For veterinarians who treat avian and small exotic animals, there are few commercially available drug products labeled for use in such patients. Most medications administered to small exotic animals by veterinarians are commercially available products approved for use in dogs, cats, or humans; these products are typically diluted or extemporaneously prepared (compounded) because they are not commonly available in concentrations that allow for accurate measurement of the doses required for small patients. Preparation of compounded products from bulk materials for use in animals is not allowed under the most recent FDA compliance policy guidelines if commercial preparations are available. Therefore, most veterinarians who treat birds or other small exotic pets frequently resort to reformulation of existing commercial drug formulations. Unfortunately, the stability and integrity of most compounded preparations used in veterinary medicine have not been assessed.
For years, exotic animal veterinarians have prescribed analgesic and anti-inflammatory medications for their patients, but recently, the recognition and alleviation of pain in exotic animals has become widely acknowledged as an essential component of their clinical veterinary care. Although NSAIDs are commonly used to alleviate pain and inflammation, few are commercially available in oral formulations, whether as a liquid or a tablet, that allow for oral administration of accurate doses in small birds and exotic animals. Therefore, a need exists for oral formulations of NSAIDs that can be administered in accurate doses to even the smallest avian and exotic animal patients to provide analgesic and anti-inflammatory effects.
At present, the 2 NSAIDs most commonly selected for oral administration in exotic animal clinical practice are meloxicam and carprofen. Meloxicam is a COX-2 selective oxicam NSAID that is available in the United States as a liquid suspensiona (approved for use in dogs) and as a tabletb (approved for use in humans). Carprofen is a weak inhibitor of both COX isoforms1 (COX-1 and -2) and is available in the United States (for oral administration in dogs) in caplet and chewable tablet forms.c
The commercially available oral formulations of carprofen and meloxicam are marketed in concentrations that do not allow administration of accurate doses in small exotic animals. Historically, veterinarians have diluted the commercially available meloxicam suspension or crushed and suspended carprofen caplets into extemporaneously compounded oral suspensions to accommodate the lower dosages required in exotic animal patients. Often these preparations are made in commercial suspending vehicles or in water and either stored at room temperature or refrigerated for variable periods. Flavoring agents, suspending vehicles, and water have the potential to hydrolyze, oxidize, or otherwise inactivate many drugs. Because pain in exotic animals is often difficult to assess, the clinician may unknowingly be administering compounded products that are entirely inactive.
The stabilities (at various temperatures) of several drugs prepared extemporaneously for oral administration in humans have been evaluated, but similar studies are lacking for those drugs that are most applicable in clinical veterinary medicine.2–7 To our knowledge, there are no published reports of studies to evaluate whether meloxicam and carprofen remain stable after commercial liquid forms are diluted or commercial caplet forms are crushed and suspended. If the drugs are not stable once the commercial formulations have been altered by one of the aforementioned methods, it is possible that the compounded medication will not provide the desired therapeutic effect (ie, analgesia or anti-inflammatory effects) when administered to a patient. In addition, we are not aware of any published reports of studies to determine the extent of variability, if any, in the distribution of these drugs in these compounded formulations once they have been diluted or suspended. A nonuniform dispersal of drug into a more aqueous or hydrophobic portion of the suspension may alter the drug concentration throughout the compounded preparation in a way that vigorous shaking will not reverse. Variability of these drugs in compounded preparations might allow inappropriately high doses to be inadvertently administered to an exotic animal, resulting in adverse effects; conversely, inappropriately low doses might be administered to the patient, with minimal (if any) treatment benefits.
The purpose of the study of this report was to determine dispersion uniformity and stability of meloxicam and carprofen in extemporaneously prepared suspensions during a 28-day period. Commercially available oral formulations of meloxicam and carprofen were diluted or suspended to concentrations commonly used to treat companion exotic animals and stored at room temperature or refrigerated for 28 days.
Materials and Methods
Sample preparation—The concentrations for each drug preparation used in the study were considered representative of concentrations in preparations that are commonly used in clinical avian and exotic animal practice. Commercially available oral formulations of meloxicama and carprofenc were used. Meloxicam was diluted in DW (meloxicam-DW), in MCGd (meloxicam-MCG), or in a 1:1 mixture of MCG and SSe (meloxicam-MCG-SS) each to nominal concentrations of 0.25, 0.5, and 1.0 mg/mL. Carprofen suspensions were prepared by crushing an appropriate number of 25-mg caplets 100 times to form a uniform powder that was mixed with a small volume of either a 1:1 mixture of MCG and SS (carprofen-MCG-SS) or a commercially available SFVCf,g (1:1 vehicle mixture; carprofen-SFVC). Following rinses of the mortar and pestle, each carprofen preparation was diluted to nominal concentrations of 1.25, 2.5, and 5.0 mg/mL.
The drug preparations were stored in 4-oz (118.3-mL) amber glass prescription bottles. Two aliquots of each drug preparation at each concentration were immediately refrigerated and stored at 3° to 5°C (37.4° to 41.0°F; approx 4°C [39.2°F]) until assayed; the remaining 2 aliquots were stored at 20° to 24°C (68.0° to 75.2°F; approx 22°C [71.6°F]) until assayed.
Sample collection—Drug preparations were vigorously shaken by hand for 30 seconds prior to each sample collection in an attempt to provide sample homogeneity. A 0.4-mL sample was withdrawn from the center of each preparation by use of a positive-displacement pipetteh at the midlevel of the liquid. Refrigerated aliquots were wrapped in ice packs between sample collections to maintain appropriate storage temperature for each aliquot. Each 0.4-mL sample was expelled into 39.6 mL of acetonitrile-water (1:1) diluent. Diluted samples were vortexed for 2 minutes and then centrifuged at 700×g for 2 minutes at 20°C.
Drug distribution—One aliquot of each drug preparation at each concentration and temperature was analyzed for this phase of the study. Drug concentrations were determined in 20 subsamples of each drug aliquot to evaluate concentration accuracy and the uniformity of carprofen or meloxicam distribution in the various vehicles. Room-temperature samples were collected immediately after preparation, and refrigerated samples were collected approximately 3 hours after refrigeration (to allow samples to reach the appropriate storage temperature). The distribution of meloxicam in MCG-SS was evaluated only in room-temperature aliquots (as the study progressed, variability associated with use of this vehicle combination in meloxicam preparations stored at room temperature became apparent and refrigerated meloxicam samples prepared with these vehicles were not subsequently evaluated). For each drug preparation, concentration accuracy was determined by comparing the actual drug concentration with the nominal drug concentration and calculating the percentage recovery. Variability was determined by calculating the coefficient of variation from the percent relative SD; low variability was defined as a coefficient of variation < 10%.
Drug stability—One aliquot of each drug preparation at each concentration and temperature was analyzed for this phase of the study. Samples were collected in triplicate from each of the refrigerated and room-temperature aliquots of each drug preparation at 0, 7, 14, 21 and 28 days after preparation. On day 0, room-temperature samples were collected immediately after preparation and the refrigerated samples were collected approximately 3 hours after refrigeration. Each drug preparation was inspected by the same observer (MJK) prior to sample collection; color, odor, opacity, and presence of visible solids were recorded. The pH of each preparation was measuredi on days 0 and 28. Also on days 0 and 28, a 0.4-mL sample of each drug preparation was collected from the center region of the liquid by use of a sterile syringe with a 16-gauge hypodermic needle; these samples were submitted to the microbiology laboratory at the Veterinary Medical Teaching Hospital, University of California, for aerobic and anaerobic bacterial culture.
HPLC analysis—Concentrations of meloxicam and carprofen in samples were determined by HPLC analysisj according to previously described methods.8,9 Degradation by-products were not quantitated. A reverse-phase column with octyldecyl packing materialk was used (particle size, 5 mm; length, 250 mm; internal diameter, 4.6 mm; guard column, 12.5 ×4.6 mm). An isocratic mobile phase of 50% water-acetic acid (99:1 [vol/vol]) and 50% acetonitrile was used at a flow rate of 1 mL/min. Carprofen and meloxicam were detected via UV absorption at 270 and 355 nm, respectively. Racemic carprofenl was dissolved in methanol to a concentration of 1.0 mg/mL and diluted with a 1:1 acetonitrile-water solution to prepare calibration standards (1 to 200 mg/mL). A linear correlation between UV absorption and carprofen concentration was found over this range in the carprofen calibration curves (R2 > 0.987). Meloxicam sodiumm was dissolved in a 1:1 acetonitrile-water solution to a concentration of 1.0 mg/mL and diluted with a 1:1 acetonitrile-water solution to prepare calibration standards (0.25 to 40 mg/mL). A linear correlation between UV absorption and meloxicam concentration was found over this range in the meloxicam calibration curves (R2 > 0.992). Limit of detection (calculated as the concentration equivalent to the mean value plus 3SD of the background responses in 20 blank samples) was 0.07 mg/mL for meloxicam and 0.08 mg/mL for carprofen. Limit of quantitation (calculated as the mean value plus 10SD of the background responses) was 0.09 mg/mL for meloxicam and 0.11 µg/mL for carprofen.
Data analysis—Mean ± SD drug concentrations in samples were calculated for each drug preparation at each concentration, time interval, and temperature. For assessment of drug distribution, concentrations determined by HPLC analysis were compared with nominal concentrations by use of a 2-tailed t test (19 degrees of freedom). For all values, a value of P £ 0.05 was defined as significant. For assessment of drug stability, a drug preparation was considered stable if the concentration on day 28 was 3 90% of the original concentration on day 0.
Results
Drug distribution—Mean ± SD actual concentrations of the 20 samples for the meloxicam preparations were compared with the nominal concentrations (Table 1). For the meloxicam-DW preparations, the actual and the nominal drug concentrations were significantly different in 2 of the 6 preparations; however, the meloxicam-DW preparations at both temperatures had the most accurate concentrations of meloxicam, with drug recoveries ranging from 93% to 106%. All of the actual concentrations of meloxicam in the meloxicam-MCG preparations were significantly different from the nominal concentrations, but because the drug concentrations in the meloxicam-MCG (0.25 mg/mL) and meloxicam-MCG (0.5 mg/mL) preparations at both 22°C and 4°C were considered accurate with little variability, the difference was not considered clinically important. At both temperatures, the drug distributions in the meloxicam-MCG (1.0 mg/mL) preparations were more variable than those of the meloxicam-MCG preparations of lower concentrations; flocculation was visible in the former. The MCG-SS mixture produced a foamy vehicle for drug suspension; in all meloxicam-MCG-SS preparations, the actual and nominal meloxicam concentrations were significantly different. The accuracy of meloxicam concentrations in the various meloxicam-MCG-SS preparations was low; at room temperature, percentage meloxicam recovery for the meloxicam-MCG-SS (0.25 mg/mL) and meloxicam-MCG-SS (0.5 mg/mL) samples was 62% and 54%, respectively. The variability of meloxicam concentrations in the various meloxicam-MCG-SS preparations was high; however, meloxicam concentration in the meloxicamMCG-SS (1 mg/mL) preparation was more accurate (recovery, 92%) and precise (much lower variability) than concentrations in the other 2 meloxicam-MCG-SS preparations.
Variability of meloxicam concentrations in preparations of an oral formulation of meloxicam diluted with various vehicles at room temperature (20° to 24°C) and after refrigeration (3° to 5°C).
| Preparation | Nominal meloxicam concentration (mg/mL) | Actual meloxicam concentration (mg/mL) | Recovery (%) | CV(%) |
|---|---|---|---|---|
| DW (approx 22°C) | 0.25 | 0.26 ± 0.03 | 104 | 2.7 |
| 0.5 | 0.50 ± 0.03 | 99 | 5.9 | |
| 1.0 | 1.05 ± 0.09 | 105 | 8.0 | |
| DW (approx 4oC) | 0.25 | 0.23 ± 0.03† | 93 | 9.8 |
| 0.5 | 0.49 ± 0.02 | 98 | 5.0 | |
| 1.0 | 1.06 ± 0.06† | 106 | 5.2 | |
| MCG (approx 22°C) | 0.25 | 0.28 ± 0.02† | 111 | 8.7 |
| 0.5 | 0.56 ± 0.04† | 113 | 7.8 | |
| 1.0 | 0.96 ± 0.12† | 96 | 12.5 | |
| MCG (approx 4°C) | 0.25 | 0.28 ± 0.02† | 112 | 6.4 |
| 0.5 | 0.54 ± 0.05† | 107 | 8.8 | |
| 1.0 | 0.83 ± 0.20† | 83 | 23.9 | |
| MCG-SS (1:1 ratio; approx 22°C) | 0.25 | 0.16 ± 0.09† | 62 | 54.8 |
| 0.5 | 0.27 ± 0.16† | 54 | 57.6 | |
| 1.0 | 0.92 ± 0.06† | 92 | 6.2 |
Room-temperature samples were collected immediately after preparation, and refrigerated samples were collected approximately 3 hours after refrigeration (to allow samples to reach the appropriate storage temperature).
*Data are presented as mean ± SD (n = 20). †Value significantly (P ≤ 0.05) different from nominal concentration.
CV = Coefficient of variation (% relative SD).
To convert temperatures in degrees Celsius to degrees Fahrenheit, multiply by 9/5 and add 32.
Mean ± SD actual concentrations of the 20 samples for the carprofen preparations were compared with the nominal concentrations (Table 2). Carprofen concentrations in all preparations of carprofen-SFVC were 93% to 99% of expected concentrations, and there was low variability in all the preparations, although the differences between actual and nominal concentrations for the refrigerated preparations were significant. The room-temperature carprofen-MCG-SS preparations were also foamy, and the foam remained separated as a congealed raft after mixing. At room temperature, the mean carprofen concentrations in preparations involving the MCG-SS vehicle mixture were highly inaccurate and variable with only 65% to 73% recovery achieved. However, the preparations kept at 4°C were more accurate, had less variability, and were visibly more homogeneous; in the refrigerated samples, the foam was incorporated into the liquid rather than separated as a congealed raft. In all carprofen preparations involving MCG and SS, the actual concentrations were significantly different from the nominal concentrations.
Variability of carprofen concentrations in preparations of crushed carprofen caplets suspended with various vehicles at room temperature (20° to 24°C) and after refrigeration (3° to 5°C).
| Preparation | Nominal carprofen concentration (mg/mL) | Actual carprofen concentration (mg/mL) | Recovery (%) | CV(%) |
|---|---|---|---|---|
| Commercial SFVC (1:1 ratio; approx 22°C) | 1.25 | 1.23 ± 0.03 | 98 | 3.4 |
| 2.5 | 2.44 ± 0.11 | 98 | 4.8 | |
| 5.0 | 4.93 ± 0.27 | 99 | 5.6 | |
| Commercial SFVC (1:1 ratio; approx 4°C) | 1.25 | 1.17 ± 0.09† | 94 | 7.6 |
| 2.5 | 2.33 ± 0.14† | 93 | 5.8 | |
| 5.0 | 4.63 ± 0.45† | 93 | 9.7 | |
| MCG-SS (1:1 ratio; approx 22°C) | 1.25 | 0.83 ± 0.42† | 67 | 50.1 |
| 2.5 | 1.83 ± 1.06† | 73 | 57.6 | |
| 5.0 | 3.26 ± 1.37† | 65 | 42.1 | |
| MCG-SS (1:1 ratio; approx 4°C) | 1.25 | 1.12 ± 0.17† | 90 | 14.7 |
| 2.5 | 2.17 ± 0.22† | 87 | 10.1 | |
| 5.0 | 4.16 ± 0.27† | 83 | 6.5 |
Room-temperature samples were collected immediately after preparation, and refrigerated samples were collected approximately 3 hours after refrigeration (to allow samples to reach the appropriate storage temperature).
See Table 1 for key.
Drug stability—During storage, the meloxicamDW preparations settled into 2 distinct layers that were easily resuspended and subjectively appeared homogenous after shaking. For these preparations at both storage temperatures, drug concentrations were > 90% of the original concentration during the entire 28-day study period with the exception of the refrigerated meloxicam-DW (0.25 mg/mL) preparation, which remained at 100% of the original concentration through 21 days but was only 80% of the original concentration on day 28 (Table 3). The meloxicam-MCG (0.25 mg/mL) and meloxicam-MCG (0.5 mg/mL) preparations remained homogeneous throughout the 28-day period, and all of these preparations were > 90% of their original concentrations on day 28. However, in the meloxicam-MCG (1.0 mg/mL) preparations at both temperatures, considerable quantities of foam developed on the first day of preparation (day 0), flocculence was evident after shaking throughout the 28-day study, and some of the preparation dried and adhered to the sides of the prescription bottles by day 14. These preparations typically had inconsistent meloxicam concentrations during the entire 28-day study period.
Stability of meloxicam in preparations of an oral formulation of meloxicam diluted with various vehicles assessed at intervals during a 28-day period of storage at room temperature (20° to 24 °C) or refrigeration (3° to 5°C).
| Actual meloxicam concentration* (mg/mL) | ||||||
|---|---|---|---|---|---|---|
| Preparation | Nominal meloxican concentration (mg/mL) | Day 0 | Day 7 | Day 14 | Day 21 | Day 28 |
| DW (approx 22°C) | 0.25 | 0.25 ± 0.01 | 0.26 ± 0.01 | 0.28 ± 0.02 | 0.29 ± 0.01 | 0.23 ± 0.01 |
| 0.5 | 0.47 ± 0.04 | 0.51 ± 0.04 | 0.53 ± 0.01 | 0.58 ± 0.08 | 0.46 ± 0.03 | |
| 1.0 | 0.96 ± 0.05 | 1.13 ± 0.04 | 1.14 ± 0.04 | 0.76 ± 0.13 | 0.98 ± 0.03 | |
| DW (approx 4°C) | 0.25 | 0.25 ± 0.05 | 0.25 ± 0.02 | 0.26 ± 0.01 | 0.26 ± 0.01 | 0.20 ± 0.01 |
| 0.5 | 0.46 ± 0.02 | 0.52 ± 0.02 | 0.54 ± 0.02 | 0.54 ± 0.02 | 0.50 ± 0.06 | |
| 1.0 | 1.06 ± 0.03 | 1.15 ± 0.04 | 1.25 ± 0.16 | 0.93 ± 0.04 | 1.09 ± 0.10 | |
| MCG (approx 22°C) | 0.25 | 0.27 ± 0.01 | 0.30 ± 0.01 | 0.29 ± 0.01 | 0.22 ± 0.03 | 0.27 ± 0.09 |
| 0.5 | 0.56 ± 0.10 | 0.55 ± 0.02 | 0.59 ± 0.01 | 0.52 ± 0.05 | 0.52 ± 0.02 | |
| 1.0 | 0.72 ± 0.06 | 0.69 ± 0.05 | 0.72 ± 0.04 | 1.19 ± 0.02 | 0.78 ± 0.02 | |
| MCG (approx 4°C) | 0.25 | 0.29 ± 0.03 | 0.25 ± 0.03 | 0.26 ± 0.01 | 0.18 ± 0.05 | 0.27 ± 0.06 |
| 0.5 | 0.46 ± 0.03 | 0.68 ± 0.02 | 0.56 ± 0.04 | 0.61 ± 0.03 | 0.46 ± 0.03 | |
| 1.0 | 0.76 ± 0.04 | 1.15 ± 0.04 | 0.75 ± 0.03 | 1.16 ± 0.09 | 0.53 ± 0.0 |
On the day of preparation (day 0), room-temperature samples were collected immediately after preparation, and refrigerated samples were collected approximately 3 hours after refrigeration (to allow samples to reach the appropriate storage temperature).
*Data are presented as mean 6 SD (n = 3).
The carprofen-SFVC (5.0 mg/mL) preparation at room temperature retained > 90% of the original concentration on day 28, but the other 5 carprofenSFVC preparations retained 3 90% of the original concentration only through day 21 (Table 4). From day 0, variability in the carprofen concentrations of the carprofen-MCG-SS (1.25 mg/mL) preparations at both temperatures was evident; a solid crust adhered to the sides of each bottle that could not be resuspended by shaking. In some of the MCG-SS preparations with higher concentrations of carprofen, a change in concentration > 20% was identified at some time points; however, carprofen concentrations on day 28 were 95% to 97% of the original concentration for the carprofen-MCG-SS (2.5 mg/mL) and carprofen-MCG-SS (5.0 mg/mL) preparations at both temperatures.
Stability of carprofen in preparations of crushed carprofen caplets suspended with various vehicles assessed at intervals during a 28-day period of storage at room temperature (20° to 24°C) or refrigeration (3° to 5°C).
| Actual carprofen concentration* (mg/mL) | ||||||
|---|---|---|---|---|---|---|
| Preparation | Nominal carprofen concentration (mg/mL) | Day 0 | Day 7 | Day 14 | Day 21 | Day 28 |
| Commercial SFVC (1:1 ratio; approx 22°C) | 1.25 | 1.20 ± 0.05 | 1.46 ± 0.28 | 1.25 ± 0.12 | 1.09 ± 0.02 | 1.03 ± 0.05 |
| 2.5 | 2.49 ± 0.06 | 3.08 ± 0.46 | 2.22 ± 0.06 | 2.25 ± 0.05 | 2.11 ± 0.07 | |
| 5.0 | 5.19 ± 0.13 | 5.95 ± 0.16 | 4.52 ± 0.05 | 4.62 ± 0.04 | 4.83 ± 0.64 | |
| Commercial SFVC (1:1 ratio; approx 4°C) | 1.25 | 1.50 ± 0.05 | 1.25 ± 0.05 | 1.18 ± 0.03 | 1.13 ± 0.05 | 1.05 ± 0.08 |
| 2.5 | 2.51 ± 0.01 | 2.71 ± 0.04 | 2.47 ± 0.39 | 2.29 ± 0.06 | 2.14 ± 0.06 | |
| 5.0 | 5.22 ± 0.22 | 5.39 ± 0.24 | 4.72 ± 0.51 | 4.69 ± 0.06 | 4.38 ± 0.53 | |
| MCG-SS (1:1 ratio; approx 22°C) | 1.25 | 1.01 ± 0.07 | 0.52 ± 0.19 | 0.57 ± 0.13 | 0.77 ± 0.23 | 0.53 ± 0.03 |
| 2.5 | 3.24 ± 0.28 | 1.85 ± 0.99 | 1.33 ± 0.23 | 2.29 ± 0.31 | 2.43 ± 0.37 | |
| 5.0 | 4.94 ± 0.20 | 1.54 ± 0.77 | 3.44 ± 0.48 | 4.74 ± 0.33 | 4.76 ± 0.54 | |
| MCG-SS (1:1 ratio; approx 4°C) | 1.25 | 0.99 ± 0.12 | 0.99 ± 0.12 | 0.93 ± 0.01 | 0.95 ± 0.04 | 0.91 ± 0.03 |
| 2.5 | 3.16 ± 0.23 | 2.94 ± 0.01 | 2.53 ± 0.08 | 2.63 ± 0.07 | 2.41 ± 0.03 | |
| 5.0 | 4.03 ± 0.43 | 5.86 ± 0.65 | 4.54 ± 0.08 | 4.79 ± 0.04 | 4.75 ± 0.55 |
On the day of preparation (day 0), room-temperature samples were collected immediately after preparation, and refrigerated samples were collected approximately 3 hours after refrigeration (to allow samples to reach the appropriate storage temperature).
See Table 3 for key.
The pH values of each preparation on day 0 and day 28 were measured (Table 5). All meloxicam-DW and meloxicam-MCG preparations had only slight reductions in pH values on day 28, compared with values on day 0, and the range of pH value changes of these preparations was –0.12 to –0.25. The pH values of all carprofen suspensions on day 28 also varied only slightly from the values on day 0, and the range of pH value changes of these preparations was only –0.02 to +0.13.
Assessment of pH values of preparations of an oral formulation of meloxicam diluted with and crushed carprofen caplets suspended with different vehicles before and after a 28-day storage period.
| pH Value | ||
|---|---|---|
| Preparation | Day 0 | Day 28 |
| Meloxicam-DW (approx 22°C) | ||
| 0.25 mg/mL | 4.31 | 4.10 |
| 0.5 mg/mL | 4.04 | 3.92 |
| 1.0 mg/mL | 3.95 | 3.81 |
| Meloxicam-DW (approx 4°C) | ||
| 0.25 mg/mL | 4.20 | 4.01 |
| 0.5 mg/mL | 4.04 | 3.89 |
| 1.0 mg/mL | 3.97 | 3.76 |
| Meloxicam-MCG (approx 22°C) | ||
| 0.25 mg/mL | 4.12 | 3.97 |
| 0.5 mg/mL | 4.05 | 3.88 |
| 1.0 mg/mL | 3.98 | 3.73 |
| Meloxicam-MCG (approx 4°C) | ||
| 0.25 mg/mL | 4.14 | 3.91 |
| 0.5 mg/mL | 4.06 | 3.85 |
| 1.0 mg/mL | 3.98 | 3.76 |
| Carprofen-SFVC (approx 22°C) | ||
| 1.25 mg/mL | 4.20 | 4.23 |
| 2.5 mg/mL | 4.26 | 4.24 |
| 5.0 mg/mL | 4.30 | 4.36 |
| Carprofen-SFVC (approx 4°C) | ||
| 1.25 mg/mL | 4.21 | 4.21 |
| 2.5 mg/mL | 4.22 | 4.27 |
| 5.0 mg/mL | 4.35 | 4.37 |
| Carprofen-MCG-SS (approx 22°C) | ||
| 1.25 mg/mL | 4.54 | 4.62 |
| 2.5 mg/mL | 4.57 | 4.66 |
| 5.0 mg/mL | 4.63 | 4.76 |
| Carprofen-MCG-SS (approx 4°C) | ||
| 1.25 mg/mL | 4.57 | 4.60 |
| 2.5 mg/mL | 4.59 | 4.65 |
| 5.0 mg/mL | 4.69 | 4.68 |
For the pH of each preparation, data are presented as n = 1.
No change in odor or color was detected in any of the meloxicam or carprofen preparations on day 28. Other than the described flocculence in the meloxicam-MCG (1.0 mg/mL) preparations and foam in all the carprofen-MCG-SS preparations, no opacity was identified in any other preparation. Samples of the carprofen-SFVC (2.5 mg/mL) and carprofen-MCG-SS (5.0 mg/mL) preparations stored at 22°C that were collected at day 28 yielded growth of Eubacterium sp and Bacillus sp, respectively; all other preparations did not yield any bacterial growth.
Discussion
The specific goals of our study were to determine whether extemporaneous preparations of carprofen and meloxicam (in which the required drug concentrations were accurately achieved) could be prepared at concentrations appropriate for administration to small birds and exotic animals and stored for 28 days without detrimental changes to those preparations. The compounding vehicles that were used were selected to meet 3 specific criteria. First, only vehicles readily available to veterinarians or compounding pharmacists were considered. Second, the vehicles were chosen for their palatability to avian and exotic animal patients. Third, the extemporaneous drug preparations were used over the course of 28 days to assess stability, with multiple samples taken from the same bottle, so vehicle preservation was necessary to minimize microbial growth over the shelf life of the suspension. The MCGSS vehicle and commercial SFVC contain preservatives (parabens and potassium sorbate); these were therefore chosen on the basis of their historic safety and utility.10 Because the oral formulation of meloxicam used contains sodium benzoate, our initial goal was to simply add a diluent, regardless of whether it contained a preservative, to that meloxicam formulation to prepare the lower concentrations commonly used in exotic animal veterinary practice.
In the distribution phase of the present study, DW allowed excellent meloxicam recovery and minimal variation among samples. In the meloxicam-DW preparations, the drug settled during storage but was easily resuspended and subjectively appeared homogenous after the preparations were shaken. With the exception of the meloxicam-DW (0.25 mg/mL) preparation stored at 4°C, all of the other meloxicam-DW preparations retained > 90% of their original concentrations at 28 days, regardless of storage at room or refrigeration temperatures. The concentration of drug in the meloxicam-DW (0.25 mg/mL) preparation stored at 4°C remained stable through 21 days; therefore, it is possible that laboratory error in sample collection or analysis on day 28 may have been responsible for this reduction in concentration. Because only a small number of samples (n = 3) were analyzed for each preparation at each time point during the stability phase of the study, it is also possible that analysis of a larger number of samples may have revealed an acceptable concentration in these final samples of the meloxicam-DW (0.25 mg/mL) preparation stored at 4°C. These results suggest that dilutions of the commercial meloxicam oral formulation can be prepared successfully with DW and the resultant preparations can be stored at room temperature or refrigerated for 28 days without detrimental change; however, because the preservatives in the formulation are diluted during the preparatory process, refrigeration of these preparations would be prudent.
In clinical veterinary practice, access to DW can be limited; in such instances, distilled water would be an appropriate substitute for the dilution of these products. Simply defined, DW has been purified by passage through ion-exchange columns; for veterinarians, the necessary equipment might not be readily available or affordable. Distilled water is purified by a series of evaporation and collection processes to render it free of many solubilized minerals and contaminants. The products used in the present study could be diluted in either of these water sources without any reasonable expectation of negative effects on drug stability. It is appropriate, however, to assure that the water source is as pure as possible to eliminate unwanted contaminants or microbes that might alter the resultant preparations.
Acceptable accuracy and variation in drug concentration and drug stability were identified in the meloxicam-MCG (0.25 mg/mL) and meloxicam-MCG (0.5 mg/mL) preparations at both temperatures during the 28-day study period. However, the meloxicam-MCG (1 mg/mL) preparations precipitated and remained flocculent after shaking in both phases of the study, most likely contributing to the large fluctuations in concentration that were detected in these preparations at several time points throughout the 28-day period. The reasons for this are unclear. Because the volume of the oral formulation of meloxicam required to prepare the 1 mg/mL preparation in MCG was greater than the meloxicam volumes needed for the MCG preparations of lower concentration, it is possible that the MCG interacted with some component of the commercial meloxicam formulation and resulted in flocculation within the preparation. On the basis of these findings, we do not recommend the use of MCG to dilute the commercial oral formulation of meloxicam to a concentration of 1 mg/mL because of the unreliable suspending characteristics of MCG at this drug concentration.
Concentrations of carprofen in the carprofen-SFVC preparations were accurate and had little variability; > 90% of nominal concentrations were identified in all of the preparations. We chose this combination of vehicles because of their ease of use and availability. But on day 28, only the carprofen-SFVC (5.0 mg/mL) preparation stored at room temperature had > 90% of the original drug concentration. All of the preparations that included the SFVC did maintain 3 90% of the original concentration at 21 days, so it is possible that gradual degradation of carprofen may have been occurring. Additionally, human error, variable shaking techniques or storage conditions, and many other factors can contribute to changes in an extemporaneous preparation that may result in clinically important differences in drug concentration. Although it is possible that the bacterial growth identified in the carprofen-SFVC (2.5 mg/mL) preparation that was stored at room temperature was attributable to hand contamination, we would still recommend refrigerating this preparation during its shelf life. Given that there are numerous suspending and flavoring agents commercially available for use, there is no way to extrapolate the results of our study involving this SFVC to suspending and flavoring components of any other composition.
We chose to also evaluate the combination of MCG and SS with both meloxicam and carprofen because this vehicle combination is generally less expensive and more readily available outside the United States than commercially available suspending and flavoring agents.2 In our study, the mixture of MCG and SS in a 1:1 ratio was a foamy, suboptimal vehicle for drug suspension, and during the stability phase of the study, a solid crust formed and adhered to the sides of many of the prescription bottles; this crust could be only partially resuspended. This 1:1 ratio of vehicles was chosen on the basis of results of other drug stability studies11,12 in which this specific combination was used successfully. Because of the variability associated with use of this vehicle combination in meloxicam preparations stored at room temperature, refrigerated meloxicam samples prepared with these vehicles were not subsequently evaluated and analysis of drug stability was not attempted. The refrigerated carprofen-MCG-SS preparations had less variability in drug concentration and greater drug recovery than the room-temperature preparations, so we decided to analyze drug stability in these carprofen preparations. With regard to stability, considerable variability in carprofen concentrations was detected in several of the preparations at both temperatures over the 28-day period, even though 4 of the 6 preparations had > 90% of the initial day 0 concentration remaining on day 28. Because of the heterogeneity of the preparations and their variation in drug concentrations over time, we would not recommend the use of a 1:1 mixture of MCG and SS for dilution of the oral formulation of meloxicam or for suspension of crushed carprofen caplets. Further studies to evaluate extemporaneous preparations of carprofen and meloxicam in MCG-SS mixtures of different ratios would be required to determine whether more homogeneous preparations of these drugs could be formulated with these vehicles.
In the present study, no clinically important change in pH was detected in preparations of either drug at any concentration after 28 days of storage. This finding allowed confidence that preparations of meloxicam or carprofen that are stored for 28 days should not undergo alteration in pH that may ultimately affect drug stability, palatability, and tolerance of the preparations.
Overall, our data suggest that preparations of meloxicam diluted with DW have uniform drug distribution and preparation stability for 28 days when stored at either room temperature or refrigerated.
Because dilution of the preservative in the oral formulation of meloxicam occurs during mixing with DW, we would recommend refrigeration of any meloxicam-DW preparation for the duration of its shelf life. In the meloxicam-MCG (0.25 mg/mL) and meloxicam-MCG (0.5 mg/mL) preparations, drug distribution and stability after 28 days of storage at both temperatures were acceptable. In the carprofen-SFVC preparations, carprofen was distributed uniformly but drug concentrations > 90% of the original concentration were only retained for 21 days in 5 of 6 of the preparations. Because of bacterial growth in one of the room-temperature preparations, refrigeration is recommended if carprofen is prepared in MCG or the SFVC. Use of MCG and SS in a 1:1 mixture is not recommended for the extemporaneous preparation of either commercially available carprofen caplets or the oral formulation of meloxicam.
ABBREVIATIONS
| NSAID | Nonsteroidal anti-inflammatory drug |
| COX | Cyclooxygenase DW Deionized water |
| MCG | Methylcellulose gel (1%) |
| SS | Simple syrup (commercial preparation) |
| SFVC | Suspending and flavoring vehicle combination (1:1 mixture) |
| HPLC | High-performance liquid chromatography |
Metacam, 1.5 mg/mL, Boehringer Ingelheim Vetmedica, Merial Ltd, Duluth, Ga.
Mobic, 7.5- and 15-mg tablets, Boehringer Ingelheim, Ridgefield, Conn.
Rimadyl, 25-, 75-, and 100-mg caplets, Pfizer Animal Health, Exton, Pa.
Methylcellulose, 1% gel, Gallipot Inc, Saint Paul, Minn.
Simple syrup, Gallipot Inc, Saint Paul, Minn.
Ora-Plus, Paddock Laboratories Inc, Minneapolis, Minn.
Ora-Sweet, Paddock Laboratories Inc, Minneapolis, Minn.
Transferpettor, BrandTech Scientific Inc, Essex, Conn.
pH meter 340, Corning Inc, Corning, NY.
Waters 501 and 510 pumps, 712 autosampler, and 484 detector, Waters Corp, Milford, Mass.
Zorbax RX-C18, Agilent, Palo Alto, Calif.
Pfizer Animal Health Inc, Groton, Conn.
Sigma-Aldrich, St Louis, Mo.
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