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A hollow fiber membrane (HFM) was previously characterized as a potential permeation component of a dissolution/permeation system. Two objectives were to assess the impact of micellization on drug permeation across HFM and identify a preferred permeation model from three models: permeation from only free drug, permeation from both free drug and micelle-bound drug, and permeation with enhancement from micelle shuttling. HFM studies were conducted under unsaturated drug conditions, using griseofulvin and the more hydrophilic drug meloxicam, with and without surfactant [sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (10) lauryl ether]. Griseofulvin was micelle incorporated to a greater extent than meloxicam, such that griseofulvin flux decreased to a greater extent than for meloxicam. The griseofulvin permeation model from only free drug was rejected, since griseofulvin flux required free drug to be about 5-20 fold higher in HFM flux studies than supported by solubility studies, depending on surfactant. Permeation from both free griseofulvin and micelle-bound griseofulvin successfully accommodated observed flux, where micelle permeability was about 5-fold lower than free drug permeability for HFM with 10 KDa MWCO. Permeation with enhancement from micelle shuttling was not the preferred explanation, although the model accommodated flux data and provided aqueous boundary layer thicknesses similar to other setups., Competing Interests: Declaration of competing interest There are no conflicts of interest for these authors to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-β (Aβ) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer's disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events (AEs) were mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aβ peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aβ1-40 and Aβ1-42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development.

Background: The objective of this study was to develop a more bio-available and safe nanosuspension of meloxicam (MX), which could dramatically improve inflammation targeting., Methods and Results: MX-loaded bovine serum albumin (BSA) nanosuspensions were prepared using acid-base neutralization in aqueous solution and the prepared nanosuspensions were characterized. The results obtained showed that the prepared nanosuspensions had a narrow size distribution with a mean particle size of 78.67±0.22 nm, a polydispersity index of 0.133±0.01, and a zeta potential of -11.87±0.91 mV. The prepared MX nanosuspensions were spherically wrapped by BSA with a smooth surface as shown by transmission electron microscopy. Stability studies showed that the nanosuspensions were physically stable at 4°C with a shelf life of at least 6 months. In the in vitro dissolution test, the MX-loaded BSA nanosuspension (MX-BSA-NS) exhibited sustained release. In addition, an in vivo pharmacokinetic study in rats following intravenous injection showed that the half-life ( t 1/2 ), mean residence time (MRT), and area under the concentration-time curve (AUC 0-∞ ) of MX-BSA-NS was increased by 169.83%, 150.13%, and 148.80%, respectively, in comparison with MX conventional solution (MX solution). Furthermore, results from inflammation targeting studies showed that the concentration of MX increased significantly in inflamed tissues but was reduced in normal tissues compared with the MX solution group after injection of MX-BSA-NS., Conclusion: The prepared MX-BSA-NS significantly increased the inflammation-targeting properties and bioavailability of MX, suggesting its potential as a promising formulation for the targeted drug delivery of MX in future clinical applications., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to determine meloxicam in beagle dog plasma. Sample pretreatment involved a one-step protein precipitation with methanol of 0.1 mL plasma. Analysis was performed on a Venusil ASB-C 18 column with mobile phase consisting of methanol-water (containing 0.1% formic acid) (75:25, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization source. Each plasma sample was chromatographed within 4.1 min. The linear calibration curves for meloxicam was obtained in the concentration range of 10.3-4.12 × 10 3  ng/mL (r ≥ 0.99). The intra- and inter-day precisions (relative standard deviation) were ≤ 15%, and accuracy (relative error) was within ±7.3%. The method herein described was fully validated and successfully applied to the pharmacokinetic study of meloxicam tablets in beagle dog., (Copyright © 2018 John Wiley & Sons, Ltd.)

The objective of this study reported here was determine whether differences occurred in meloxicam pharmacokinetics between postpartum cows and mid-lactation cows. Preliminary data from a separate study (P. J. Gorden, unpublished data) in postpartum cows demonstrated elevated plasma and milk concentration profiles compared to previously published data (Malreddy, Coetzee, KuKanich, & Gehring, ). Two different groups were enrolled, each with 10 cows. The treatment group (TRT) was postpartum cows treated with meloxicam, and the positive control (PC) group was cows in mid-lactation treated with meloxicam. Plasma and milk meloxicam concentrations between the TRT and PC group were compared. Significant differences in meloxicam concentration in plasma were determined at all time points from 8 hr to 120 hr post-treatment. In milk, there was a treatment (p = .003), time (p < .001), and treatment by time interaction (p < .001). Significant differences in milk meloxicam concentration were determined at all time points from 8 hr to 96 hr post-treatment, except for the 16-hr time point. The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed. These data suggest higher bioavailability as the underlying mechanism. Further research is needed to determine the mechanisms underlying differences this outcome., (© 2018 John Wiley & Sons Ltd.)

This work deals with fast-dissolving drug delivery systems of meloxicam (MX) derived from electrospun polyvinylpyrrolidone (PVP)/2-hydroxypropyl-β-cyclodextrin (HPβCD) nanofiber mats. Electrospinning of solutions with different solvent systems [dimethylformamide (DMF) and ethyl alcohol (EtOH)] was performed. Prepared films were evaluated for morphology, physical, and mechanical properties. MX content, dissolving time, MX release, and cytotoxicity of films were investigated. In vivo studies were also performed in healthy human volunteers. The results showed that MX/HPβCD complexes improved the solubility of MX. PVP also increased MX solubility and the stability of MX/HPβCD complexes. Films were successfully prepared by two solvent systems with fiber in the nanometer range. MX was well incorporated into the films (100% efficiency). The X-ray patterns and DSC experiment indicated an amorphous form of MX. A fast disintegration time and burst release of MX was obtained from EtOH system. Cytotoxicity testing of the films produced by EtOH system proved safer than the DMF system. In vivo studies revealed that films rapidly dissolved in the mouth and had a less bitter taste than MX. These results suggest that electospun films from EtOH system may be a good candidate for fast-dissolving drug delivery systems to increase palatability of dosage forms.

NSAIDs are often used in horses with colic syndrome during the postoperative period, due to their ability to contrast endotoxemia and to promote an analgesic and anti-inflammatory effect. As the pharmacokinetics of a drug are often modified in unhealthy animals compared to healthy subjects, the aim of this study was to evaluate the pharmacokinetic profile of meloxicam after i.v. administration in horses undergoing laparotomy for colic syndrome. Eight horses received 0.6 mg/kg of meloxicam i.v. towards the end of surgery. Blood samples were taken at scheduled time points during the following 24 hr. The serum concentration of the drug was determined by HPLC. Terminal half-life (6.88 ± 2.96 hr), volume of distribution at steady-state (186.53 ± 61.20 ml/Kg) and clearance (27.91 ± 5.72 ml kg -1  hr -1 ) were similar to those reported in literature for healthy horses. This result suggests that no adjustment of the approved dose should be necessary when meloxicam is used to treat horses in the immediate postoperative period after surgery for colic syndrome., (© 2017 John Wiley & Sons Ltd.)

Dissolving microneedles (MNs) offered a simple, minimally invasive method for meloxicam (MX) delivery to the skin. However, the fabrication of dissolving MNs still faced some challenges, such as significant time consumption, loss of drug activity, and difficulty in regulating MN drug loading. To address these issues, we developed the tip-dissolving (TD) MNs. Several kinds of drugs were encapsulated successfully, and the quantity of MX ranged from 37.23 ± 8.40 to 332.53 ± 13.37 μg was precisely controlled. The effects of fabrication process on biomacromolecules stability were studied, and it was found that tyrosinase kept 90.4% activity during the fabrication process. The whole process for the fabrication of MNs only takes approximately 1 h. In order to further evaluate the potential of the TD MNs, MX TD MNs were prepared for in vitro release experiments, in vivo release experiments, safety evaluation, pharmacokinetic studies, and pharmacodynamic studies. The results demonstrated that MX TD MNs offered several advantages, including rapid release of the encapsulated drug (91.72% within 30 min), efficient drug delivery to skin (79.18%), no obvious skin irritation, decent relative bioavailability (122.3%), and strong anti-inflammatory and analgesic effects. Based on these results, we envisage that the TD MNs have promising potential for transdermal drug delivery of MX.

The aim of this article was to study the trans-epithelial absorption to reach the blood and to target the brain by axonal transport using nasal formulations with nanonized meloxicam (nano MEL spray) and its salt form known as meloxicam potassium monohydrate (MELP spray). The physicochemical properties and the mucoadhesivity of nasal formulations were controlled. In vitro and in vivo studies were carried out. These forms were first investigated in "nose-to-brain" relation. It was found that the in vitro study and in vivo study did not show any significant correlation. In vitro experiments demonstrated faster dissolution rate and higher diffusion of MELP from the spray compared with the nano MEL spray. The administration of the nano MEL spray resulted in faster absorption and constant plasma concentration of the drug after five minutes of administration as compared to MELP. The axonal transport of the drug was justified. MEL appeared in the brain tissues after the first five minutes of administration in the case of both spray forms, but its amount was too small in comparison with the total plasma concentration. The application of the nano MEL spray resulted in the same AUC in the brain as the intravenous injection. The "nose-to-blood" results predicted the nasal applicability of MEL and MELP in pain management. The "nose-to-brain" pathway requires further study.

The aim of the study was to develop a novel drug-in-adhesive patch for transdermal delivery of meloxicam (MLX). The formulation involved a strategy to combine a chemical enhancer with an ion-pair agent. Diethylamine (DETA) was selected as the counter ion to form the ion-pair agent MLX-DETA. MLX-DETA was characterized by nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). The ion-pair lifetime (T life ) of MLX-DETA was 164.1 μs. The water solubility of MLX-DETA was increased nearly 9.3-fold, compared with that of MLX. Oleic acid (OA) was selected as the chemical enhancer, and the optimized formulation consisted of 5% (w/w) MLX-DETA, 5% (w/w) oleic acid, and DURO-TAK® 87-4098 adhesive as the pressure-sensitive adhesive matrix. The permeation study in vitro showed that both the counter ion and chemical enhancer were effective in improving the skin permeation of MLX. Tissue distribution studies demonstrated that higher accumulation of MLX following application of the MLX-DETA patch to the skin could be obtained in rats compared with the MLX-patch group. In conclusion, to increase the skin absorption and obtain a sustained release for the transdermal delivery of MLX, preparation of a drug-in-adhesive patch by combining an ion pair (MLX-DETA) with a permeation enhancer (OA) is a suitable strategy.

Objectives: The aim of the study was to assess the impact of the differences in dissolution profiles of meloxicam tablets on the in-vivo bioavailability parameters after oral administration., Methods: Compare in-vitro dissolution testing in the recommended media to evaluate in-vivo bioequivalence outcomes for the Biopharmaceutics Classification System Class II weak acidic drugs. Nine Beagle dogs received a single oral administration of each formulation (7.5 mg) in a three-way crossover design., Key Findings: The dissolution of meloxicam from both test products showed marked differences with that from the reference tablet in pH 1.0, 4.5 and 6.8 media at 50 or 75 rpm. Both formulations exhibiting slow or fast dissolution were then compared with the reference product for in-vivo bioequivalence study. Both products were bioequivalent with the reference tablet in either extent or rate of oral absorption. It indicated that the dissolution profiles which discriminated between the formulations in vitro did not accurately predict the in-vivo bioequivalence outcomes., Conclusions: Comparative dissolution profiles using similarity factor (f 2 ) in the recommended media should be relaxed to fulfil the requirements for the development, scale-up and postapproval changes to immediate release oral solid dosage forms of meloxicam., (© 2017 Royal Pharmaceutical Society.)

In this study, we compared the plasma concentrations of meloxicam in pediatric rat pups (ages: 7, 14, 21, and 28 d) with those of young adult rats. Adult rats received 1.34 mg/kg SC meloxicam to determine the target peak plasma concentration (Cmax) for comparison with the pediatric animals. Pediatric rats received 1.34 mg/kg SC meloxicam, and in all age groups, Cmax met or exceeded that in adults (11.5 ±2.7 μg/mL). Plasma concentrations were similar between male and female pups within age groups, and peak plasma concentration was achieved more rapidly in rat pups than adults. The analgesic efficacy of this dose was not evaluated in this study.

The aims of the investigation were to establish for the first time (i) clinical efficacy and (ii) pharmacokinetic profile of meloxicam intravenously (IV) administered in male Mediterranean buffalo calves after surgical orchiectomy. The study was performed on 10 healthy buffalo calves, between 4 and 5 months old and between 127 and 135 kg of body weight (b.w.). An IV injection of 0.5 mg/kg b.w. of meloxicam was administered in six calves (treated group, TG) immediately after surgery; the other four animals were used as untreated control group (CG). The clinical efficacy of meloxicam was evaluated pre- and post-surgery by monitoring respiratory rate (RR), heart rate (HR), rectal temperature (T°C), serum cortisol levels (SCL) and pain score (PS). Significant inter-groups differences were detected at sampling times (T): 4 hour (h) for RR (P<0.05), at T1-4-6-8 h for PS (P<0.05) and at T4-6-8 h for SCL (P < 0.0001). Regarding the mean intra-group values observed pre (T0) and post-surgery (from T15 min to T72 h), significant difference between the groups were found for RR (P<0.01), PS and SCL (P<0.05). The pharmacokinetic profile was best fitted by a two-compartmental model and characterized by a fast distribution half-life and slow elimination half-life (0.09 ± 0.06 h and 21.51 ± 6.4 h, respectively) and meloxicam mean concentrations at 96 h was of 0.18 ± 0.14 μg/mL. The volume of distribution and clearance values were quite low, but reasonably homogenous among individuals (Vdss 142.31 ± 55.08 mL/kg and ClB 4.38 ± 0.95 mL/kg/h, respectively). The IV administration of meloxicam in buffalo calves shows encouraging effects represented by significant and prolonged analgesic effects, significant reduction of SCL as well as similar pharmacokinetic profile to bovine calves.

This study evaluated the pharmacokinetic profile of a single dose of meloxicam (1.0 mg/kg) administered subcutaneously (n = 6) or intravenously (n = 2) to black-tailed prairie dogs (Cynomys ludovicianus). Blood was collected immediately before (time 0) and at 0.5, 1, 2, 4, 8, 12 and 24 h after drug administration. Plasma meloxicam concentrations were quantified with HPLC-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. The peak plasma concentrations, time to peak plasma concentration, and terminal half-life of meloxicam after subcutaneous administration (median [minimum-maximum]) were 4.30 (3.00-4.89) μg/mL, 2.00 (0.62-4.00) h, and 11.88 (7.35-18.64) h, respectively. Plasma concentrations of meloxicam for prairie dogs in the present study showed high absorption and slow elimination after drug administration. The results of this study suggest that a 1.0-mg/kg SC dose of meloxicam administered every 24 h might be excessive for prairie dogs, although the ideal therapeutic dose in terms of safety and efficacy is unknown in this species.

The aim of the presented work was to design, formulate and evaluate the properties of low-acyl gellan macro beads with the potential application as carriers for oral delivery of meloxicam (MLX) in the prophylaxis of colorectal cancer. The beads were obtained by means of ionotropic gelation technique. Calcium chloride (1.0%, 9.0 × 10 -2  M) was used as the cross-linking agent. Nine different polymer, drug and surfactant (Tween ® 80) mixtures were used for production of the beads. The quantitative compositions of the mixtures were generated with the application of the Design of Experiments (DoE) modulus from the STATISTICA Software. The prepared formulations revealed 7.2-27.0% of drug loading and 29.2-50.7% drug encapsulation efficiency. It turned out that 0.5% amount of gellan gum in the mixtures was not sufficient to obtain spherical beads. The morphology and surface of the dried beads were analyzed by SEM. Raman spectra confirmed that MLX did not undergo structural changes during production of the beads. The swelling behavior and degradation of the beads were evaluated in three simulated gastrointestinal fluids at different pH (1.2; 4.5; 6.8). The MLX in vitro release studies were conducted on USP apparatus IV, working in the open loop mode. The obtained results showed that MLX release from the dried beads was pH-dependent. The formulations obtained from mixtures containing 1.0 and 1.5% of gellan may be considered as oral dosage forms for MLX, intended to omit the stomach and release the drug in the distal parts of the gastrointestinal tract.

OBJECTIVE To determine the pharmacokinetics of meloxicam in domestic hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg). ANIMALS 8 healthy adult White Leghorn hens. PROCEDURES Hens were administered 1 mg of meloxicam/kg PO once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma, egg whites (albumen), and egg yolks were analyzed by high-performance liquid chromatography. RESULTS The half-life, maximum concentration, and time to maximum concentration of meloxicam in plasma samples were 2.8 hours, 7.21 μg/mL, and 2 hours, respectively. Following meloxicam administration, the drug was not detected after 4 days in egg whites and after 8 days in egg yolks. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that meloxicam administered at a dose of 1 mg/kg PO in chickens appears to maintain plasma concentrations equivalent to those reported to be therapeutic for humans for 12 hours. The egg residue data may be used to aid establishment of appropriate drug withdrawal time recommendations.

Introduction: The long term administration of Meloxicam for the management of arthritis, a chronic disorder, results in gastrointestinal disturbances leading to poor patient compliance. Considering the favorable molecular weight, therapeutic dose, biological half-life and log P value of meloxicam for transdermal delivery, its fast dissolving microneedle patch, with an ability to breach the stratum corneum and efficiently deliver the cargo to deeper skin layers, were developed., Methods: Microneedle patch of low molecular weight polyvinyl alcohol and polyvinylpyrrolidone was prepared using Polydimethylsiloxane micromolds. The ratio of polyvinyl alcohol to polyvinyl pyrrolidone and solid content of matrix solution was optimized to achieve maximum needle strength. The optimized batch was extensively evaluated for in vitro dissolution, drug release, stability, ex vivo skin permeation/deposition, histopathology and in vivo pharmacodynamic study., Results: The patch containing 9:1 polyvinyl alcohol to polyvinylpyrrolidone ratio with 50% solid content had shown maximum axial needle fracture force (0.9N) suitable for penetrating the skin. The optimized batch was found to be fast dissolving and released almost 100% drug in 60min following dissolution controlled kinetics. The formulation showed a significant drug deposition within skin (63.37%) and an improved transdermal flux (1.60μg/cm 2 /h) with a 2.58 fold enhancement in permeation as compared to plain drug solution. The formulation showed a comparable anti-inflammatory activity in rats when compared to its existing approved marketed oral tablet. Histopathology and stability evaluations demonstrated acceptable safety and shelf-life of the developed formulation., Conclusion: The successful verification of safety, efficacy and stability of microneedle patch advocated the suitability of the formulation for transdermal use., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Meloxicam is a nonsteroidal anti-inflammatory drug commonly used in avian species. In this study, the pharmacokinetic parameters for meloxicam were determined following single intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administrations of the drug (1 mg/kg·b.w.) in adult African grey parrots (Psittacus erithacus; n = 6). Serial plasma samples were collected and meloxicam concentrations were determined using a validated high-performance liquid chromatography assay. A noncompartmental pharmacokinetic analysis was performed. No undesirable side effects were observed during the study. After i.v. administration, the volume of distribution, clearance and elimination half-life were 90.6 ± 4.1 mL/kg, 2.18 ± 0.25 mL/h/kg and 31.4 ± 4.6 h, respectively. The peak mean ± SD plasma concentration was 8.32 ± 0.95 μg/mL at 30 min after i.m. administration. Oral administration resulted in a slower absorption (t max  = 13.2 ± 3.5 h; C max  = 4.69 ± 0.75 μg/mL) and a lower bioavailability (38.1 ± 3.6%) than for i.m. (78.4 ± 5.5%) route. At 24 h, concentrations were 5.90 ± 0.28 μg/mL for i.v., 4.59 ± 0.36 μg/mL for i.m. and 3.21 ± 0.34 μg/mL for p.o. administrations and were higher than those published for Hispaniolan Amazon parrots at 12 h with predicted analgesic effects., (© 2016 John Wiley & Sons Ltd.)

Colorectal cancer (CRC) is the third most common cancer globally and the second most common cause of cancer-related deaths. Site-specific delivery of drugs leads to an increase in the availability of drugs at the targeted region. The objective of the present investigation was to develop a dually functional microparticulate colon-targeted drug delivery system of meloxicam for potential application in the prophylaxis of colorectal cancer. Chitosan microspheres were prepared by using emulsification-chemical cross-linking technique. Formulation parameters studied include chitosan concentration, drug to polymer ratio, agitation speed, emulsifier concentration, quantity of cross-linking agent and time for cross-linking. In vitro evaluation of microspheres revealed premature release of drug in the upper part of gastrointestinal tract. Since coating of microspheres is difficult to accomplish (with reproducible results), they were compacted to tablets. Enteric coating of tableted microspheres was achieved using Eudragit® S100. In vitro evaluation and SEM studies depict that the microspheres remain intact during compression process. The developed system was further evaluated for in vivo pharmacokinetic and roentgenography studies. In vivo pharmacokinetic evaluation in rabbits reveal that the onset of drug absorption from the coated tableted microspheres (T lag time  = 4.67 ± 0.58 h) was significantly delayed compared to uncoated tableted microspheres. In vivo roentgenographic study revealed that the system remained intact, until it reaches to the colonic region (5 h). Thus, from the results of the study, it can be revealed that the developed system could serve as a potential tool for efficient delivery of drug to the colonic region.

Dry powder inhalers (DPIs) have been among the fastest developing inhaler forms in the past decades. Researches are focusing on the formulation of carrier-free powders to obtain a higher deep-lung deposition and hereby to increase the effectiveness of the medicine. The aim of our study was to prepare a carrier-free dry powder formulation of meloxicam potassium (MP), a novel salt form of meloxicam, using a one-step co-spray drying technology. Different types of excipients were used to modify the crystal structure and to increase aerosolization efficacy. Micrometric properties and the crystal structure were characterized. Aerodynamic properties were tested in vitro using an Andersen Cascade Impactor. A new in silico Stochastic Lung Model was also applied to quantify the amount of particles deposited at the target area. The results have shown that formulated DPI samples are fulfilling the requirements of effective pulmonary drug delivery: they include spherical particles with low density and 1-5μm size distribution. The in silico deposition results correspond with the in vitro measurements and demonstrate that the engineered microcomposites reach a high lung deposition. MP offers a novel opportunity for a well-controlled DPI formulation prepared by a solution-based co-spray drying method., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this study, we evaluated the pharmacokinetic profiles of meloxicam and sustained-release (SR) buprenorphine in prairie dogs. The 4 treatment groups were: low-dose meloxicam (0.2 mg/kg SC), high-dose meloxicam (4 mg/kg SC), low-dose buprenorphine SR (0.9 mg/kg SC), and high-dose buprenorphine SR (1.2 mg/kg SC). The highest plasma concentrations occurred within 4 h of administration for both meloxicam treatment groups. The therapeutic range of meloxicam in prairie dogs is currently unknown. However, as compared with the therapeutic range documented in other species (0.39 - 0.91 μg/mL), the mean plasma concentration of meloxicam fell below the minimal therapeutic range prior to 24 h in the low-dose group but remained above therapeutic levels for more than 72 h in the high-dose group. These findings suggest that the current meloxicam dosing guidelines may be subtherapeutic for prairie dogs. The highest mean plasma concentration for buprenorphine SR occurred at the 24-h time point (0.0098 μg/mL) in the low-dose group and at the 8-h time point (0.015 μg/mL) for the high-dose group. Both dosages of buprenorphine SR maintained likely plasma therapeutic levels (0.001 μg/mL, based on previous rodent studies) beyond 72 h. Given the small scale of the study and sample size, statistical analysis was not performed. The only adverse reactions in this study were mild erythematous reactions at injection sites for buprenorphine SR.

OBJECTIVE To determine pharmacokinetics after IM and oral administration of a single dose of meloxicam to American flamingos (Phoenicopertus ruber). ANIMALS 14 adult flamingos. PROCEDURES Flamingos were allocated to 2 groups. Each group received a dose of meloxicam (1 mg/kg) by the IM or oral route. After a 4-week washout period, groups received meloxicam via the other route of administration. Plasma meloxicam concentrations were measured with high-performance liquid chromatography. Data for each bird were analyzed. Estimated values of selected pharmacokinetic parameters were compared by use of a linear mixed-effects ANOVA. Pooled concentration-time profiles for each route of administration were analyzed to examine the influence of body weight on pharmacokinetics. RESULTS Mean ± SD maximum plasma concentration was 1.00 ± 0.88 μg/mL after oral administration. This was approximately 15% of the mean maximum plasma concentration of 5.50 ± 2.86 μg/mL after IM administration. Mean time to maximum plasma concentration was 1.33 ± 1.32 hours after oral administration and 0.28 ± 0.17 hours after IM administration. Mean half-life of the terminal phase after oral administration (3.83 ± 2.64 hours) was approximately twice that after IM administration (1.83 ± 1.22 hours). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the extent and rate of meloxicam absorption were less after oral administration than after IM administration. Intramuscular administration resulted in a short period during which mean plasma concentrations met or exceeded reported efficacious analgesic concentrations in other species, whereas oral administration did not. These results suggested that higher doses may be required for oral administration.

Background: Meloxicam (MLX) is classified as NSAID that is used for the treatment of rheumatoid arthritis and osteoarthritis. Poor water solubility of MLX leads to its slow oral absorption and slow onset. Preparation of solid dispersion (SD) could improve the water solubility of poorly water soluble drugs. It has been demonstrated that orally disintegrating tablets (ODTs) show faster onset of action and could be more appropriate for the treatment of acute pain., Method: The purpose of this study is to improve the solubility of MLX through the preparation of its SD and then decrease the onset of action by preparation of ODTs from prepared SD. MLX SDs were prepared by solvent evaporation method. MLX, polyvinylpyrrolidone k30 (PVP k30), crospovidone and sodium lauryl sulfate (SLS) with different ratios were dispersed in molten menthol as solvent. Menthol was separated by freeze drying. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis approved amorphous form of MLX in SDs., Result: The optimum SD with highest saturation solubility in water (12.60±1.2 microgram/ml) which consists of MLX, PVP, crospovidone and SLS in a ratio of 1:1:1:0.03 was used for the preparation of MLX ODTs. ODTs were prepared by direct compression method and optimized by 23 factorial design. The effect of the superdisintegrant concentration, mannitol/avicel ratio and the level of compression force was evaluated on the disintegration time, hardness and percent of dissolved MLX after 30 min of prepared MLX ODTs. The optimized ODT formulation contained 10% superdisintegrant, mannitol and avicel a ratio of 2:1 compressed using a high level of compression force., Conclusion: Optimized ODT showed hardness (48±4.3 N) and friability (0.81±0.07%). This formulation provided rapid disintegration in 19±2 seconds of which 77.8±5.1% of drug was released within 30 minutes. The present study demonstrated an effective method for the preparation of suitable dosage form of MLX with improved solubility and onset of action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

OBJECTIVE To determine the pharmacokinetics of a single dose of meloxicam after IM and oral administration to healthy lesser flamingos (Phoeniconaias minor) by use of a population approach. ANIMALS 16 healthy captive lesser flamingos between 1 and 4 years of age. PROCEDURES A single dose of meloxicam (0.5 mg/kg) was administered IM to each bird, and blood samples were collected from birds at 3 (n = 13 birds), 2 (2), or 1 (1) selected point between 0 and 13 hours after administration, with samples collected from birds at each point. After a 15-day washout period, the same dose of meloxicam was administered PO via a red rubber tube and blood samples were collected as described for IM administration. Pharmacokinetic values were determined from plasma concentrations measured by high-performance liquid chromatography. RESULTS Plasma drug concentrations after IM administration of meloxicam reached a mean ± SD maximum value of 6.01 ± 3.38 μg/mL. Mean area under the concentration-versus-time curve was 17.78 ± 2.79 μg•h/mL, and mean elimination half-life was 1.93 ± 0.32 hours. Plasma concentrations after oral administration reached a mean maximum value of 1.79 ± 0.33 μg/mL. Mean area under the curve was 22.16 ± 7.17 μg•h/mL, and mean elimination half-life was 6.05 ± 3.53 hours. CONCLUSIONS AND CLINICAL RELEVANCE In lesser flamingos, oral administration of meloxicam resulted in higher bioavailability and a longer elimination half-life than did IM administration, but the maximum plasma concentration was low and may be insufficient to provide analgesia in flamingos. Conversely, IM administration achieved the desired plasma concentration but would require more frequent administration.

Critically evaluating the pharmacokinetic behavior of a drug in the body provides crucial information about how to effectively treat a patient. Pharmacokinetic studies that exist in fish have primarily focused on drugs used to treat infectious disease, with minimal attention given to analgesic drugs. The objective of this study was to determine the pharmacokinetics of meloxicam (1 mg/kg) in Nile tilapia ( Oreochromis niloticus ) (n = 12). A single dose of meloxicam was administered either i.v. or i.m. Blood samples were obtained at predetermined times after drug injection. Plasma meloxicam concentrations were determined by a validated liquid chromatography/mass spectrometry method, and noncompartmental pharmacokinetic analysis was performed. The mean peak plasma concentration after i.m. injection was 1.95 μg/ml. The mean terminal half-life of meloxicam after i.v. and i.m. administration was 1.36 and 1.8 hr, respectively. The area under the plasma concentration-versus-time curve extrapolated to infinity was 11.26 hr·μg/ml after i.v. administration and 5.72 hr·μg/ml after i.m. administration. Bioavailability of meloxicam after i.m. administration was approximately half that of i.v. administration. Elimination was rapid in both the i.m. and i.v. routes of administration, suggesting that maintaining clinically relevant plasma concentrations may be difficult using this dose. This study represents the first pharmacokinetic evaluation of a nonsteroidal anti-inflammatory drug in a fish species, and further studies evaluating efficacy are needed.

Meloxicam is a cyclooxygenase (COX) inhibitor with a higher selectivity for cyclooxygenase-2 (COX-2) than for cyclooxygenase-1 (COX-1). In the laboratory setting, this nonsteroidal anti-inflammatory drug (NSAID) is commonly selected for analgesia in mice and administered every 24 h. This study characterizes the plasma concentration achieved from a dose of 1.6 mg/kg of meloxicam administered once every 24 h subcutaneously for 72 h in male and female C57BL/6 mice. These values were compared, over time, to reference COX-2 inhibition constants for meloxicam. No significant differences in trough plasma concentrations were noted between genders. The plasma concentrations were below the COX-2 IC50 after 12 h. To maintain a plasma concentration at or above the COX-2 whole blood IC50, the study results suggest an administration frequency of every 12 h when using a dose of 1.6 mg/kg in C57BL/6 mice., (© 2016 John Wiley & Sons Ltd.)

The aim of the present study was to develop amorphous solid dispersion (ASD) of meloxicam (MEL) for providing rapid onset of action. ASDs of MEL with polyvinylpyrrolidone (PVP) K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and Eudragit EPO (MEL/EPO) were prepared. The physicochemical properties were characterized by focusing on morphology, crystallinity, dissolution properties, stability, and the interaction of MEL with coexisting polymers. MEL/EPO was physicochemically stable after storage at 40°C/75% RH for 30 days. In contrast, recrystallization of MEL was observed in MEL/PVP and MEL/HPC at 40°C/50% RH for 30 days. Infrared spectroscopic studies and (1)H NMR analyses of MEL/EPO revealed that Eudragit EPO interacted with MEL and reduced intermolecular binding between MEL molecules. Intermolecular interaction of drug molecules is necessary for the formation of crystalline. Thus, the interaction of MEL with Eudragit EPO and interruption of the formation of supramolecular interaction between MEL molecules might lead to the inhibition of crystal growth of MEL. Of all the MEL solid dispersions prepared, MEL/EPO showed the largest improvement in dissolution behavior. Oral administration of MEL/EPO to rats showed rapid and enhanced MEL exposure with a 2.4-fold increase in bioavailability compared with crystalline MEL. Based on these findings, MEL/EPO was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration.

Imaging of inflammation has an important role in dissolving problems in diagnosis and therapy of patients with inflammatory disorders. In this study meloxican as a nonsteroidal anti-inflammatory drug (NSAID) has been labeled with thechnetium-99m-tricarbonyl core ([(99m) Tc (CO)3 (H2 O)3 ](+) ) in order to evaluate its feasibility as an inflammation imaging agent for in vivo use. (99m) Tc-tricabonyl labeling of meloxicam was performed by its incubation with prepared precursor (99m) Tc-tricabonyl and heating in a boiling water bath for 30 min while various range of pH (1-9) was adjusted. The stability of (99m) Tc-tricarbonyl-Meloxicam was checked in human serum at 37 °C, and biodistribution was studied in mice. Labeling yield of 98.1 ± 0.4% was obtained corresponding to a specific activity of 0.14 GBq/µmol. The radioconjugate showed good stability in human serum. Our main achievement was high accumulation of (99m) Tc-tricarbonyl-Meloxicam in the inflammated muscle in mice (T/NT = 3.90 at 4 h post injection) which may diagnostically be beneficial for distinguish sites of inflammation., (Copyright © 2016 John Wiley & Sons, Ltd.)

Aim: To examine whether strict control of clinical trial conditions could reduce apparent differences of pharmacokinetic (PK) parameters among ethnic groups., Methods: Open-label, single dose PK studies of moxifloxacin, simvastatin and meloxicam were conducted in healthy male subjects from three East Asian populations (Japanese, Chinese and Koreans) and one Caucasian population as a control. These three drugs were selected because differences in PK parameters have been reported, even though the backgrounds of these East Asian populations are similar. Moxifloxacin (400 mg) was administered orally to 20 subjects, and plasma and urine levels of moxifloxacin and its metabolite (M2) were measured. Simvastatin (20 mg) was given to 40 subjects, and plasma levels of simvastatin and simvastatin acid were measured. Meloxicam (7.5 mg) was given to 30 subjects and its plasma concentration was determined. Intrinsic factors (polymorphism of UGT1A1 for moxifloxacin, SLCO1B1 for simvastatin, and CYP2C9 for meloxicam) were also examined., Results: AUCinf values for moxifloxacin, simvastatin and meloxicam showed no significant differences among the East Asian groups. Cmax values of moxifloxacin and simvastatin, but not meloxicam, showed significant differences. There were no significant differences of data for M2 or simvastatin acid. Genetic analysis identified significant differences in the frequencies of relevant polymorphisms, but these differences did not affect the PK parameters observed., Conclusions: Although there were some differences in PK parameters among the three East Asian groups, the present study performed under strictly controlled conditions did not reproduce the major ethnic differences observed in previous studies., (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

OBJECTIVE To determine the pharmacokinetics of meloxicam after single IV and IM injections in red-eared slider turtles (Trachemys scripta elegans). ANIMALS 8 healthy red-eared slider turtles. PROCEDURES Turtles received 1 dose of meloxicam (0.2 mg/kg) IV or IM (4 turtles/route), a 30-day washout period was provided, and then turtles received the same dose by the opposite route. Blood samples were collected at predetermined times for measurement of plasma meloxicam concentration. Pharmacokinetic values for each administration route were determined with a 2-compartment open model approach. RESULTS For IV administration, mean ± SD values of major pharmacokinetic variables were 1.02 ± 0.41 hours for distribution half-life, 9.78 ± 2.23 hours for elimination half-life, 215 ± 32 mL/kg for volume of distribution at steady state, 11.27 ± 1.44 μg•h/mL for area under the plasma concentration versus time curve, and 18.00 ± 2.32 mL/h/kg for total body clearance. For IM administration, mean values were 0.35 ± 0.06 hours for absorption half-life, 0.72 ± 0.06 μg/mL for peak plasma concentration, 1.5 ± 0.0 hours for time to peak concentration, 3.73 ± 2.41 hours for distribution half-life, 13.53 ± 1.95 hours for elimination half-life, 11.33 ± 0.92 μg•h/mL for area under the plasma concentration versus time curve, and 101 ± 6% for bioavailability. No adverse reactions were detected. CONCLUSIONS AND CLINICAL RELEVANCE Long half-life, high bioavailability, and lack of immediate adverse reactions of meloxicam administered IM at 0.2 mg/kg suggested the possibility of safe and effective clinical use in turtles. Additional studies are needed to establish appropriate administration frequency and clinical efficacy.

Aims: To determine the plasma disposition of meloxicam in goats following S/C, oral or I/V administration at a single dose of 0.5 mg/kg bodyweight., Methods: Five healthy Saanen goats, aged 12-14 months and weighing 35-40 kg, were used for a three phase cross-over design with a 10-day washout period, with meloxicam administered I/V, then orally and S/C. Heparinised blood samples (5 mL) were collected from all animals prior to drug administration (0 hours) and subsequently up to 96 hours. Concentrations of meloxicam in plasma were measured using high performance liquid chromatography. Concentration-time curves were fitted and pharmacokinetic parameters were estimated for each administration group., Results: Subcutaneous administration of meloxicam exhibited unique plasma distribution characteristics that differed from oral and I/V administration. Mean peak plasma concentrations were greater (1.91 (SD 0.39) vs. 0.71 (SD 0.17) µg/mL) and the time to reach them shorter (3.20 (SD 1.64) vs. 14.33 (SD 2.19) hours) following S/C compared with oral administration (p<0.05). The terminal half-life was longer (15.16 (SD 4.74) vs. 10.69 (SD 1.49) hours) and the MRT was shorter (15.67 (SD 2.37) vs. 24.33 (SD 3.12) hours) following S/C than oral administration (p<0.05), but bioavailability was similar (98.24 (SD 9.62) vs. 96.49 (SD 10.71)%)., Conclusion and Clinical Relevance: Subcutaneous administration of meloxicam resulted in long-term presence of drug at high concentration in goat plasma. This unique plasma disposition characteristic may offer an advantage in some clinical cases towards potentially improving the treatment efficacy in goats.

SoluMatrix® meloxicam has been developed using SoluMatrix Fine Particle Technology™ to produce a meloxicam drug product with enhanced absorption properties to enable treatment at lower doses than available oral meloxicam drug products. This follows recognition of serious dose-dependent adverse events (AEs) associated with nonsteroidal anti-inflammatory drugs, including meloxicam. This study investigated the pharmacokinetic (PK) properties of SoluMatrix meloxicam 5-mg (fasting conditions) and 10-mg capsules (fasting and fed conditions) and compared SoluMatrix meloxicam 10-mg capsules with meloxicam 15-mg tablets under fasting conditions. This four-period crossover study randomized 28 healthy adult participants to receive single doses of SoluMatrix meloxicam 5-mg capsules (fasting) and 10-mg capsules (fasting or fed) and meloxicam tablets 15 mg (fasting). Meloxicam plasma concentrations were assessed through 96 h postdose. Safety was assessed. Twenty-five participants (89.3 %) completed the study. Under fasting conditions, SoluMatrix meloxicam 10 mg [1252.8 (254.22) ng/mL] produced similar meloxicam mean (standard deviation (SD)) maximum plasma concentrations vs meloxicam 15-mg tablets [1288.8 (424.40) ng/mL]. The overall mean (SD) systemic meloxicam exposure was 33 % lower for SoluMatrix meloxicam 10 mg [29,173.01 (11,042.09) ng*h/mL] vs meloxicam 15-mg tablets [40,875.6 (11,733.47) ng*h/mL]. The median time to maximum plasma meloxicam levels occurred earlier following SoluMatrix meloxicam 5 mg (2.0 h) and 10 mg (2.0 h) administration vs meloxicam 15-mg tablets (4.0 h). Few study-medication-related AEs were reported. SoluMatrix meloxicam 10 mg was more rapidly absorbed and associated with a lower overall exposure compared with meloxicam 15-mg tablets in this study in healthy adults under fasting conditions.

Purpose: Studies have shown altered pharmacokinetic patterns (PK) in patient suffering from acute pain. Thus, we aimed to simulate pharmacokinetics of meloxicam and ibuprofen in pain and pain-free states using a physiological based software program to identify the underlining mechanistic changes for the observed differences., Method: Published in vivo data of meloxicam and ibuprofen were used for the simulations. Two drug formulations were studied: a fast dissolving (FD) and regular release (RR) tablet formulation. The oral bioavailability was compared between these formulations in vagally suppressed rats (gastric dysfunction) and a control group. For ibuprofen additional human data of a control and post dental surgery group were used. All simulations were performed using GastroPlus™. The in vivo drug release and PK of all formulations were estimated for both drugs using the software's immediate release (IR) or gastric release (GR) models., Result: For meloxicam, the IR model predicted the in vivo absorption in the control group after administration of the FD and RR formulations. When gastric dysfunction was induced, the IR model did not predict absorption while the GR model did for both formulations, FD and RR. For ibuprofen, the predictions were also very close for both formulations, using the IR model for the control group and the GR model for the vagally suppressed condition in rats and humans., Conclusions: Gastric control of the drug release in pain/disease state was identified as the major factor causing the observed differences in the pharmacokinetics. Computer simulations of disease states can be employed to optimize drug release from dosage forms to overcome the reported shortfalls in the drug absorption., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To determine the pharmacokinetics of meloxicam in Caribbean flamingos ( Phoenicopterus ruber ruber), a pilot study was performed first, followed by a complete pharmacokinetic study. Four healthy birds were divided into 2 groups and administered 1 mg/kg of either oral (n = 2) or subcutaneous (n = 2) meloxicam. Plasma meloxicam concentrations were determined with liquid chromatography-mass spectrometry. Based on the pilot study results, 12 healthy birds were assigned into 2 groups and administered either 3 mg/kg PO (n = 6) or 1.5 mg/kg SC (n = 6) of meloxicam. Blood samples were collected at baseline and at 9 time intervals per group after administration of meloxicam in all flamingos. Plasma concentrations after administration of 3 mg/kg PO meloxicam reached a mean maximum plasma concentration of 1.449 μg/mL at 2.35 hours with a terminal half-life of 1.832 hours. After administration of 1.5 mg/kg SC meloxicam, maximum plasma concentration was 4.059 μg/mL at 0.91 hour with a terminal half-life of 1.104 hours. The plasma profile from the main oral study (3 mg/kg PO) differed markedly from the pilot study (1 mg/kg PO), suggesting a delayed absorption with the higher dose and lack of dose proportionality. The different doses for subcutaneous administration resulted in a proportional change in plasma concentrations. Further studies are needed to evaluate the effects of the drug volume administered and fasting status when oral dosing is used. Future studies are also needed to investigate multiple-dose pharmacokinetics of meloxicam and to determine the therapeutic meloxicam plasma concentration in Caribbean flamingos.

Background: Meloxicam (MLX) is a nonsteroidal anti-inflammatory drug used in the relief of postoperative pain for human and veterinary medicine. This study was designed to investigate the effect of surgery on the plasma disposition of MLX in dogs undergoing ovariohysterectomy following a single intravenous injection at a dose of 0.2 mg/kg bodyweight. Eight crossbred bitches were used in the study. A two-phase experimental design with a 10-day washout period was used. Pre-operative MLX was administered intravenously to 8 bitches about 10 days before surgery (Phase I, control) at a dose of 0.2 mg/kg bodyweight and peri-operative MLX was administered intravenously after anaesthesia and 15 min before the start of surgery (Phase II). Blood samples were collected from all animals at various times between 1 and 96 h after the drug administrations in both phases. The drug concentrations were analysed using high performance liquid chromatography., Results: The volume of plasma MLX distribution at steady-state (Vdss) of the control group (Vdss: 263.0 ml/kg) was significantly greater (P < 0.05) compared to that of the surgery group (Vdss: 149.3 ml/kg). The AUC values were higher (29.5 vs. 23.0 μg.h(2)/ml) and the CL values were lower (7.7 vs. 10.5 ml.h/kg) in the surgery group compared to the control group, respectively, but differences were not significant., Conclusions: The results of the present study indicated that surgery could alter the plasma disposition of MLX and thus the drug efficacy and side effects such as gastrointestinal ulceration, unusual bleeding and loss of kidney function/failure when repeated doses are used.

Meloxicam is an anti-inflammatory and analgesic drug used to treat many pathological conditions in turtles. With the aim to fill the lack of data about its pharmacokinetic in this species, eighteen turtles (Trachemys scripta scripta) were divided in three groups and treated with a single dose of meloxicam (0.2 mg/kg) by intramuscular, intracoelomic and oral route, respectively. At scheduled time points, blood samples were collected and meloxicam concentrations were determined by HPLC. Pharmacokinetic parameters were calculated from the obtained concentration-time curves. After intramuscular treatment, a plasma peak of meloxicam equal to 1590.03 ± 1845.32 ng/mL (mean ± SD) and a Tmax of 1.17 ± 0.45 h were reached, indicating a quick absorption of the drug. The intracoelomic administration brought to the largest AUC (12621.04 ± 6203.79 h*ng/mL) and to a Cmax and a Tmax equal to 1154.52 ± 662.78 ng/mL and 2.82 ± 1.39 h, respectively. Following oral treatment, the plasma concentrations of meloxicam were very low indicating a scarce absorption. Further studies are warranted to determine the effective plasma concentration of meloxicam in turtles and, consequently, the dosage regimen., (© 2015 John Wiley & Sons Ltd.)

The amphiphilic chitosan derivatives, N-naphthyl-N,O-succinyl chitosan (NSCS), N-octyl-N-O-succinyl chitosan (OSCS) and N-benzyl-N,O-succinyl chitosan (BSCS), were synthesized. Meloxicam (MX) was loaded into polymeric micelles (PMs), and the effects of hydrophobic moieties of the inner core segment on the loading efficiency, stability of MX-loaded PMs, cytotoxicity, drug release, and porcine small intestine permeation were investigated. Among the hydrophobic cores, the N-octyl moiety revealed the highest MX loading efficiency and most stable MX-loaded PMs compared to the other hydrophobic cores. All PMs were spherically shaped (size 213-282 nm) and had low toxicity against Caco-2 cells. The release of MX from PMs was found to be dependent on both hydrophobic cores and hydrophilic shells. In acidic medium at 0-2h, low cumulative MX release was obtained in the MX-loaded OSCS PMs compared to MX-loaded NSCS PMs and MX-loaded BSCS PMs as well as MX free drug. However, when the pH was increased to 6.8, the MX release significantly increased in all MX-loaded PMs. Furthermore, the intestinal permeation rates of MX from all MX-loaded PMs were not significantly different. These results suggest that MX was successfully incorporated into the PMs at high efficiency and good stability by optimizing the hydrophobic moieties of the inner core segments., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British × Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma (LOQ= 0.025 μg/mL) and muscle, liver, kidney, and fat samples (LOQ = 2 ng/g) after extraction using validated LC-MS-MS methods. The mean (± SD) Cmax , Cmin , and Caverage plasma meloxicam concentrations were 4.52 ± 0.87 μg/mL, 2.95 ± 0.77 μg/mL, and 3.84 ± 0.81 μg/mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67 ± 118.16 ng/g) and kidney samples (52.73 ± 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21 days after repeated oral administration., (© 2015 John Wiley & Sons Ltd.)

This article reports on the micro- and nanonization of meloxicam (MEL) with the aim of developing pre-dispersions as intermediates for the design of intranasal formulations. As a new approach, combined wet milling technology was developed in order to reduce the particle size of the MEL. Different milling times resulted in micro- or nanosized MEL in the pre-dispersions with polyvinyl alcohol as stabilizer agent, which were directly used for preparing intranasal liquid formulations with the addition of sodium hyaluronate as mucoadhesive agent. Reduction of the MEL particle size into the nano range led to increased saturation solubility and dissolution velocities, and increased adhesiveness to surfaces as compared with microsized MEL particles. A linear correlation was demonstrated between the specific surface area of MEL and the AUC. The in vitro and in vivo studies indicated that the longer residence time and the uniform distribution of nano MEL spray throughout an artificial membrane and the nasal mucosa resulted in better diffusion and a higher AUC. Nanosized MEL may be suggested for the development of an innovative dosage form with a different dose of the drug, as a possible administration route for pain management., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Meloxicam, a non-steroidal anti-inflammatory drug, is approved for use in horses in several countries, but an equine formulation is not available in North America. However, meloxicam is being used in an extra-label manner in horses in Canada. The purpose of this study, therefore, was to assess the bioequivalence of an approved oral meloxicam suspension (Metacam 15 mg/mL for horses; Boehringer Ingelheim Vetmedica GmBH, Ingelheim, Germany) from the European Union with human meloxicam tablets (Meloxicam 15 mg tablets; TEVA Canada, Toronto, Ontario) compounded with molasses to improve palatability and administration. The geometric mean ratios (GMR test/reference) and the 90% confidence intervals of the pivotal pharmacokinetic parameters (area under the curve and maximum concentration) were within the defined limits of 80% to 125% generally accepted for products to be considered bioequivalent. Therefore, use of human meloxicam tablets compounded with molasses would be expected to produce a similar clinical response in horses as the approved oral product from the European Union.

The purpose of this study was to compare the pharmacokinetics of meloxicam in mature swine after intravenous (i.v.) and oral (p.o.) administration. Six mature sows (mean bodyweight ± standard deviation = 217.3 ± 65.68 kg) were administered an i.v. or p.o. dose of meloxicam at a target dose of 0.5 mg/kg in a cross-over design. Plasma samples collected up to 48 h postadministration were analyzed by high-pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by noncompartmental pharmacokinetic analysis. Mean peak plasma concentration (CMAX ) after p.o. administration was 1070 ng/mL (645-1749 ng/mL). TMAX was recorded at 2.40 h (0.50-12.00 h) after p.o. administration. Half-life (T½ λz ) for i.v. and p.o. administration was 6.15 h (4.39-7.79 h) and 6.83 h (5.18-9.63 h), respectively. The bioavailability (F) for p.o. administration was 87% (39-351%). The results of this study suggest that meloxicam is well absorbed after oral administration., (© 2014 John Wiley & Sons Ltd.)

Data on reptile analgesia are scarce for nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids and almost completely lacking in sea turtles, even though emergencies requiring correct pain management are very frequent in their rehabilitative medicine; therefore, dosage regimens extrapolated from other species involve the risk of clinical failure and damage to the animals. We describe the pharmacokinetic behavior of meloxicam in the loggerhead sea turtle (Caretta caretta). We chose meloxicam because of its selective anti-cyclooxygenase-2 activity and lesser adverse side effects. No data are available on the capacity of turtles to tolerate NSAIDs, so we chose a dose of 0.1 mg/kg of meloxicam. Plasma concentrations of meloxicam were unexpectedly low both for intravenous (IV; maximum concentration [C(max)] = 0.04±0.02 µg/mL) and intramuscular (IM; C(max) = 0.07±0.09 µg/mL) administration. A double-peak phenomenon occurred after both IV (time for second peak concentration T(max2) = 10.33±10.89 h) and IM (T(max2) = 1.17±0.75 h). The second peak after IM injection was premature, so some difficulty and delay in absorption appears to be an appropriate explanation. Furthermore, the area under the curve, and therefore systemic bioavailability (F = 31.82±28.24%), after both IV (0.30±0.29) and IM (0.10±0.03) injection appeared particularly limited. Terminal elimination slope and mean residence time indicated fast elimination after IM dosing; as a consequence, plasma concentrations dropped below analytic limits in 8 h. Considering that IM is the favored route of administration of drugs in rescue centers, it is unlikely that meloxicam at 0.1 mg/kg is an appropriate choice, particularly in long-term pain management protocols.

Objective: To investigate renal, gastrointestinal, and hemostatic effects associated with oral administration of multiple doses of meloxicam to healthy Hispaniolan Amazon parrots (Amazona ventralis)., Animals: 12 Hispaniolan Amazon parrots., Procedures: Birds were assigned to receive meloxicam oral suspension (1.6 mg/kg, PO, q 12 h) and 2.5 mL of tap water inserted into the crop by use of a gavage tube (n = 8) or the equivalent volume of tap water only (control group; 4) for 15 days. Urine and feces were collected 2 hours after treatment administration each day. Feces were evaluated for occult blood. Results of a CBC and serum biochemical analysis and measured N-acetyl-β-d-glucosaminidase (NAG) activity and whole blood clotting time were evaluated before, during, and after completion of treatments. Results of urinalysis and measured urine NAG activity were also evaluated., Results: Birds treated with meloxicam had a significant increase in number of WBCs and decrease in PCV from before to after treatment. The PCV also decreased significantly, compared with results for the control group; however, WBC count and PCV for all birds remained within reference ranges throughout the study. One parrot treated with meloxicam had a single high value for urine NAG activity., Conclusions and Clinical Relevance: Meloxicam administered orally at the dosage used in this study caused no apparent negative changes in several renal, gastrointestinal, or hemostatic variables in healthy Hispaniolan Amazon parrots. Additional studies to evaluate adverse effects of NSAIDs in birds will be needed.

A simple, rapid, specific and reliable high-performance liquid chromatographic assay of meloxicam in human plasma has been developed using a C18 reversed-phase analytical column. Reversed-phase chromatography was conducted using a mobile phase of 0.02 potassium dihydrogen phosphate (adjusted to pH 2.7 with phosphoric acid)-acetonitrile-triethylamine (35:65:0.05, v/v) with UV detection at 354 nm. The drug in human plasma was deproteinized using a combination of methanol and chloroform. This method is simple, rapid and consistent with a high recovery of meloxicam in human plasma ranging from 93.29 to 111.09%. Regression analysis for the calibration plot for plasma standards obtained for the drug concentrations between (25-4000) ng/mL indicated excellent linearity (r ≥ 0.9997). The proposed method was applied to study the bioequivalence between Mobic (original) and Melocam (generic) products. The study was conducted on using two tablets (4 × 7.5 mg) of each of the commercial product and the reference standard in a two-way open randomized crossover design involving 20 volunteers. Area under the concentration-time curve, peak concentration (C(max)) and time to reach C(max) were 72,868.61 ng h/mL, 2133.93 ng/mL and 4.06 h for Mobic, and 78,352.52 ng h/mL, 2525.18 ng/mL and 3.61 h for Melocam. Two C(max) were discovered in the pharmacokinetic profiles which confirm enterohepatic recirculation., (Copyright © 2014 John Wiley & Sons, Ltd.)

To investigate a novel route for providing analgesia to processed piglets via transmammary drug delivery, meloxicam was administered orally to sows after farrowing. The objectives of the study were to demonstrate meloxicam transfer from sows to piglets via milk and to describe the analgesic effects in piglets after processing through assessment of pain biomarkers and infrared thermography (IRT). Ten sows received either meloxicam (30 mg/kg) (n = 5) or whey protein (placebo) (n = 5) in their daily feedings, starting four days after farrowing and continuing for three consecutive days. During this period, blood and milk samples were collected at 12-hour intervals. On Day 5 after farrowing, three boars and three gilts from each litter were castrated or sham castrated, tail docked, and administered an iron injection. Piglet blood samples were collected immediately before processing and at predetermined times over an 84-hour period. IRT images were captured at each piglet blood collection point. Plasma was tested to confirm meloxicam concentrations using a validated high-performance liquid chromatography-mass spectrometry method. Meloxicam was detected in all piglets nursing on medicated sows at each time point, and the mean (± standard error of the mean) meloxicam concentration at castration was 568.9±105.8 ng/mL. Furthermore, ex-vivo prostaglandin E2 (PGE2) synthesis inhibition was greater in piglets from treated sows compared to controls (p = 0.0059). There was a time-by-treatment interaction for plasma cortisol (p = 0.0009), with meloxicam-treated piglets demonstrating lower cortisol concentrations than control piglets for 10 hours after castration. No differences in mean plasma substance P concentrations between treatment groups were observed (p = 0.67). Lower cranial skin temperatures on IRT were observed in placebo compared to meloxicam-treated piglets (p = 0.015). This study demonstrates the successful transfer of meloxicam from sows to piglets through milk and corresponding analgesia after processing, as evidenced by a decrease in cortisol and PGE2 levels and maintenance of cranial skin temperature.

Postcataract endophthalmitis treatment through eye drops is of low corneal bioavailability and short residence time. The dominant NSAIDs therapy also suffers from severe ocular irritancy and low patients compliance. This study dispersed bovine serum albumin (BSA) coated meloxicam (MX) nanocrystals encapsulating nanoaggregates (BSA-MX-NA) in contact lenses to reduce drug ocular irritancy and increased drug release duration. The BSA-MX-NA (∼100 nm) were prepared using acid-base neutralization in aqueous solutions and were dispersed in poly(hydroxylethyl methacrylate) gels, which are common contact lens materials. Drug release studies showed that the gels released the drug for about 5 days. The proposed drug transport mechanism is a diffusion process which can be described by the Ritger-Peppas model with the diffusional exponent n of 0.4768. The drug release can be affected by the gel thickness and the cross-linking degree. A 400 micro thick gels with 100 μL cross-linker TEGDMA leads to an adequate meloxicam release for therapeutic application. The ocular irritation studies showed that BSA-MX-NA loaded p-HEMA gels are significantly less irritating to the ocular tissues as compared to marketed MX solutions. The developed contact lenses loaded with BSA-MX-NA could be very useful for extended delivery in postcataract endophthalmitis treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The present study aimed to develop nanocrystal formulations of meloxicam (MEL) in order to enhance its biopharmaceutical properties and provide a rapid onset of action. Nanocrystal formulations were prepared by wet-milling and lyophilization with hydrophilic polymers used as aggregation inhibitors. Aggregation inhibitors were selected based on high-throughput screening of crystal growth inhibition in supersaturated MEL solution. Supersaturation of MEL was observed in PVP K-30, HPC-SSL, and POVACOAT Type F solution. Although the particle size distributions of pulverized MEL with PVP K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and POVACOAT Type F (MEL/POVA) were in the nanometer range following lyophilization, increases in micron-sized aggregates were observed after storage at 60°C for 21 days. The order of increased amount of aggregates was MEL/POVA≫MEL/HPC>MEL/PVP. These findings showed that hydrophilic polymers that inhibited crystal growth in supersaturated MEL solutions tended to prevent aggregation. The dissolution behavior of all nanocrystal formulations tested was markedly enhanced compared with that of unpulverized MEL. Oral administration of MEL/PVP showed a 2.0h shortened Tmax and a 5.0-fold increase in bioavailability compared with unpulverized MEL. These findings showed that the MEL/PVP mixture was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration., (Copyright © 2014 Elsevier B.V. All rights reserved.)