Indomethacin Concentrations Research Articles

Gastroprotective Effect of Enteral Nutrition Formula in Mice Injected Subcutaneously with Indomethacin.

We have previously shown that two enteral nutrition formulas suppressed gastric lesions induced by the oral administration of indomethacin (IND) in mice. However, the mechanism of their protective effect is unknown. In this study, the effect of the two enteral nutrition formulas on gastric lesions induced by subcutaneous IND injection was investigated, with the objective of exploring the possibility that they may interact directly with IND in the gastrointestinal tract. Ten-week-old, male, ICR mice were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition formula (25 mL/kg). IND was injected subcutaneously at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of mice given enteral nutrition formula was reduced to 56–89% and 34–61%, respectively, compared with the mice given purified water. The time courses of plasma IND concentrations were comparable among the three groups. These results suggested that the effect of these enteral nutrition formulas on gastric lesions did not originate from their direct interaction with IND in the gastrointestinal tract or their effect on the disposition of IND.

Study of the Inhibitory Effects of Enteral Nutrition Formula on Indomethacin-Induced Gastric Lesions in Mice.

We investigated the effects of enteral nutrition formula on non-steroidal anti-inflammatory drug (NSAID)-induced gastric lesions in mice. Male ICR mice aged 7–9 weeks old were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition (25 or 50 mL/kg each). Indomethacin (IND) was orally administered at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of the mice given enteral nutrition showed a significant, dose-dependent decrease compared to the purified water-treated group, and no significant difference was seen between the two enteral nutrition-treated groups. Comparable time courses of plasma IND concentrations suggest that enteral nutrition does not inhibit gastrointestinal absorption of IND. Our findings indicate that administering enteral nutrition could inhibit the onset of NSAID-induced gastric ulcers.

Manganese dioxide‐graphene nanocomposite film modified electrode as a sensitive voltammetric sensor of indomethacin detection

Excess amount of analgesic and anti‐inflammatory drug, such as indomethacin, often leads to serious gastrointestinal complications; therefore, amount of such active compound should be regulated in commercial drugs. This study proposes an efficient analytical technique to detect indomethacin selectively. We prepared and investigated electrochemical properties of a manganese dioxide‐graphene nanocomposite film modified glassy carbon electrode (MnO2‐Gr/GCE). The behavior of the modified electrode as electrocatalyst towards indomethacin oxidation was also examined. The cyclic voltammetric results reveal that the electrocatalytic activity for the oxidation of indomethacin can significantly be enhanced on the MnO2‐Gr/GCE. Indomethacin exhibited a sensitive anodic peak at about 0.90 V at MnO2‐Gr/GCE. The data obtained from differential pulse voltammetry showed that the anodic peak currents were linearly dependent on the indomethacin concentrations in the range of 1.0 × 10−7 to 2.5 × 10−5 mol/L with a detection limit of 3.2 × 10−8 mol/L (S/N = 3). Most importantly, the proposed method shows efficient and selective sensing of indomethacin in commercial pharmaceutical formulations. This is the first report of a voltammetric sensor for indomethacin using MnO2‐Gr/GCE. We believe that this new method can be commercialized for routine applications in laboratories.

A sensitive simultaneous determination of dopamine, acetaminophen and indomethacin on a glassy carbon electrode coated with a new composite of MCM-41 molecular sieve/nickel hydroxide nanoparticles/multiwalled carbon nanotubes

A novel chemically modified electrode is constructed based on a multiwalled carbon nanotubes, nickel(II) hydroxide nanoparticles and MCM-41 molecular sieve composite modified glassy carbon electrode. It is demonstrated that the sensor can be used for the simultaneous determination of dopamine (DA), acetaminophen (ACT) and indomethacin (INDO). The measurements were carried out by the application of differential pulse voltammetry (DPV), cyclic voltammetry (CV) and chronoamperometry (CA). Under the optimum conditions the modified electrode provides a linear response versus DA concentrations in the range of 1.5–45μM and 70–350μM, ACT concentrations in the range of 0.2–20μM and 20–220μM and INDO concentrations in the range of 0.8–40μM and 60–160μM, respectively using the differential pulse voltammetry method. The modified electrode was used for determination of DA, ACT and INDO in real samples with satisfactory results.

Topical therapies for rheumatoid arthritis by gel ointments containing indomethacin nanoparticles in adjuvant-induced arthritis rat.

Indomethacin (IMC), a nonsteroidal anti-inflammatory drug, has been used in the treatment of rheumatoid arthritis (RA), although its clinical use has been limited by its systemic side effects that include gastrointestinal lesions. Therefore, the development of IMC formulations that do not cause gastrointestinal lesions is highly anticipated. In this study, we designed new topical formulations containing IMC solid nanoparticles (IMCnano gel ointment), and investigated their pharmacokinetics. In addition, we demonstrate the preventive effects of this topical application of IMC nanoparticles on inflammation in adjuvant-induced arthritis rat (AA rat). The IMCnano gel ointment was prepared using Bead Smash 12 (a bead mill) and additives including 2-hydroxypropyl-β-cyclodextrin, methylcellulose and Carbopol 934; the mean particle size of the IMC nanoparticles was 173 ± 91 nm (means ± S.D.). The application of the IMCnano gel ointment attenuated the increase in paw edema of the hind feet of AA rats in comparison with AA rats treated with gel ointment containing IMC microparticles (IMCmicro gel ointment, particle diameter 17.1 ± 11.6 mm, means ± S.D). In addition, the accumulation of IMC from the IMCnano gel ointment in skin tissue was significantly large than for the IMCmicro gel ointment; however, the plasma IMC concentrations were similar for the IMCmicro and IMCnano gel ointments. Our findings suggest that the dermal application of nanoparticles may enable a medication to be applied without high-systemic drug levels, which could provide efficient and effective therapy that spares patients from unwanted side effects. A formulation of a topical drug delivery system using IMC nanoparticles may provide a delivery option for the clinical treatment of RA.

Pharmacokinetics of Indomethacin in Pregnancy

Although indomethacin has been widely used for the treatment of preterm labor over the past 40 years, there are few reports regarding its pharmacokinetics in pregnant women. This opportunistic study assessed the steady-state pharmacokinetics of indomethacin in pregnant subjects to whom an oral dose of 25 mg every 6 h was prescribed. Indomethacin concentrations in plasma and urine were analyzed by a validated high-performance liquid chromatography method with mass spectrometric detection. The mean area under the plasma concentration versus time curve at steady state (AUCss) was 1.91 ± 0.53 μg·h/mL, mean peak plasma concentration (C max) was 1.02 ± 0.49 μg/mL, and mean time to reach C max (t max) was 1.3 ± 0.7 h. The mean apparent clearance at steady state was 14.5 ± 5.5 L/h, which is higher than the apparent clearance reported in the literature for non-pregnant subjects. Indomethacin crosses the placenta; the mean fetal/maternal ratio from five sets of cord blood samples collected at delivery was 4.0 ± 1.1. Further studies are needed to determine whether any dose adjustments are necessary as a result of the increased clearance of indomethacin during pregnancy.

Pharmacokinetics of Indomethacin in Chronic Migraine Patients after Withdrawal from the Overused Combination of Indomethacin, Prochlorperazine and Caffeine

Indomethacin, in combination with prochlorperazine and caffeine (IPC), is often overused by migraine patients who develop medication-overuse headache. Indomethacin clearance is slower in chronic migraine patients overusing IPC combination than in migraine patients only occasionally taking it. The objective of this study was to verify if indomethacin reduced clearance reverted to normal values after withdrawal of the overused IPC combination. Therefore, we repeated the study of indomethacin pharmacokinetics in 9 female chronic migraine patients after 3 months from inpatient withdrawal treatment from IPC combination overuse. The IPC combination (indomethacin 50 mg, prochlorperazine 8 mg, caffeine 150 mg) habitually taken was administered by rectal route to each patient. Blood samples were drawn before dosing and at the following post-dose times: 0.5, 1, 2, 3, 4, and 6 h. Indomethacin concentrations were measured by HPLC method. We found that 4 of 9 patients (group A) who were still overusing the combination and suffering from daily headache had still high indomethacin concentrations after 6 hours, therefore showing a slow elimination of the drug. Instead, in the 5 patients (group B) who had discontinued overuse of IPC combination after withdrawal treatment, indomethacin concentrations after 6 hours were significantly lower than those measured before withdrawal (P < 0.05, Student’s t-test for paired data), and also than those observed in group A (P < 0.05, ANOVA and Newman-Keuls’test). Hence, by suspending IPC abuse indomethacin clearance reverts to normal values and this is associated with an improvement of migraine. Instead, the higher plasma levels of indomethacin in patients who continue IPC abuse do not solve migraine and might support medication-overuse headache.

Preparation and Comparative Bioavailability Studies of Indomethacin-Loaded Cetyl Alcohol Microspheres.

The purpose of the present study was to compare the in vitro release and to find out whether the bioavailability of a 75 mg indomethacin capsule (Microcid SR) was equivalent to optimized formulation (indomethacin-loaded cetyl alcohol microspheres). Indomethacin-loaded cetyl alcohol microspheres were prepared by meltable emulsified cooling-induced technique. Surface morphology of microspheres has been evaluated using scanning electron microscopy. A single dose, randomized, complete cross over study of IM microspheres was carried out on 10 healthy male and female Albino sheep's under fasting conditions. The plasma was separated and the concentrations of the drug were determined by HPLC-UV method. Plasma indomethacin concentrations and other pharmacokinetic parameters obtained were statistically analyzed. The SEM images revealed the spherical shape of fat microspheres, and more than 98.0% of the isolated microspheres were in the size range 12–32 μm. DSC, FTIR spectroscopy and stability studies indicated that the drug after encapsulation with fat microspheres was stable and compatible. Both formulations were found to be bioequivalent as evidenced by in vivo studies. Based on this study, it can be concluded that cetyl alcohol microspheres and Microcid SR capsule are bioequivalent in terms of the rate and extent of absorption.

Possible role of prostaglandins in post-tetanic potentiation at the nerve-muscle junction in the longitudinal muscle strip of guinea-pig ileum.

The effect of tetanic stimulation on the twitch responses of the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum to electrical stimulation was investigated in the presence of naloxone. Under this condition, or after the addition of PGE2, twitch contractions were maximal and no potentiation of twitches following tetanus was observed. In the presence of indomethacin (1 mumol litre-1) twitches were diminished and post-tetanic potentiation (PTP) was manifested. PTP was seen with indomethacin concentrations of 1 to 20 mumol litre-1 or after simultaneous addition of diphloretin phosphate (16 mumol litre-1). Thus it seems unlikely that the effect of prostaglandins released during tetanic stimulation would be of key importance for the manifestation of PTP. Rather it is thought that a decrease in the release of acetylcholine from motor nerve terminals, and consequently smaller twitches in the presence of indomethacin, offer favourable conditions for PTP.

Comparative Bioavailability Studies of Two Indomethacin Controlled Release Formulations in Healthy Albino Sheep's

The purpose of the present study was to compare the in vitro release and to findout the bioavailability of a 75 mg indomethacin capsule (Microcid®SR - reference - product A) was equivalent to optimized formulation (indomethacin loaded microspheres – test – product B). Indomethacin (IM) loaded carnauba wax fat microspheres were prepared by using meltable emulsified dispersion cooling induced solidification technique utilizing a wetting agent. Solid, discrete, reproducible free flowing microspheres were prepared. The yield of the microspheres was up to 92%, having smooth surfaces, with free flowing and good packing properties, angle of repose, % Carr’s index and tapped density values were within the limit. More than 98.0% of the isolated spherical microspheres were in the particle size range of 1135 - 1360 mm were confirmed by scanning electron microscopy (SEM). The drug loaded in microspheres was stable and compatible, as confirmed by DSC and FTIR studies. A single dose, randomized, complete cross over study of IM (75 mg) microspheres was carried out on 10 healthy male and female Albino sheep’s under fasting conditions. The plasma was separated and the concentrations of IM were determined by HPLC-UV method. Plasma IM concentrations and other pharmacokinetic parameters obtained were statistically analyzed. Based on this study, is it possible to conclude that drug loaded microspheres and Microcid®SR capsule are bioequivalent in terms of the rate and extent of absorption.

Indomethacin Pharmacodynamics Are Altered by Surfactant: A Possible Challenge to Current Indomethacin Dosing Guidelines Created Before Surfactant Availability

The effect of surfactant administration for respiratory distress syndrome (RDS) on indomethacin (INDO) pharmacodynamics and dosing requirements for patent ductus arteriosus (PDA) closure and renal toxicity was evaluated. A 22-year prospective cohort study including 442 INDO-treated patients given 466 INDO treatment courses. The database included demographic information, medical problems, and medications. Neonates with a PDA confirmed by echocardiography were treated with INDO, 0.25-0.3 mg/kg. Subsequent INDO dosing was based on a combined pharmacokinetic/pharmacodynamic (PK/PD) approach. Data were fit to an Emax model and ANOVA was used to compare mean closure levels between groups. PDA closure was successful in 405 of 442 patients (91.6%) and in 434 of 466 treatment courses (93.1%) using an individualized PK/PD dosing approach. Renal toxicity was documented in 56 of 442 patients (12.7%) or 56 of 466 treatment courses (12.0%). Patients not treated with synthetic surfactant trended toward lower mean INDO concentrations at PDA closure compared to patients treated with synthetic surfactant (1.65 vs. 2.01 mg/l; P > 0.05) and significantly lower mean INDO concentrations at PDA closure compared to patients treated with natural surfactant (1.65 vs. 2.15 mg/l; P < 0.002). This requires an increased total dose of ~0.3 mg/kg or an individual dose increase of 0.1 mg/kg. Administration of natural or synthetic surfactant for RDS may increase the INDO concentrations and doses needed for PDA closure in premature infants.

Preparation, evaluation and bioavailability studies of indomethacin-bees wax microspheres

The present study envisages the preparation of microspheres containing indomethacin (IM) as model drug and bees wax as carrier, and to compare the in vitro release and pharmacokinetics of prepared IM formulation with commercially available oral formulation MicrocidSR. The microsphere formulations were prepared by meltable emulsified dispersion and cooling induced solidification. Surface morphology of microspheres has been evaluated using scanning electron microscopy (SEM). The SEM images revealed the spherical shape of microspheres and more than 98.0% of the isolated microspheres were in the size range 115-855 mum. Differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy studies indicated that the drug after encapsulation with bees wax was stable and compatible. A single dose randomized complete cross over study of IM (75 mg) microspheres was carried out on 8 healthy Albino sheeps. Plasma IM concentrations and other pharmacokinetic parameters obtained were statistically analyzed. The T (max), C (max), AUC(O-24) and T (1/2) values of MicrocidSR and optimized formulation were 3.0 h, 2038 +/- 51.31 ng/ml, 9528 +/- 129.65 ng/ml h(-1), and 2.59 +/- 0.02 h(-1); and 3.2 h, 1940 +/- 22.61 ng/ml, 8751 +/- 41.32 ng/ml h(-1), and 2.68 +/- 0.02 h(-1), respectively. Beeswax microspheres showed controlled release and it can be concluded that both the prepared formulation and MicrocidSR are bioequivalent.

Patent Ductus Arteriosus: Indomethacin, Ibuprofen, Surgery, or No Treatment at All?

Patent Ductus Arteriosus: Indomethacin, Ibuprofen, Surgery, or No Treatment at All?

Increased Indomethacin Dosing for Persistent Patent Ductus Arteriosus in Preterm Infants: A Multicenter, Randomized, Controlled Trial

We conducted a multicenter, randomized, controlled trial to determine whether higher doses of indomethacin would improve the rate of patent ductus arteriosus (PDA) closure. Infants (<28 weeks gestation) who received a conventional, prophylactic 3-dose course of indomethacin were eligible if they had continued evidence of persistent ductus patency on an echocardiogram obtained before the third prophylactic indomethacin dose. Infants (n = 105) were randomized to receive an extended 3-day course of either low-dose (0.1 mg/kg/d) or higher-dose (0.2 or 0.5 mg/kg/d) indomethacin. An echocardiogram was obtained 24 hours after the last dose of study drug. Despite increasing serum indomethacin concentrations by 2.9-fold in the higher-dose group, we failed to detect a significant decrease in the rate of persistent PDA (low = 52%; higher = 45%, P = .50). The higher-dose group had a significantly higher occurrence of serum creatinine >2 mg/100 mL (low = 6%, higher = 19%, P < .05) and moderate/severe retinopathy of prematurity (ROP) (low = 15%, higher = 36%, P < .025). The incidence of moderate/severe ROP was directly related to the poststudy indomethacin concentrations (odds ratio = 1.75, confidence interval: 1.15-2.68, P < .01). Increasing indomethacin concentrations above the levels achieved with a conventional dosing regimen had little effect on the rate of PDA closure but was associated with higher rates of moderate/severe ROP and renal compromise.

Prevention of Indomethacin-Induced Gastric Mucosal Injury in Helicobacter pylori-Negative Healthy Volunteers: A Comparison Study Rebamipide vs Famotidine

The clinical efficacy of gastroprotective drugs or low-dose H2 receptor antagonists in the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is limited. The aim of the present study was to investigate efficacy of rebamipide and famotidine in Helicobacter pylori (H. pylori)-negative healthy volunteers taking NSAID. This study was a randomized, two way crossover study comparing the preventive effect rebamipide 100 mg, t.i.d. and famotidine 10 mg, b.i.d against indomethacin (25 mg, t.i.d.)-induced gastric mucosal injury in H. pylori-negative healthy volunteers. 12 subjects satisfied criteria and were randomized. Endoscopy was performed at baseline and again after the treatment for 7 days, and symptoms were recorded during the treatment. Tissue levels of lipid peroxides and myeloperoxidase and serum indomethacin concentrations were also measured. Subjective symptoms were developed in 58% (7/12) of the rebamipide group, and in 75% (9/12) of the famotidine group (no significant differences). The incidence of gastric lesions (modified Lanza score 2 or higher) was 17% (2/12) in the rebamipide group and 25% (3/12) in the famotidine group. Peptic ulcers did not occur in both groups. There were no significant differences in tissue levels of lipid peroxide and myeloperoxidase and serum level of indomethacin between two groups after the treatment. In conclusion, these data recommend rebamipide (100 mg, t.i.d.) or famotidine (10 mg, b.i.d.) for the prevention of acute gastric injury induced by NSAID in patients without a particular risk factor.

Coating of indomethacin-loaded embolic microspheres for a successful embolization therapy

Indomethacin-loaded dietheylaminoethyl trisacryl® microspheres (DEAE-MS), originally designed for therapeutic embolization, were encapsulated using two methods: coacervation and solvent evaporation/extraction. This encapsulation was achieved using a biocompatible polymer, the PLGA 50 : 50, and aimed to control the release of the anti-inflammatory non-steroidal drug (AINSD) in the occluded vessel. PLGA degradation study showed that it had an erosion half-life of ∼35 days. Scanning electron microscopy (SEM) photographs showed that microcapsules (MC) prepared by coacervation had a wrinkled surface while those prepared using solvent-removal process showed non-porous, smooth surface, those of originally DEAE-MS showed a macro-porous, rough surface. The mean diameters were 61 µm for naked DEAE-MS vs. 71 µm and 65 µm for MC prepared by coacervation and solvent evaporation/extraction method, respectively. In vitro release study of indomethacin adsorbed onto MS indicated that drug release from MC was controlled by a diffusion process. Indomethacin diffusivity from MC was much lower than its free diffusivity from MS (mean 14.5 and 10.5 times lower for formulations prepared by coacervation and solvent evaporation/extraction method, respectively). This indicates that efficient indomethacin concentrations could be maintained over much longer time-periods in the embolized region, which is assumed to be beneficial in inhibiting normally occurring inflammatory reaction and the subsequent revascularization; responsible for treatment failure when definitive occlusion is required.

Orogastric and Intravenous Indomethacin Administration to Very Premature Neonates With Patent Ductus Arteriosus: Population Pharmacokinetics, Absolute Bioavailability, and Treatment Outcome

A population pharmacokinetic model was developed after administration of orogastric and/or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants. Plasma indomethacin concentrations (n=227) were obtained from 90 preterm infants of median gestational age 27 weeks, mean postnatal age of 12 days, and a mean current weight (WT) of 1010 g. Infants received one to three courses of indomethacin (0.1 mg/kg per day for 6 days). A one-compartment model was fitted to the data to obtain estimates of clearance (CL), volume of distribution (V), absorption rate constant (Ka) and orogastric bioavailability (F), using NONMEM. Model robustness was assessed by bootstrapping with replacement (500 samples). The structural model was: CL (L/h)=0.0166 (WT / 0.936)1.54; V (L)=0.484 (WT / 0.936)1.41; F=0.986; Ka (h(-1))=0.786. The interindividual variability for CL and V was 57.7% and 45.6%, respectively. There remained considerable residual unexplained variability (45.4%). Mean (range) conditional estimates from individual infants for CL, V, and elimination half-life were 18.9 (4.7-45.5) mL/h/kg, 509 (191-1120) mL/kg, and 20.0 (12.0-37.3) hours, respectively. Complete ductus closure occurred in 67% of patients. Infants of lower gestational age or birth weight had less chance of successful ductal closure. There was no obvious dose-response relationship between systemic exposure to varying plasma indomethacin concentrations and ductus closure, which does not support individualized indomethacin dosing based on monitoring to a target plasma concentration.

Plasma and Cerebrospinal Fluid Concentrations of Indomethacin in Children After Intravenous Administration

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4-144 months) received indomethacin (0.35 mg/kg) as a 10-minute intravenous infusion prior to surgery under spinal anaesthesia. A single CSF and plasma sample from each individual was collected 14 to 225 minutes after the infusion. Indomethacin concentrations were determined from the CSF, plasma, and protein-free plasma. Total plasma, protein-free plasma, and CSF concentrations of indomethacin ranged between 90 and 2200 ng/mL (median, 780 ng/mL), 0.3 and 0.8 ng/mL (median, 0.5 ng/mL), and 0.2 and 5.0 ng/mL (median, 1.4 ng/mL), respectively. The CSF to plasma concentration ratio remained less than 0.01. There was no correlation between the administration time and CSF concentrations. Eleven children developed 12 nonserious adverse effects, from which 5 were central nervous system (CNS) effects (agitation). In conclusion, indomethacin permeated into the CSF of children, which enables both desired and adverse CNS effects of indomethacin.

Mode of Administration-Dependent Brain Uptake of Indomethacin: Sustained Systemic Input Increases Brain Influx

Nonsteroidal anti-inflammatory drugs, including indomethacin, have been found in both epidemiological and clinical studies to reduce the prevalence and severity of Alzheimer's disease. However, long-term use of indomethacin is limited by significant gastrointestinal and renal toxicities. An indomethacin prodrug that delivers low and continuous blood levels of the drug showed a superior safety profile and similar efficacy in comparison to an equivalent dose of free indomethacin because of limited systemic exposure and preferred brain uptake. The purpose of the present investigation was to evaluate whether sustained systemic input causes an increased brain influx in comparison to rapid input of the drug. Oral indomethacin, indomethacin prodrug, or intravenous indomethacin infusion was administered to rats. The infusion was designed to mimic the plasma indomethacin levels resulting from the prodrug. The resultant blood levels and brain indomethacin uptake were evaluated. The brain indomethacin concentrations 8 h following indomethacin administration were 0.45, 0.3, and 0.31 microg/g after the oral indomethacin, oral prodrug, and intravenous infusion, respectively. The corresponding plasma concentrations were 14.1, 4.1, and 4 microg/ml. Therefore, brain versus plasma indomethacin level ratios were 2.5-fold higher after slow systemic input of indomethacin in comparison to rapid drug input. In conclusion, indomethacin brain uptake was found to be mode of administration-dependent, and a sustained input function increases the drug brain uptake. Thus, these unique results indicate that an appropriate indomethacin controlled release delivery system may induce the desirable brain-related pharmacodynamic effects, while avoiding the concentration-dependent adverse effects. These findings may contribute to improved therapy in Alzheimer's disease.

Comparative bioavailability studies of indomethacin from two-controlled release formulations in healthy albino sheep

The objective of the study was to obtain the pharmacokinetic data of two controlled release formulations of (75 mg) indomethacin and to compare the relative bioavailability of the test formulation (product B cetostearyl alcohol microspheres) with standard formulation (product A-Microcid®SR 75 mg capsule). A single dose randomized (4×2) complete cross over study of the indomethacin (75 mg) was carried out on 8 healthy albino sheep. The study was carried out on two separate occasions with a washout period of 2 weeks. Blood samples were collected at pre-determined time intervals. Plasma indomethacin concentrations and other pharmacokinetic parameters obtained were statistically analyzed. The results of the paired t-test for the comparison of pharmacokinetic data showed that there was no significant variation between the products A and B. Products did not show any significant difference between them with regard to the T max , C max , AUC 0-24 , AUCo-oo, MRT, Ka, Kel , K 1/2 , 3.0 h, 2054 ± 55.78 ng/ml, 9637 ± 132.87 ng h/ml, 9870 ± 129.22 ng h/ml, 4.76 ± 0.10 h, 0.3812 ± 0.002 h -1, 0.2713 ± 0.004 h -1, 2.55 ± 0.03 h -1, respectively for product A and 3.5 h, 1929 ± 20.32 ng/ml, 8343 ± 40.04 ng h/ml, 8617 ± 46.88 ng h/ml, 4.98 ± 0.02 h, 0.3648 ± 0.002 h -1, 0.2427 ± 0.010 h -1, 2.86 ± 0.20 h -1 for product B. From the dissolution studies and in vivo bioavailability studies, it was concluded that the products A and B are bioequivalent.