sampling primarily followed the schedules that were demonstrated in the pharmacodynamic studies except during the first 30 min after drug administration. Each rat received only one drug injection. Three rats were used at each time point of blood sampling. Before blood sampling, rats received diethyl ether anesthesia and then 2 mL blood was collected by direct cardiac puncture. Each rat received only one puncture and was then killed by an overdose of diethyl ether.
The buprenorphine concentrations in blood were measured using high performance liquid chromatography with fluorescence detection, as previously described (12). In brief, it was comprised of a one-step extraction procedure with ethyl acetate and normal-phase chromatography on a Betasil Silica column. Buprenorphine propionate and decanoate were used as internal standards when appropriate. The recoveries of buprenorphine and internal standards were more than 84%. Calibration graphs of buprenorphine were linear over the concentration range 1–1500 ng/mL with a coefficient of variation, both within- and between-day, <10% at any level. The limit of quantitation of buprenorphine in blood was 1.0 ng/mL. The concentration-time profiles of buprenorphine in blood were fitted using the computer program WinNonLin Professional Version 4.1 (Pharsight Corporation, Mountain View, CA). Akaike information criteria, weighted residual sum of squares, and residual plots were used to judge the goodness-of-fit of the model to the data (13). After simulation, an open two-compartment model for IM injection was applied with the following equation: buprenorphine concentration (Ct) = Be–ßt + Ae–
t + C(0)e–Kat, where A, B, C were the intercepts; , ß, Ka were the first rate constants for the central and tissue compartments and the absorption; and t was the time of blood sampling (14). A flip-flop model was also used to interpret the pharmacokinetic data of IM buprenorphine esters (15).
Values are expressed as mean ± sem. In the pharmacodynamic studies, the sample size in each group was predetermined (16). A 4-s difference between the medication groups and the vehicle group was expected if the difference was significant. The error was set at 0.05 (two-sided) and the ß error at 0.20. The projected sample size was 6 rats for each group (16). Results of the pharmacodynamic studies were measured by a two-way analysis of variance with repeated measures. The Dunnett test was used for post hoc analysis to evaluate the differences between groups at each time-point of testing. Bonferroni correction was used when appropriate. In the pharmacokinetic studies, the differences between groups were evaluated by a one-way analysis of variance followed by the Bonferroni test. A P value < 0.05 was considered significant.
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Results
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After IM injection, buprenorphine HCl (in saline) 0.06, 0.2, and 0.6 µmol/kg produced a significant dose-dependent antinociceptive effect with a rapid onset time of 15 min and durations of 2, 5, and 5 h, respectively (Table 1, Fig. 2A). Buprenorphine HCl 0.02 µmol/kg produced only a minimum antinociceptive effect at 1 h after IM injection (Fig. 2A). The efficacies between buprenorphine HCl 0.2 and 0.6 µmol/kg were not significant (Table 1, Fig. 2A).
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Table 1. The Pharmacokinetic Parameters and the Antinociceptive Effect of Buprenorphine in Rats After IM Buprenorphine HCl, Base and Its Ester Derivatives Buprenorphine Propionate, Enanthate, and Decanoate
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Figure 2. The antinociceptive effects (2A) and the concentration-time profiles of buprenorphine in blood (2B) after IM injection of buprenorphine HCl in 0.9% saline in rats. The antinociceptive effects were evaluated by the plantar test and the blood concentrations of buprenorphine were determined by high performance liquid chromatography. Values are expressed as mean± sem (n = 6 for each dose in Fig. 2A and n = 3 for each time point in Fig. 2B). In Figure 2A, a two-way analysis of variance with one-way repeated method followed by the Dunnett test was used to evaluate the differences between the medication groups and the vehicle group at each time point of testing (*P < 0.05).
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For the pharmacokinetic studies, the blood concentrations of buprenorphine after IM injections of buprenorphine HCl 0.02, 0.06, 0.2, and 0.6 µmol/kg are shown in Figure 2B. The pharmacokinetic parameters are given in Table 1. Although there were several pharmacokinetic parameters obtained after calculation, only parameters related to the duration of the antinociceptive effect and prodrug characteristic (i.e., the terminal half-lives and AUCs; areas under the blood concentration-time curve to time infinity) were demonstrated. In the dose range 0.02 to 0.6 µmol/kg, buprenorphine pharmacokinetics were linear, as demonstrated by a dose-related increase in AUCs and similar terminal half-lives (Table 1, Fig. 3).
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Figure 3. The correlation between the AUCs (3A) or terminal half-lives (3B) and doses after IM injection of buprenorphine HCl in 0.9% saline. AUC, area under the blood–concentration time curve to time infinity. Data are expressed as mean ± sem (n = 3 for each time point). No correlation between the terminal half-lives and doses was found (4B).
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After IM injection, buprenorphine base, propionate, enanthate, and decanoate 0.6 µmol/kg (in oil) also produced a significant antinociceptive effect but with an onset time of 2 h and durations of 26, 28, 52, and 70 h, respectively (Table 1, Fig. 4A). Buprenorphine HCl (in oil) did not produce any significant effect (Fig. 4A). The differences in efficacies among groups were buprenorphine base and propionate > decanoate (Table 1).
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Figure 4. The antinociceptive effects (4A) and the concentration-time profiles of buprenorphine in blood (4B) after IM injection of buprenorphine HCl, base, propionate, enanthate, and decanoate in oil in rats. The antinociceptive effects were evaluated by the plantar test and the blood concentrations of buprenorphine were determined by high performance liquid chromatography. Values are expressed as mean ± sem (n = 6 for each dose in Fig. 4A and n = 3 for each time point in Fig. 4B). In Figure 4A, a two-way analysis of variance with one-way repeated method followed by the Dunnett test was used to evaluate the differences between the medication groups and the vehicle group at each time point of testing (*P < 0.05). After IM injection of buprenorphine HCl in oil, the concentration of buprenorphine was too small and not detectable.
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The blood concentrations of buprenorphine after IM buprenorphine base, propionate, enanthate, and decanoate are shown in Figure 4B, and the related pharmacokinetic parameters in Table 1. The differences in terminal half-lives among treatments were buprenorphine decanoate > enanthate > propionate and base > HCl (Table 1, Fig. 4B). IM buprenorphine base, propionate, enanthate, and decanoate (in oil) 0.6 µmol/kg produced AUCs for buprenorphine similar to that of IM buprenorphine HCl (in saline) 0.6 µmol/kg (Table 1). After IM injection of buprenorphine HCl in oil, the concentration of buprenorphine was too small and not detectable. The solubilities of buprenorphine HCl, base, propionate, enanthate, and decanoate in sesame oil were 0.13, 10.8, 61.5, 232, and 125 mg/mL, respectively.
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Discussion
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An analgesic with a long-acting effect is particularly desirable in patients with long-lasting pain. In the current study, three novel depots of buprenorphine esters, buprenorphine propionate, enanthate, and decanoate, were found to produce a significantly long-acting effect that was 6-fold, 10-fold, and 14-fold longer than that of the traditional form, buprenorphine HCl in saline (5 h). These esters were also shown to be prodrugs of buprenorphine.
In the pharmacokinetic study, IM buprenorphine HCl (in saline) 0.02 to 0.6 µmol/kg produced a dose-related increase in AUCs (Figs. 2B, 3A, and Table 1). In the pharmacodynamic study, IM buprenorphine HCl (in saline) 0.02 to 0.2 µmol/kg also produced a dose-related increase in antinociception (Table 1, Fig. 2A). However, despite a larger blood concentration (Fig. 2B), the antinociception and duration of action of buprenorphine HCl 0.6 µmol/kg did not differ from that of buprenorphine HCl 0.2 µmol/kg (Table 1, Fig. 2A). This meant that a ceiling effect of antinociception occurred.
In the current study, a depot formulation with prodrug design was used. Esterification of drugs with various fatty acids increases their lipophilicity (3–6). When these prodrug-type esters are dissolved in injectable oils and given IM, long durations of actions are obtained because of their slow release from the oily vehicles (5,6). Once released from the vehicles, they are converted to their active drugs and exert their pharmacologic actions (17). In our study, several buprenorphine prodrug-type esters were synthesized and formulated. Our study further demonstrated that they had a long-acting effect.
In our study, we also evaluated whether these buprenorphine esters were prodrugs of buprenorphine. After IM injections of these esters (in oil), the AUCs of buprenorphine were found to be similar to that of IM buprenorphine HCl (in saline) (Table 1). This meant that the buprenorphine esters buprenorphine propionate, enanthate, and decanoate were totally converted to buprenorphine after IM injection and these esters were prodrugs of buprenorphine.
Because buprenorphine base has a higher lipophilicity than that of buprenorphine HCl, theoretically, buprenorphine base in oil should have a slow drug release profile and a long-duration of action (3). In the current study, we did find that buprenorphine base in sesame oil had a long duration of action which was 5.2-fold longer than that of buprenorphine HCl in saline. However, this action was not as long as those of buprenorphine enanthate and decanoate. The discrepancy might be explained, at least in part, by differences in lipophilicity, which causes different drug release profiles from the oily vehicle and different durations of action (3).
In the current study, the antinociceptive effect of buprenorphine HCl in oil was also evaluated. In this dosage form, buprenorphine HCl was formulated in sesame oil. However, we found that buprenorphine HCl had a very poor solubility (0.13 mg/mL) in sesame oil. This was the reason why no buprenorphine was detected in the pharmacokinetic study and no antinociception was detected in the pharmacodynamic study after IM injection of this form. Buprenorphine HCl in oil is not a suitable form for pain management.
In our study, the antinociceptive effects of buprenorphine prodrugs were evaluated only at a dose of 0.6 µmol/kg. Theoretically, a larger dose of buprenorphine prodrug may obtain a larger blood concentration of buprenorphine, which causes a more potent antinociceptive effect with longer duration of action (3). Also, if the blood concentration of buprenorphine is large enough, a ceiling effect of antinociception may occur (1). However, these effects were not tested in the current study and are worth further evaluation.
Several buprenorphine esters have been synthesized and evaluated (8,18–20). However, most of the studies focused on their transdermal characteristics (8,18). Only two studies evaluated the antinociceptive effect of two esters (19,20). After IM injection, buprenorphine benzoate and palmitate demonstrated a long-acting antinociceptive effect in rats (19,20). However, in these studies, the pharmacokinetic profiles and the prodrug’s characteristics of these esters were not evaluated. In the current study, not only the antinociceptive effect but also the pharmacokinetic characteristics of the three buprenorphine esters were evaluated. All these esters were found to be prodrugs of buprenorphine and had a long-acting effect.
Although anesthesiologists may use a syringe or patient-controlled analgesia pump to produce a sustained analgesia in patients who require it, a single IM injection of a long-acting opioid has advantages over these methods (3,4), e.g., reduction of time required by health care personnel to dispense and administer drugs, reduction of use of related disposable products, reduction of overall health care costs, and enhancement of patient convenience and compliance in daily activity. Despite these advantages, careful monitoring and continuous dosing with an antagonist may be required if side effects occur after the administration of a long-acting opioid (3). Although buprenorphine has a superior safety profile than the other opioids, as demonstrated by a ceiling effect on its side effects (1), the long-acting formulation of buprenorphine may share the advantages and disadvantages of other long-acting drugs (3).
In clinical practice, IM buprenorphine HCl 0.6 µmol/kg (0.3 mg) given to an adult provides a 6- to 8-hour duration of action (7 hours on average) (1). In our study, IM injection of 0.6 µmol/kg buprenorphine HCl in rats had a 5-hour duration of action. According to the ratio (1.4) obtained from humans versus rats (7 hours/5 hours), we estimate that IM injection of proper doses of buprenorphine propionate, enanthate, and decanoate in humans may have a 1.6-, 3.0-, and 4.1-day duration of action. Because patients who experience moderate to severe pain, such as postoperative pain, posttraumatic pain, and burn pain, may need analgesics in the first 3 days after trauma, the novel depots of buprenorphine esters may be suitable alternatives to traditional analgesics for the management of these pains.
In conclusion, IM injection of novel depots of buprenorphine esters, buprenorphine propionate, enanthate, and decanoate produced a long-lasting antinociceptive effect in rats. Among these esters, buprenorphine decanoate in oil produced a 14-fold longer duration of action than did the traditional form, buprenorphine HCl in saline. These esters were also proven to be prodrugs of buprenorphine.
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Footnotes
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Accepted for publication January 9, 2006.
Supported, in part, by the research fund of the Chi-Mei Medical Center, Tainan, Taiwan (Grant CMFH 8901).
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Abstract
Introduction
