Sustained-Release Injectable Hydrogel Formulations for Administration of Sodium Salicylate in Broiler Chickens.
Key words: hydrogel. sodium salicylate, sustained release, pharmacokinetic, avian, broiler chickens
Birds eliminate drugs much faster than mammals. (1) There are numerous reports on higher clearance of drugs in birds, (2-4) which could be a result of their higher metabolic rates. In broiler chickens, the half-life of salicylic acid at a dose of 50 mg/kg after intravenous (IV) administration is 3.35 to 4 hours (2,5) and 3.95 after oral administration. (5) The plasma concentration of sodium salicylate (NaSA) at 50 mg/kg after IV and oral administration reaches more than 50 [micro]g/mL, (2,5) which has been reported as the effective concentration required for antipyretic and analgesic effects in humans. (2) However, in an intra-articular sodium urate crystals model of nociception in domestic fowl, no analgesic effect was found after oral administration of NaSA at 100 mg/kg, whereas intramuscular (IM) injection at 500 mg/ kg provided analgesia for 1 hour only. (6) Other studies on the analgesic effects of carprofen in lame broiler chickens and butorphanol in lame turkeys reported similar problems of short duration of analgesia and a need for a higher dose or repeated administration to prolong the efficacy of the analgesic. (7-9) This repeated administration can be challenging in clinical cases, and repeated handling of birds can cause considerable stress. Corticosterone levels have been documented to increase after repeated handling in chickens, Japanese quail (Coturnix japonica), great tits (Parus major), and Adelie penguins (Pygoscelis adeliae). (10,11) Other physiologic changes associated with stress, such as increased breathing rate, high body temperature, and increased heart rates due to repeated handling, also are noted in birds. (12) Also, risks of injuring birds that are not used to handling are higher because of their natural instinct to escape. Therefore, there is a need to develop a sustained-released drug delivery system for birds, which will benefit the patient and veterinarian.
Hydrogels are hydrophilic, 3-dimensional, polymeric networks that are held together through physical bonds or chemically crosslinked through covalent bonds. Hydrogels have a highly porous structure, which gives them the unique ability to absorb large amounts of water or biological fluids and swell without the loss of structure or dissolution. (13) Hydrogels have the capability to be loaded with different drugs depending on the desired application and potentially can release these drugs in a sustained manner, depending on the diffusion coefficient of the drugs through the hydrogel network. These abilities arise from the porosity of hydrogels, which can be controlled easily by either altering the size or connectivity of the pores in the hydrogel or using physical and chemical strategies to slow release of the drug entrapped by the hydrogels. (14) Depending on the type of polymer and crosslinking agent used in their construction, many hydrogels exhibit low toxicity and are highly biodegradable. This makes them ideal for biological applications. (13) They are widely used as pharmaceutical excipients and in food. For example, a popular natural polysaccharide polymer used in hydrogel production is sodium alginate, which can be extracted and isolated from marine brown algae. It exhibits low toxicity and is biodegradable in biological environments. (15)
Yadav and Shivakumar (16) prepared a carboxymethyl chitosan, pH-sensitive hydrogel for the sustained release of theophylline under basic conditions. In vitro, the hydrogel showed sustained release of theophylline for up to 12.5 hours, with a maximum release of 90%. In vivo after oral administration, the hydrogels had a sustained release of the drug for up to 25 hours compared to 12.5 hours in vitro, with the maximum theophylline concentration released being 30 jug/ mL.
We compared the pharmacokinetics of NaSA formulated using 2 different sodium alginate hydrogel complexes to that of an aqueous solution of NaSA after SC administration in broiler chickens. These pharmacokinetic parameters from broiler chickens then could be extrapolated to rare and endangered avian species with less error compared to extrapolation from mammalian studies. (17)
Methods and Materials
Drugs and reagents
Reagents used in the study were low viscosity sodium alginate 99.5% from brown algae, Reagent-Plus 99.5% NaSA, calcium chloride, orthophosphoric acid, acetic acid, and acetonitrile (Sigma Chemical Co, St Louis, MO, USA). All reagents used for high performance liquid chromatography (HPLC) analysis were analytical grade. The mobile phase was prepared with purified water (Milli-Q PFplus system, Millipore Corporation, Billerica, MA, USA).
All in vitro drug assays were conducted on a Shimadzu UV-1800 240V IVDD UV spectrophotometer (Shimadzu Corp, Kyoto, Japan) and all results were recorded and analyzed using the UVProbe 2.5 computer program (Shimadzu). The absorbance of the complexed NaSA was measured at a wavelength of 530 nm. The spectrometer was set to spectrum mode to assess corresponding peaks, and the spectrometer was calibrated with the solvent to minimize background spectra produced by the solvents.
Preparation of hydrogel films
The low alginate gel (LALG) was prepared by dissolving 1 g alginate and 9 g NaSA in 60 mL water over 2 hours. Then, 0.3 g calcium chloride (CaCl2) was added in 5 mL sterile water and the solution allowed to congeal overnight with stirring. The high alginate gel (HALG) was prepared by dissolving 3 g alginate and 12 g NaSA in 80 mL sterile water over 2 hours. Then, 1 g Ca[Cl.sub.2] in 5 mL sterile water was added and the solution allowed to congeal overnight with stirring. Both hydrogels were freeze dried. The dried hydrogels were reconstituted in 60 mL (LALG) and 80 mL (HALG) sterile water. The final [Ca.sup.2+] concentrations were 0.50% for LALG and 1.25% for HALG. The final concentration of NaSA in both hydrogels was 150 mg/mL. The reconstituted solution was filtered through a 0.2-[micro]m syringe (Phenomenex, North Shore City, New Zealand) filter immediately before injection.
In vitro release studies
The in vitro release of the entrapped model drug was assessed by placing the dried hydrogel film in water (60 mL; LALG and 80 raL; HALG) maintained at 40[degrees]C (to simulate core body temperature of a broiler chicken) with gentle stirring. Under these conditions the hydrogel did not dissolve, but absorbed water and released the drug. At 0, 0.5, 1, 2, 4, and 24 hours, 1 mL solution was withdrawn and replaced with 1 mL blank medium. The withdrawn drug solution was diluted 250-fold with purified water. Then, 1 mL diluted solution was mixed with 4 mL ferric chloride solution (5% wt/vol) and measured with ultraviolet-visible (UV-Vis) spectroscopy at maximum wavelength ([[lambda].sub.max]) of 230 nm. The UV-Vis spectroscope measures the resultant colored complex formed between salicylate ions and ferric ions.
All in vitro experiments were measured over a 24-hour period. Results are expressed as the drug concentration percentage released from the hydrogel compared to the total percentage of drug present in the experiment. The following equation was used to determine the percentage of drug released over the time period:
% Drug release = [C.sub.d]/[C.sub.md] x 100%
where [C.sub.d] is the combined concentration of drug released into the medium at each time interval and [C.sub.md] is the maximum concentration of drug that could be released by the hydrogel.
Pharmacokinetic study in broiler chickens
Study design: This study was approved by Massey University Animal Ethics Committee. This study was conducted in 18 healthy, 40-day old Ross broiler chickens with an average weight of 3.9 [+ or -] 0.47 kg. These chickens were divided into 3 separate groups, each comprising 6 chickens. Each chicken was restrained manually for catheterization of the medial metatarsal vein with a 22-gauge catheter. The catheters were firmly fixed by wrapping the catheterized leg with cohesive bandages. The patency of the catheter was maintained by filling the catheter with 0.5 mL 10% heparin saline solution after each sample. All chickens were kept in the 3 groups under standard conditions and all were fed ad lib with commercially available feed and a 24-hour supply of fresh drinking water. One of the 3 groups of chickens (control group) received subcutaneous (SC) injection of an aqueous NaSA solution. The other 2 groups (denoted as LALG and HALG) received the appropriate NaSA hydrogel formulation.
Drug administration: The SC injections were done on midline in the caudodorsal region of the neck using a 25-gauge needle. The NaSA for injection in the control group was made by dissolving 150 mg NaSA in 1 mL sterile water. The solution for injection was filtered through 0.2-[micro]m syringe filters and immediately administered at the dose of 150 mg/kg. The 2 NaSA formulations in hydrogels also were administered SC in a similar way as the aqueous solution.
Sample collection: Serial blood samples of 2 mL were collected in heparinized vials at 0, 0.25, 0.5, 1, 4, 8, 16, and 24 hours from chickens in the control group and at 0, 0.25, 1, 4, 8, 16, 24, 48, 72, 96, and 120 hours from chickens in the LALG and HALG groups. The blood samples were immediately centrifuged at 2400 g for 10 minutes. The plasma was collected in 1.5-mL microcentrifuge tubes and flash frozen on dry ice. Finally, the plasma samples were stored at -70[degrees]C until analysis.
Sample preparation for HPLC analysis: For analysis, 300 [micro]L plasma was diluted with 300 [micro]L water. Then, 300 [micro]L diluted plasma was added to 700 [micro]L 10% acetic acid in acetonitrile and vortex mixed for 2 minutes. The samples were centrifuged at 5000g for 15 minutes, and the supernatant was separated and dried under a gentle stream of compressed air at 20[degrees]C. The dried samples were rehydrated with 200 [micro]L mobile phase and centrifuged at 5000 g for 10 minutes. Then, 50 [micro]L supernatant was injected into the HPLC system.
Chromatographic analysis: The plasma samples were analyzed using the Thermo Scientific Dionex Ultimate 3000 HPLC equipped with a photodiode array detector (Thermo Fisher Scientific, Waltham, MA, USA). The system consisted of SRD3400 solvent rack, HPG-3400A pumps, WPS3000TSI auto-injector, TCC-3000 column compartment, and PDA-3000 photodiode array detector. Separation of NaSA was achieved using a Phenomenex C18A (150 * 4.6 mm i.d., 5-[micro]m particle size) column at 40[degrees]C. The mobile phase consisted of water : acetonitrile : orthophosphoric acid (71:28:1) with a flow rate of 1 mL/min under isocratic conditions. (18,19) The wavelength of the detector was set at 230 nm. NaSA peaks eluted at approximately 8.5 minutes and were analyzed by using Chromeleon 7.2 software (Thermo Fisher Scientific). The standard curve was prepared by using Chromeleon and the unknown NaSA concentration was calculated by linear regression using the Chromeleon software. The lower limit of quantification and the lower limit of detection for this method was 100 and 50 ng/mL, respectively. This method was linear from 50 to 500 [micro]g/mL with a correlation coefficient of 0.9970. The average recovery of NaSA in spiked plasma was 99.89 [+ or -] 2.54%. The intra- and interday variations ranged from 0.92% to 1.39% and 0.23% to 1.78%, respectively.
Pharmacokinetic analysis: Pharmacokinetic parameters were determined by a compartmental approach from the individual plasma concentration data using PKSolver 'add-on' for Excel 2010. (20) The method of residuals and Akaike's information criteria were used to determine the goodness of fit in the above model. The rate constants of the absorption ([K.sub.a]) and terminal ([K.sub.10]) phases were calculated by linear regression of the logarithmic plasma concentration. Half-lives of the absorption ([T.sub.[1/2][alpha]]) and terminal ([T.sub.[1/2][beta]]) phases were calculated as [In.sub.2]/[K.sub.[alpha]] and [In.sub.2]/[K.sub.10], respectively. Additionally, a noncompartmental approach was applied to calculate the area under the curve (AUC) and the area under the first moment (AUMC) using the linear trapezoidal method. Mean residence time (MRT) was calculated as AUMC/AUC.
The data are presented as mean [+ or -] standard deviation (SD). The pharmacokinetic parameters from three different groups were compared by the Kruskal-Wallis test using Prism 6 for Macintosh (GraphPad Software, La Jolla, CA, USA). Significance was set at P < .05.
In vitro drug release
Both hydrogels released the drug in a sustained manner (Fig 1). In both cases, 80% of drug release was achieved up to 3.5 hours, with the release leveling out to minimal release past this time.
The plasma concentration data fitted a single compartment model. The mean pharmacokinetic parameters for NaSA after SC administration of all three formulations are given in Table 1. Figure 2 represents the semi-log plot of the mean concentration time curve of broiler chickens administered with NaSA in aqueous solution (control) and LALG and HALG gel formulations. No significant difference was found between the [C.sub.max] (P = .82) of the three formulations. A significantly longer time was needed for chickens in the HALG group to achieve the [C.sub.max] ([T.sub.max]) (6.61 [+ or -] 2.54 hours) compared to the LALG (3.34 [+ or -] 1.69) and control groups (2.43 [+ or -] 0.66 hours; P < .05). Absorption half-life increased significantly after administration of NaSA using the HALG formulation (3.33 [+ or -] 1.41 hours) as compared to the LALG (1.10 [+ or -] 1.19 hours) or the aqueous (0.76 [+ or -] 0.37 hours) solutions. The [AUC.sub.(0-t)] was significantly higher in LALG group (2803 [+ or -] 823) compared to the HALG (2372 [+ or -] 893) and aqueous formulation (1350 [+ or -] 533) groups (P < .05). A similar trend was observed with [AUC.sub.(0-[infinity])]. The time above minimum effective concentration (MEC; 50 Mg/mL in humans) was significantly higher in LALG (24 [+ or -] 8.9 hours) and HALG (26 [+ or -] 4.0 hours) groups compared to the aqueous formulation control group (10 [+ or -] 5.6 hours) (P < .01). No significant difference was found in duration above MEC between the LALG and HALG groups. No gross inflammatory signs at the injection site were seen in any bird.
The objective of this study was to formulate an injectable hydrogel for sustained delivery of NaSA in broiler chickens. To our knowledge, this is the first in vivo report of hydrogels as a sustained-release delivery method for salicylic acid in birds. Significant differences were found in the pharmacokinetics of NaSA injected SC using different formulations. The gel containing a higher concentration of sodium alginate and [Ca.sup.2+] (HALG) was able to maintain the MEC (50 [micro]g/mL) for NaSA for 26 [+ or -] 4.0 hours compared to 24 [+ or -] 8.9 hours for the gel with lower alginate and [Ca.sup.2+] concentration (LALG) and 10 [+ or -] 5.6 hours in the control group. Absorption half-life was significantly longer with HALG compared to the LALG and aqueous formulations, which shows slower release of NaSA from the HALG hydrogel formulation. Cross-linking is higher with HALG compared to LALG; the overall effect of increased crosslinking is to produce smaller pores within the hydrogel, which in turn results in reduced swelling of the hydrogel. Hence, reduced pore size and reduced swelling capability increases the time for drug release. This is of considerable importance in the case of NaSA, a small molecule, regardless of other factors in vitro (aqueous buffers) or in vivo (biological fluids). (14) No significant difference was found in other pharmacokinetic parameters, which could be a result of a higher variation within each group due to a smaller group size (n = 6).
The results of the in vitro study could not be used to simulate in vivo release in a membrane-less model. In a membrane-less model, the hydrogel loaded with drug is placed in water. It can be used only for the gels, which do not readily dissolve in water. The in vitro drug release experiment was performed only once. Our objective was to select the best hydrogels for the animal model rather than a stand-alone study. Therefore, it was important to conduct a pharmacokinetic study in broiler chickens to estimate sustained release properties of the hydrogels used in this study.
Sterilization could be a challenge in preparation of injectable hydrogel formulations for animal use. All steps to formulate the hydrogels were followed under sterile conditions and using sterile materials. The final solution was filtered before the injection to eliminate any bacteria or fungi. Micro-filtration through a 0.2-[micro]m filter is a standard technique used routinely to sterilize drug solutions. (21) The physical properties of the hydrogel may have changed after the filtration step; however, in this study, we assumed that physical characteristics of the gel did not change when compared to control injections. The concentration time curve (Fig 2) in broiler chickens suggested that the hydrogel with a higher sodium alginate content released NaSA significantly more slowly than the control group. Thus, any change in physical properties due to filtration did not affect the release rates of the drug; without filtration, there may be an even slower release. In our study, no test was conducted to evaluate the effects of filtration on the physical properties and release rates of NaSA from the hydrogel formulation. Laniesse et al (22) also used microfiltration for sterilization of a P407-based butorphanol formulation for SC administration in Hispaniolan Amazon parrots (Amazona ventralis) and did not find any change in physical properties. The polymer used in the current study was different from that of Laniesse's study and, thus, may not provide an accurate basis for comparison with the hydrogels used in the current study.
Previous methods used for sustained release of analgesics in birds are osmotic pumps and lipid encapsulations. Osmotic pumps were used for sustained release of butorphanol over a week in the common peafowl (Pavo cristatus). (23) The limitations to the use of osmotic pumps include the need to implant the device into the bird, which requires the bird to be anesthetized for implantation and removal of the device. Added to the high cost of buying the pump itself, this method for sustained drug release is expensive. Two studies in psittacine species for sustained release used liposome encapsulation of butorphanol. (24,25)
Poloxamers have been used to produce longer acting butorphanol (26) and doxycycline gel formulations for birds. (27) Both formulations were successful in maintaining the minimum concentration required for effect. These polymers are synthetic nonionic block copolymers of polypropylene oxide and polyethylene oxide usually used as surfactants. The rheological properties of some poloxamers (P338, P407) depend on temperature. Poloxamer solutions are liquid at temperatures below 4[degrees]C to 5[degrees]C and above 70[degrees]C but form highly thixotropic gels over the temperature range 20[degrees]C to 50[degrees]C. The gelation is caused by physical entanglement and packing of the micellar structures that form on heating solutions. (28) This type of gel could be expected to have different drug release properties from the alginate gel used in this study.
Alginate is a natural polysaccharide. Alginates are salts of alginic acids extracted from the brown alga Laminaria japonica and form gels with a wide variety of viscosities, and their viscosity remains constant at temperatures of 20[degrees]C to 80[degrees]C. The advantages of these gels are absence of any need for heating for gel formation. A feature of alginate gels is the need to add calcium salts to manipulate their cross-linking and swelling.
No gross inflammatory signs were observed at the injection site in the chickens after injection of the hydrogels. The hydrogels formulated in this study have a water-like consistency and can be easily injected through a 25-gauge needle. NaSA is not used routinely for pain management in birds, although it has been studied extensively in other species. A longer acting formulation may change this. The hydrogel formulation used in this study also may slow the release of commonly used analgesic drugs in birds, such as butorphanol and meloxicam, and this requires further investigation. Although the hydrogels had no adverse effects in broiler chickens and none are reported, (13) this may not be true for other avian species. Therefore, further work is required to assess the safety profile of alginate hydrogels in avian species of interest.
Alginate-based hydrogels have potential to be used for sustained drug delivery in birds. The ingredients are inexpensive and easily available. These gels can be dried to increase their shelf life and then reconstituted before injection. The pharmacokinetic data for NaSA hydrogel in this study indicate that it may be able to provide a prolonged analgesia (up to 26 hours), but this must be tested in a pharmacodynamics study or pharmacokinetic-pharmacodynamic modeling of NaSA hydrogels in the target species.
Samuel J. Booty, MSc, David R. K. Harding, PhD, Catherine P. Whitby, PhD, Margaret Gater, BVSc, Paul Chambers, PhD, and Preet M. Singh, PhD
From the Institutes of Fundamental Sciences (Booty. Harding. Whitby); and Veterinary, Animal, and Biomedical Sciences (Gater, Chambers, Singh), Massey University. Palmerston North 11222. New Zealand.
Acknowledgments: Supported by Massey University Research Funds (MURF).
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Caption: Figure 1. In vitro drug release experiment for LALG (dotted line) and HALG (solid line) NaSA hydrogels. The hydrogels were swollen in water and then samples were taken after 0.5, 1, 2, 4, and 24 hours of swelling. The data represent a swelling study of only one gel, which was used in the in vitro experiment.
Caption: Figure 2. Semi-log plot of mean [+ or -] SD concentration ([micro]g/mL) of NaSA in chicken plasma after subcutaneous administration of control (NaSA dissolved in water) solution (gray line, n = 6), LALG (dotted black line, n = 6) and HALG (solid black line, n = 6) NaSA hydrogel. The horizontal black line represents minimum effective concentration for NaSA in mammals. The plasma concentration of NaSA remained above the MEC for 10 [+ or -] 5.6, 24 [+ or -] 8.9, and 26 [+ or -] 4.0 hours for the control, LALG, and HALG formulations, respectively.
Table 1. Pharmacokinetic parameters (mean [+ or -] SD) determined by using a compartmental model after SC administration of NaSA as either an aqueous solution or LALG or HALG concentrations of sodium alginate hydrogel formulations in broiler chickens. The dose for NaSA was 150 mg/kg in all chickens. (a) Pharmacokinetic NaSA aqueous (n = 6) parameter [k.sub.a] 1.21 [+ or -] 0.75 (A) [k.sub.10] 0.12 [+ or -] 0.07 [C.sub.max], [micro]g/mL 121.12 [+ or -] 42.11 [T.sub.max], hr 2.43 [+ or -] 0.66 (A) [T.sub.1/2[alpha], hr 0.76 [+ or -] 0.37 (A) [T.sub.1/2[beta], hr 7.30 [+ or -] 4.08 CL/F, mL/kg/hr 113.36 [+ or -] 49.55 [AUC.sub.0-t], [micro]g/mL * hr 1350 [+ or -] 533 (A) [AUC.sub.0-[infinity]], [micro]g/mL * hr 1589 [+ or -] 758 (A) MRT, hr 11.63 [+ or -] 5.14 Pharmacokinetic NaSA LALG (n = 6) parameter [k.sub.a] 1.60 [+ or -] 1.82 (A) [k.sub.10] 0.07 [+ or -] 0.06 [C.sub.max], [micro]g/mL 125.04 [+ or -] 11.89 [T.sub.max], hr 3.34 [+ or -] 1.69 (AB) [T.sub.1/2[alpha], hr 1.10 [+ or -] 1.19 (A) [T.sub.1/2[beta], hr 14.26 [+ or -] 7.60 CL/F, mL/kg/hr 55.68 [+ or -] 19.75 [AUC.sub.0-t], [micro]g/mL * hr 2803 [+ or -] 823 (B) [AUC.sub.0-[infinity]], [micro]g/mL * hr 2991 [+ or -] 1017 (B) MRT, hr 22.16 [+ or -] 10.07 Pharmacokinetic NaSA HALG (n = 6) parameter [k.sub.a] 0.26 [+ or -] 0.16 (B) [k.sub.10] 0.12 [+ or -] 0.08 [C.sub.max], [micro]g/mL 114.98 [+ or -] 20.81 [T.sub.max], hr 6.61 [+ or -] 2.54 (B) [T.sub.1/2[alpha], hr 3.33 [+ or -] 1.41 (B) [T.sub.1/2[beta], hr 8.72 [+ or -] 6.46 CL/F, mL/kg/hr 69.46 [+ or -]26.15 [AUC.sub.0-t], [micro]g/mL * hr 2372 [+ or -] 893 (A) [AUC.sub.0-[infinity]], [micro]g/mL * hr 2440 [+ or -] 974 (A) MRT, hr 17.39 [+ or -] 8.88 Abbreviations: [k.sub.a] absorption rate constant: [k.sub.10], elimination rate constant: [C.sub.max], maximum concentration. [T.sub.max], time to maximum concentration: CL/F, apparent total plasma clearance; [T.sub.1/2[beta], elimination half-life; [T.sub.1/2[alpha]], absorption half-life: [AUC.sub.0-t], area under the curve zero to last time point; [AUC.sub.0-[infinity]], area under the curve zero to infinity; MRT. mean resident time. (a) Means in the same column with different letters represent significant differences in those pharmacokinetic parameters between groups (P < .05).
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|Title Annotation:||Original Study|
|Author:||Booty, Samuel J.; Harding, David R.K.; Whitby, Catherine P.; Gater, Margaret; Chambers, Paul; Singh,|
|Publication:||Journal of Avian Medicine and Surgery|
|Date:||Dec 1, 2018|
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