J. Anim Sci. 2006. 84:1850-1859. doi:10.2527/jas.2005-361
© 2006 American Society of Animal Science
Use of rotary fluidized-bed technology for development of sustained-release plant extracts pellets: Potential application for feed additive delivery1
J.-P. Meunier2,
J.-M. Cardot,
P. Gauthier,
E. Beyssac and
M. Alric
Equipe de Recherche Technologique Conception, Ingénierie et Développement de l’Aliment et du Médicament, Centre de Recherche en Nutrition Humaine, Faculté de Pharmacie, Université d’Auvergne, 28 place H. Dunant, 63001 Clermont-Ferrand, France
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Abstract
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The aim of this study was to develop sustained release plant extracts as a potential alternative to antibiotic growth promoters for growing pigs. Pellets with a core based on microcrystalline cellulose and 3 active compounds (eugenol, carvacrol, and thymol) were prepared using rotary fluidized-bed technology. Two particle sizes were produced that had a mean size of approximately 250 and 500 µm. Results show the process was able to produce pellets with a spherical and homogenous form when 10% of the active compounds were incorporated into the core. When active compounds were increased to 20%, the pellet became stickier, and the yield decreased from 90 to 65%. Different amounts of coating in the form of an aqueous-based ethylcellulose (EC) dispersion (Surelease) were applied to the core to modify the release of active compounds. The efficacy of the coating was evaluated in vitro using a flow-through cell apparatus. The time to achieve 50 and 90% dissolution increased with the increase in particle size (P < 0.05) and the increase in EC-coating level from 10 to 20% (wt/wt; P < 0.05), indicating the ability of the process to slow release depending on particle size and the amount of polymer applied. Differences in the release of the active compounds were observed in the same formulation of pellets, except for the formulation with small 10%-EC-coated particles, in which the active compounds were rapidly dissolved (more than 85% in 15 min or less). For all other formulations, the dissolution time for eugenol was always faster than for thymol or carvacrol. The close monitoring of plant extract behavior in the gastrointestinal tract could become a key factor in the continued use of phyto-molecules as alternatives to antibiotic growth promoters and in optimizing the balance between cost and efficacy. Different microencapsulation technologies can be used, of which the rotary fluidized bed warrants consideration because of the quality of the products obtained.
Key Words: feed additive • growing pig • in vitro dissolution • pellet • plant extract • rotary fluidized bed
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INTRODUCTION
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The safety of antibiotic growth promoters (AGP) in animal nutrition is currently under debate. The new European Union Feed Additive Regulation 1831/2003 restricts their use. This situation may be favorable to the introduction of new, seemingly safer feed additives such as phytogenic compounds. Plants contain various compounds that could be used as natural additives to improve feed intake in livestock. This includes essential oils, which are known to have antibacterial activity (Hammer et al., 1999
), and thus could be used to control the digestive ecosystem to obtain better indices of performance. Studies on the bioavailability and pharmacokinetics of various volatile terpenes, major compounds involved in the antimicrobial activity of essential oils, show that they are rapidly absorbed and metabolized (Kohlert et al., 2000). Rapid absorption limits the luminal availability of these compounds for antimicrobial activity and could explain why indifferent results have been obtained. Their effect on the microflora could be improved by the use of microencapsulation technology, which would allow a sustained release along the gastrointestinal tract and thereby increase luminal availability in the ileum and colon. Various encapsulation technologies are now emerging like the rotary fluidized-bed technologies, which can perform pelletization and coating in a single machine. The first aim of this study was to investigate the feasibility of formulating modified-release pellets containing a mixture of monoterpenoid molecules derived from essential oils prepared by rotary fluidized-bed technology. In the standard biopharmaceutical development process, the quality and efficacy of formulations are first tested in vitro (according to the USP standard) before their evaluation in vivo in costly live animal experiments. In feed, this in vitro dissolution assessment is not usually performed. The second aim, therefore, of this study was to develop suitable discriminating in vitro tests.
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MATERIALS AND METHODS
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Materials
Microcrystalline cellulose (MCC, Emcocel 50M, Penwest Pharmaceuticals Co., Danbury, CT), and polyvinylpyrrolidone (PVP, Kollidon 30 BASF Aktiengesellschaft, Ludwigshafen, Germany) were used as excipients, and carvacrol (2-Methyl-5-iso-Propylphenol), eugenol (4-Allyl-2-Methoxyphenol), and thymol (1-Methyl-3-hydroxy-4-(1-Methyl-3-hydroxy-4-Ixopropylbenzene) as active compounds (Ernesto Ventos S.A, Barcelona, Spain) in the preparation of pellets. An aqueous dispersion of ethylcellulose (EC, Surelease, Colorcon Ltd, Dartford, UK) was used as the coating.
Preparation of Pellets
Batches of around 1,000 g of pellets containing 10 or 20% of the active compounds were prepared by a Glatt GPCG1 rotary granulator (Glatt GmbH, Binzen, Germany) with a nozzle aperture of 1.2 mm. After preliminary trials, the main functional parameters were determined as follows: atomizer air pressure entrance (4 bars), product temperature (25°C during pulverization and drying until the exhaust air reached a temperature of 45°C), and disc rotation rate (720 rpm during pulverization and 180 rpm during drying). These parameters were kept constant for each batch. The granulation liquids used were a mixture of pure carvacrol, eugenol, and thymol (1:1:1, wt/wt/wt; spraying rate of 15 g/min) and water (spraying rate of 40 g/min). In general, the particle size was affected by the amount of water. Two sizes were produced by the addition of 1,400 and 1,600 mL of water to achieve mean sizes of approximately 250 and 500 µm.
Coating of Pellets
To study the influence of particle size on coating, the batches were mixed and sieved, and distinct subbatches measuring 90 to 355 µm and 355 to 800 µm were selected. The same equipment was used to coat the pellets with a dispersion of the EC polymer coating under the following conditions: 800 g of pellets, product temperature of 35°C during pulverization, final product drying until the exhaust air reached 45°C, disc rotation rate of 180 rpm, and spraying rate of 15 g/min. The formulation of polymer dispersions used in the coating process was that suggested by the manufacturer (64% of Surelease and 36% of water). The final coating weight represented 20% of the pellet weight. A sample of pellets (50 g) was withdrawn when approximately 50% of the coating was applied (i.e., coating representing 10% of the final pellet weight).
Characterization of Pellets
Four physical tests were performed to evaluate the feasibility of the process. Pellet size was determined on 100 g of spheres, using sieves of 90, 125, 180, 250, 355, 500, 710, 800, 1,000, and 1,400 µm and a vibratory shaker for 10 min. The appearance of the pellets was assessed directly (surface) or after splitting the sphere into 2 parts (cross-section) by using stereomicroscopy (Nikon SMZ 1000, Nikon France, Champignysur-Marne, France).
Percentage of active compounds recovered in the core pellets was estimated by using gas chromatography (GC) with a flame ionization detector. One gram of pellets was placed in 10 mL of acetone. The solution was stirred for 30 min (80 rpm, using a TR-225, Infors AG, Bottmingen, Switzerland), centrifuged (5,000 x g) and then filtered (0.45 µm pore size) before analysis. The GC analysis used a Hewlett-Packard HP 6890 fitted with a capillary column (HP-5, 5% Phenyl Methyl Siloxane, 30 m x 0.32 mm i.d., 0.25 µm film thickness, Interchrom, Montluçon, France). The GC temperature was programmed at a rate of 5°C/min from 100 to 150°C and 20°C/min from 150 to 300°C. Detector and injector temperatures were set at 250°C and helium gas flow-rate at 3 mL/min.
The active compound dissolution rate was determined according to the US Pharmacopeia (USP, 2003) and European Pharmacopeia (2001) methods using a flow-through cell (12 mm) and approximately 1 g of pellets from each formulation. The use of surfactants in the media for conducting dissolution studies of poorly soluble compounds under sink conditions have been described elsewhere (Noory et al., 1999; Pharmeuropa, 2001). An aqueous solution of SDS has been suggested as being physiologically representative of human intestinal fluid (Dressman et al., 1998; Dressman and Reppas, 2000). However, phosphate buffer solutions classically used in dissolution studies are not suitable for simulating a pH of 3 in the presence of SDS because of precipitation problems.
On the basis of these findings and other studies describing the pH profile of the growing pig’s gastric and intestinal region (Braude et al., 1976; Manners, 1976; Kararli, 1995; Wenk, 2001) and pellet transit time (Davis et al., 2001; Snoeck et al., 2003), we tried an alternative medium to model the composition of the gastric and intestinal contents of growing pig after-meal intake by using an electrolyte solution: NaCl (5.0 g/L), KCl (0.6 g/L), CaCl2 (0.3 g/L), added to SDS (10.0g/L) at pH 3 between 0 to 120 min, pH 5 between 120 to 150 min, and pH 6.5 between 150 to 480 min. The pH was adjusted with a solution of 0.5 N HCl.
A flow-through cell apparatus with 12-mm cells (Sotax CE 6, Allschwil, Switzerland) was used in a closed system of 500 mL of media at a temperature of 39 ± 0.5°C (to mimic the growing pig’s digestive environment), with a flow rate of 20 ± 0.5 mL/min. One milliliter of sample was collected at 5, 10, 20, 30, 40, 60, 90, 120, 135, 150, 165, 180, 240, 300, 360, and 480 min and analyzed by HPLC to obtain dissolution profiles. The method used a Water’s 515 pump (Waters, Saint-Quentin, France), 460 Kontron autosampler injector (Kontron Instruments, Milan, Italy), Merck L-4250 UV-Vis detector (Waters), and Shimadzu C-R3A chromatopac integrator (Shimadzu, Champs-sur-Marnes, France). The column was a UP5HDO-25Qs (C18, 5 µm, 250 x 4,6 mm, Interchrom) and a mobile phase composed of water-acetonitril-acetic acid (55/44.5/0.5, vol/vol/vol) with a flow rate of 1 mL/min. The injection volume was fixed at 20 µL and the detection wavelength at 280 nm. All results reported are the means (±SD) of 6 dosage unit determinations.
The gastric environment has a greater surface tension than the intestine, and this may limit the dissolution of sparingly water-soluble active compounds. The use of surfactant (which creates low surface tension) in the medium to simulate the gastric compartment could be problematic. The use of SDS could artificially increase the release of active compounds from the galenic form by promoting their dissolution. The impact of SDS in the dissolution media to simulate the gastric compartment on kinetic release was evaluated in this study by the use of media without surfactant from 0 to 120 min. Two measurements were made at 60 and 120 min. The medium was removed at 60 min for sampling and replaced with fresh medium. Before samples were taken for HPLC analysis, 1% of SDS was added to create sink conditions and homogenous distribution of the active compounds in the media.
Comparison of Curves: Statistical Methods
Values are presented as means ± SE. Comparisons between formulations were performed using Student’s t-test. All statistical analyses were conducted using SAS (SAS Inst. Inc., Cary, NC).
A model-independent approach using a similarity factor was used to compare dissolution curves. This model was introduced by Moore and Flanner (1996) and also included in notes for guidelines of the Food and Drug Administration (FDA, Rockville, MD) and The European Medicines Agency (EMEA, London, UK). This model uses a difference factor (F1) and a similarity factor (F2). The difference factor F1 calculates the percent difference between the 2 curves at each time point and is a measurement of the relative error between the 2 curves. The similarity factor F2 is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent dissolution between the 2 curves:
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where Rt is the percentage of dissolved product for the reference at time point t, Tt is the percentage of dissolved product for the test, and n is the number of time points. Generally, F1 values up to 15 (0 to 15) and F2 values greater than 50 (50 to 100) ensure sameness or equivalence of the 2 curves. Mean dissolution values are used to estimate the similarity factor. To use mean data, the percentage CV should not be more than 20% at the earlier point and not more than 10% at other time points. Because F2 values are sensitive to the number of dissolution points, only 1 measurement should be considered after 85% dissolution of the product. As we were in the development phase of a new process, we used an F1/F2 test on 6 samples only as opposed to 12 samples with the standard method (with a potential consequence being an increase of the SD) and with an F1 value lower than 15 as a limit.
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RESULTS
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Preparation of Pellet by Rotogranulation
When a spraying rate of 1,600 mL of water was used with a 10% concentration of plant extract, the pellets produced had a spherical and relatively homogenous form. No agglomeration was observed. The amount of active compounds recovered in the pellet was around 90% of initial amount. An increase in plant extract concentration from 10 to 20% increased stickiness of the pellet, reduced yield from around 90 to 65% (Table 1), and produced irregular larger pellets. The stereo-microscopic appearance of uncoated pellets is presented in Figures 1a and 1b. On the basis of initial results, only formulations with 10% of active compounds were used in the study because the operative conditions were unable to satisfactorily incorporate 20% of active compounds. When a spraying rate of 1,400 mL vs. 1,600 mL of water was used, a smaller mean diameter was obtained. In both cases the pellet obtained (with 10% of active compounds) had a homogeneous and narrow size distribution (Figures 2a and 2b) sufficient to consider a coating process. When a spraying rate of 1,600 mL of water was used, 90% of particles were between 800 and 250 µm. These values were between 500 and 180 µm when a rate of only 1,400 mL was used. The size distribution is narrower when the particle size is smaller. No difference (P > 0.05) was found in the percentage of active compounds recovered between batches with large particle size and those with small particle size with around 90% in both cases (Table 1). These results prove the feasibility of the process.
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Figure 2. Granulometry from batches of pellets containing 10% of active compounds. Error bars represent SD (n = 5). (a) 1,400 mL of water added, n = 5 means ± SD; (b) 1,600 mL of water added, n = 5, means ± SD.
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Before coating, all batches produced with 10% active compounds were mixed, and 2 size ranges of pellets, 90 to 355 µm and 355 to 800 µm, were selected. We measured the homogeneity of these 2 subbatches and observed a clear difference in particle size without particle size crossing with 80% of particles between 180 to 355 µm for the first subbatch and 355 to 710 µm for the second one.
Coating Process
Pellets obtained by direct pelletization had the characteristics required for the subsequent coating process performed by EC dispersion (Surelease). The coating appeared to be continuous and smooth, and the large pellets showed no tendency to aggregate, unlike the batch of small pellets, which tended to form double or triple units at 20% coating. On stereomicroscopy in cross-sectional view, the film applied on the large size pellets was smooth, continuous, and uniform in thickness (Figure 3), indicating an adequate balance between spray-drying and fluidizing operating conditions. Active loss of compounds appeared similar between the 2 batches (large and small size) in the different steps of the process with around 20% of active compounds lost after 20% of coating (Table 2). The core obtained during pelletization was of sufficient quality to allow good surface coating. During coating, around 20% active compounds were lost compared with about 10% before coating.
Encapsulation Efficiency of Coated Pellet
Because the pellets in the current study were a matrix core, the release of active compounds may depend on how long they diffuse within the matrix and hence on particle size. The kinetics of release from small and large uncoated particles will thus serve as a reference for assessment of the efficiency of the coating process. If the coating of small or large particles does not slow active compound release, the coating will be rejected as inefficient. Figures 4a and 4b show dissolution profiles of small and large uncoated pellets. The results indicate an increase in release kinetics with an increase in particle size (F1 > 15 and F2 < 50). For small pellets, 50% dissolution (T50%) values were around 4 min for eugenol and 5 min for carvacrol and thymol. More than 90% of active compounds (T90%) were released at 15 min for eugenol and 18 min for carvacrol and thymol. For large particles, T50% values were around 11 min for eugenol and 18 min for carvacrol and thymol, whereas T90% were released at 60 min for eugenol and 90 min for carvacrol and thymol (Table 3).
The active compound release curves of pellets of both size and the 2 levels of coating are given in Figures 5 and 6. The dissolution T50% and T90% values increased with an increase in coating level from 10 to 20% (wt/ wt; P < 0.05) indicating the ability of the coating process to slow the release in vitro according to the amount of polymer applied (Table 3
). Ten percent of coating on small particles was not enough to establish slow release; the kinetics of release of active compounds was as fast as that obtained with uncoated particle (P > 0.05). In contrast at 20% of coating, the kinetics of release was slower than that 10% of coating particles (T50% respectively of 15 to 35 min and 3 to 4 min depending on the active compounds), showing the efficiency of the coating at this concentration (P < 0.05). The coating of large particles is efficient (P < 0.05) from 10% (T50% from 24 to 35 min), and at 20% the delaying effect is increased (T50% from 31 to 60 min). In all cases, for a same coating level, the release of active compounds was faster from small particles size than from large particles size (P < 0.05).
Active Compound Release According to Physico-Chemical Structure
Differences in active compound release profiles were observed in pellets of the same formulation. Except for the formulation with small 10% EC-coated pellets whose active compounds were rapidly dissolved (more than 85% in 15 min or less), the F1/F2 test was used to compare the dissolution profile of each molecule. For all formulations, the dissolution curves for thymol and carvacrol were similar, whereas the eugenol curves differed (Figures 4, 5, and 6). These results could be explained by the physicochemical structure of thymol and carvacrol molecules, which have an alcohol function (-OH) able to easily create hydrogen bonds with the cellulosic matrix (microcrystalline cellulose). In addition, the OH function of eugenol molecules interacts preferentially with the undivided electronic doublet of the oxygen ether function in ortho position. There could be, in that case, fewer bonds available with cellulose and thus less eugenol retained in the pellets.
The experimental conditions for flow-through cells in this study made it possible to determine the kinetics of release according to the composition of the pellets (size, % of coating) and the chemical structure of the active compounds used.
Active Compound Release According to the Dissolution Media Used
Active compound release profiles from pellets coated at 20% differed according to the dissolution media used (with or without SDS) to simulate the gastric environment (Figures 7a and 7b). Dissolution T50% values (Table 4) increased when SDS was eliminated from the media between 0 to 120 min (P < 0.001). For small 20% EC-coated particles, T50% values increased from 15 to 35 to 38 to 80 min depending on the active compounds. For large 20% EC-coated particles, these values increased from 31 to 60 min to 50 to 110 min. In the conditions of this study, it was not possible to determine whether this difference was due to the fact that the active compounds were not solubilized (sink condition not fulfilled) or to the lower wetting power of the medium in the absence of SDS. Too high a percentage of surfactant can thus underestimate the time of active compound release in the gastric compartment.
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DISCUSSION
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The possible development of bacterial resistance due to the use of AGP for growth promotion has resulted in the ban of AGP in animal nutrition in the European Union. Although this decision can be seen as a precautionary measure in the interest of human health, the ban of AGP could lead to a deterioration of animal health, with increased diarrhea, weight loss, and mortality. Colibacillosis during weaning and the early fattening period could be the most difficult to control, but there is also the risk of infections due to Lawsonia anaerobic bacteria and the spirochete colitis. The antimicrobial properties of certain plant extracts and more specifically of different essential oils have been reported in numerous in vitro studies (Cowan, 1999; Dorman and Deans, 2000; Lambert et al., 2001), and selective antimicrobial effects have also been observed depending on the extract used and the dose incorporated in the feed. The action of these molecules may be the result of damage to the bacterial lipoprotein cell wall structure, which leads to leakage of cytoplasmic contents (Burt and Reinders, 2003; Walsh et al., 2003). Results of in vitro studies show that some active ingredients could have an effect at dose levels generally used in feed. Some studies have shown their potential benefit as additives in livestock feeds (Kamel, 2001; Manzanilla et al., 2004). However, the results documented are not yet comparable to those obtained with AGP. This can be explained by the bioavailability and pharmacokinetics of essential oils, such as thymol, carvacrol, citral, eugenol, menthol, and t-anethol, which are rapidly absorbed and metabolized, with the metabolites being eliminated by the kidneys in the form of glucuronides or exhaled as CO2 (Kohlert et al., 2000). An effective activity of these phyto-molecules involves a narrow control of their behavior in the digestive tract to make sure of their availability in sufficient amounts at the optimal site of action while also limiting their absorption. In the case of action on the intestinal microbial flora, these active compounds should be in direct contact with the digestive flora (Hammer et al., 1999), which are often at remote sites inside the digestive tract.
The manufacturing of controlled-release microencapsulated plant extracts is highly complex and is governed by 4 main factors: a) the active compound, b) the core properties, c) the coating process and equipment, and d) the coating material and formulation. If the core and the coating are the release controlling parameters, it is essential to use specific techniques of microencapsulation like the rotary fluidized bed to create an adequate core and a uniform application of the polymer coating. Different coating polymers are available to increase the period over which active compounds are protected against the absorption or degradation in the tract, one of the most common being ethyl cellulose. The main advantages of the use of multiparticle form (pellets) as against a unique form (tablet) in feed is a good predictable gastric emptying time (the evacuation though the pylorus is gradual as the pellets are sufficiently small to be evacuated during the digestive phase) and a well dispersed passage through the small intestine, so as to achieve gradual sustained delivery and thereby minimize the risk of local irritation (Davis et al., 2001). Pellets have the additional advantage of being easily and homogeneously mixed with feed, which facilitates administration.
The results obtained in this study show it is possible to incorporate 10% of hydrophobic molecules derived from essential oils (eugenol, carvacrol, and thymol) into a matrix of microcrystalline cellulose by wet granulation with a percentage of active compounds recovered around 90 and 80% after pelletization and coating granulation, respectively. Because eugenol, carvacrol, and thymol are volatiles, a decrease in temperature during pelleting and coating is likely to produce a corresponding increase in the yield of active compounds recovered. One of the main factors affecting pellet coating is particle size. The technology used in this study made it possible to control particle size during production by adapting the quantity of water sprayed during granulation. The conditions in which granulation was performed limited the quantity of active compounds able to be incorporated into the core to 10%. For an incorporation of more than 10%, technical problems were encountered and the quality of the core decreased drastically. To evaluate the development of formulations and to select the most appropriate, specific in vitro methods can be used. The pharmaceutical industry has developed dissolution methods over the last 30 yr, and different dissolution apparatuses exist to study all galenic forms. Of these, the flow-through cell seems to be best adapted to the study of pellet forms (Beyssac and Lavigne, 2005; Fotaki and Reppas, 2005), and it was this method we used to assess coating efficacy. The amount of coating required to apply a layer 10-µm thick (the minimum effective thickness) on particles with a diameter of 250 µm is 16.7% (wt/wt); for 500 µm this amount decreases to 8.75% (Jones 1988). The results obtained in this study confirm these data. As expected the dissolution profiles indicated that an increase in particle size slowed down active compound release. Nonsustained release was observed with small particle size 90 to 355 µm with 10% of coating, but at 20% of coating sustained release was obtained. With large particle size 355 to 800 µm, sustained release was observed up to 10% of coating. This effect was greater up to a level of 20% coating. The dissolution method used in this study was able to discriminate between the different formulations and to select the best one before in vivo trials. However, it is difficult to evaluate the predictive value of these results for in vivo extrapolation. The experimental conditions of this study may have been sub- or over-discriminative. Imposing high surfactant concentration (superior to that found in vivo) during the in vitro dissolution method to model sink conditions can lead to an increase in active compound release by direct action on the excipients used. Media without surfactant were also formulated in this study during the first 2 h of the dissolution test to simulate the gastric environment more realistically and to examine the influence of SDS on the formulation. An important characteristic of gastric fluid is that its surface tension value is close to that of water (Finholt and Solvang, 1968; Fimmel and Blum, 1983; Efentakis and Dressman, 1998), which may limit the dissolution of sparingly water-soluble active compounds. Our results showed that the elimination of SDS during the first 2 h decreased the kinetics of dissolution of the active compounds in the media used. Thus, it is essential to use a realistic amount of SDS in the dissolution test procedure to improve the predictability of the method used. Other factors relevant to dissolution, such as enzymatic secretion and buffer capacity, should be considered and will require further work or other in vitro systems. Flow-through cells are ill suited for experiments with solid feed and so limit the prediction of the release of active compounds ingested with feed. Further studies should be undertaken to determine the possible interference between additives and feed.
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IMPLICATIONS
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The potential contribution of the biopharmaceutical properties of feed additives, and in particular of plant extracts, on the zootechnical efficacy and safety is an important parameter that must be investigated. Of particular interest is the question of luminal availability in the assessment of the potential activity of active compounds after administration. The technique of in vitro dissolution, and in particular flow-through cells, can be used to select the most promising galenic form and evaluate the possible behavior of pellets in the digestive environment of livestock (e.g., the growing pig). A better understanding of the biopharmaceutical mechanism may also help in designing rational dosage regimens and improving their efficacy. This point will become a key factor in the future use of phyto-molecules as alternatives to antibiotics as growth promoters.
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Footnotes
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1 The authors are grateful to AXISS S.A.S. France for providing financial support for these investigations. 
2 Corresponding author: j-philippe.meunier{at}u-clermont1.fr
Received for publication July 7, 2005.
Accepted for publication February 6, 2006.
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J.-P. Meunier, J.-M. Cardot, E. G. Manzanilla, M. Wysshaar, and M. Alric
Use of spray-cooling technology for development of microencapsulated capsicum oleoresin for the growing pig as an alternative to in-feed antibiotics: A study of release using in vitro models
J Anim Sci,
October 1, 2007;
85(10):
2699 - 2710.
[Abstract]
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Abstract
INTRODUCTION
), carvacrol (
), thymol (
). a,bWithin a time, means with different superscript letters are different (P < 0.05). For particle size between 90 to 350 µm and 355 to 800 µm, the difference factor (F1)/similarity factor (F2) test identified a similarity between the dissolution profiles of carvacrol and thymol, whereas the eugenol curve differed. The F1/F2 test indicated significant difference for each active compound’s (eugenol, carvacrol and thymol) dissolution profile between 90 to 350 µm and 355 to 800 µm particle size.
