Improvement of solubility and dissolution rate of indomethacin by solid dispersions in gelucire 50/13 and PEG4000

The aim of this study was to prepare and characterize solid dispersions of water insoluble non steroidal anti-inflammatory drug, indomethacin [IND], with polyethylene glycol 4000 [PEG4000] and Gelucire 50/13 [Gelu.] for enhancing the dissolution rate of the drug. The solid dispersions [SDs] were prepared by hot melting method at 1:1, 1:2 and 1:4 drug to polymer ratios. Scanning electron microscopy [SEM], X-ray powder diffractometry [XRD] and differential scanning calorimetry [DSC] were used to examine the physical state of the drug. Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The data from the XRD showed that the drug was still detectable in its solid state in all SDs of IND-Gelu and disappeared in case of higher ratio of IND-PEG4000. DSC thermograms showed the significant change in melting peak of the IND when prepared as SDs suggesting the change in crystallinity of IND. The highest ratio of the polymer [1:4] enhanced the drug solubility about 4 folds or 3.5 folds in case of SDs of IND-PEG or IND-Gelu., respectively. An increased dissolution rate of IND at pH 1.2 and 7.4 was observed when the drug was dispersed in these carriers in form of physical mixtures [PMs] or SDs. IND released faster from the SDs than from the pure crystalline drug or the PMs. The dissolution rate of IND from its PMs or SDs increased with an increasing amount of polymer

A preliminary study on pharmacokinetics of oral indomethacin in premature infants in north India.

BACKGROUND & OBJECTIVES: Patent ductus arteriosus (PDA) is a frequent complication in premature infants. Intravenous indomethacin is the standard mode of medical therapy and has been shown to be efficacious in closing the ductus. In our setup, oral indomethacin is being regularly used for medical treatment of suspected or clinically diagnosed PDA. Non-availability of the parenteral preparation and lack of information regarding the pharmacokinetic disposition of indomethacin in the premature infants in north Indian population led us to conduct this pharmacokinetic study with oral indomethacin. METHODS: Twenty premature infants with gestational age 30.3 +/- 0.3 wk and birth weight, 1209.8 +/- 39.5 g; admitted to the neonatal unit of the Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh were enrolled in the study. Indomethacin was administered in a single oral dose of 0.2 mg/kg and blood samples were collected through an indwelling vascular catheter at 0 and 1, 2, 4, 8 and 12 h after administration of indomethacin. Plasma indomethacin concentrations were assayed by spectrofluorometric technique. RESULTS: Large interindividual variability was observed for peak plasma concentrations (Cmax; 137.9 +/- 14.0 ng/ml), elimination half-life (t1/2 el; 21.4 +/- 1.7 h) and area under the plasma concentrations time curve (AUC0-infinity;4172 +/- 303 ng.h/ml) in these infants. Variables like birth weight, and sex did not have any sigiificant effect on indomethacin pharmacokinetics. However, the plasma t1/2 el of indomethacin was significantly (P < 0.01) larger in older infants (gestational age > 30 wk) in comparison to younger ones (gestational age < or = 30 wk). There was a negative correlation between gestational age and elimination t1/2 (r = -0.77). INTERPRETATION & CONCLUSION: In conclusion, indomethacin pharmacokinetics showed a wide variability in premature infants. In view of these findings it can be suggested that infants of smaller gestational age are at greater risk of cumulative toxicity if more than one dose of indomethacin is given. With advancing age, metabolism as well as elimination of drug is faster that may require modification in indomethacin dose to achieve therapeutic response. These preliminary results may be of use in designing future pharmacokinetic studies of oral indomethacin in preterm neonates on a larger sample.

[Comparative dissolution study of drugs using protein hdrolysates]

Kneaded mixtures as well as physical mixtures, of an acidic drug, indomethacin, a basic drug vincamine, and a neutral drug, prednisolone, with gelatin and casein hydrolysates were prepared. Their in vitro dissolution profiles were examined. The dissolution of drugs from the kneaded mixtures was significantly increased compared to the drugs alone as well as their physical mixtures. This increase was most prominent for the acidic drug indomethacin. The casein and gelatin hydrolysates enhanced the dissolution of the three drugs by improving the wettability of the drug particles. Solubility also contributes to the enhancement of dissolution of indomethacin and prednisolone. Buffering was an additional reason in case of indomethacin

Influence of gelucires and rhodopases on sustainment of in -domethacin via solid dispersions

Solid dispersions of indomethacin in different release retarding materials; namely, Gelucire 50/02 and Gelucire 50/13, Rhodopas M and Rhodopas H were prepared by fusion and coprecipitation methods, respectively. Solid dispersions were compressed into tablets where both physical parameters and dissolution were studied. The effect of various release retardants on anti-inflammatory characteristic of indomethacin adopting rat paw edema and ulcerogenicity on rat stomach from the most appropriate preparations reached were done. A satisfactory prolongation of drug dissolution from its tablets made with Gelucires was obtained from drug tablets containing 10% w/w of Gelucire 50/02. However, drug tablets prepared with 2.5% of the same polymer showed a shorter retardation time. The percentage of drug release was decreased by increasing the percentage of Gelucire 50/02. In contrast, the increasing Gelucire 50/13 concentration caused a remarkable increase in drug release from its tablets. On the other h and, indomethacin tablets prepared with Rhodopases M and H showed a remarkable protraction of the drug release. The greatest protraction was obtained with 6% Rhodopas H that was too excessive to attain a reasonable level

Microencapsulation of indomethacin using different polymers

Indomethacin microcapsules were prepared with three different polymers; namely, ethyl cellulose 100[EC], Eudragit RSPM [Eud] and sodium carboxymethylcellulose [Na CMC] using solvent-evaporation technique with the first two polymers and coacervation-phase separation by electrolyte addition technique with the latter. Kollidon K-25 was used as a channeling agent. All the prepared microcapsules were subjected to drug content determination, microscopical examination, particle size analysis and drug release studies. The anti- inflammatory characteristic adopting rat paw edema method and ulcerogenicity in terms of ulcer index on rat stomach of indomethacin from the most appropriate preparation reached were studied

Indomethacin, esculetin and nordihydroguaiaretic acid modify arachidonate biosynthesis in rat adrenocortical cells

Se estudio la duración del efecto inhibición que produce la ACTH sobre la incorporación y transformación del ácido [1-14C] eicosatrienoico, en células corticoadrenales aisladas de ratas normales. También se investigó el efecto de la esculetina, indometacina y del ácido nordihidroguaiarético, independientemente o en presencia de ACTH o dibutiril cíclico (diBuAMPc), sobre la biosíntesis de araquidonato. La ACTH y el di BUAMPc produjeron una inhibición significativa en la biosíntese de ácido araquidónico. La depresión producida por la hormona se consideró como un efecto a corto tiempo. El ácido nordihidroguaiarético y la esculetina deprimieron la captación del ácido 20:3 (n=6) en las células corticoadrenales. Este efecto se potenció cuando las células fueron tratadas simultáneamente con ACTH o diBuAMPc. La indometacina no modificó la capacitación del ácido 20:3 (n-6) e incrementó la actividad delta5 desaturante. Este efecto indicaría que, normalmente, los metabolitos producidos por la vía de la negativa sobre la actividad delta5 desaturante producida por la ACTH y el diBuAMPc, y la modulación positiva que se infiere de los resultados obtenidos en el presente trabajo, se puede asumir que existen, por lo menos, dos mecanismos que participan en la formación del ácido 20:4(n-6). Estos mecanismos parecen operar independentemente y probablemente interaccionan produciendo un control bidireccional