Release Rate Of Indomethacin Research Articles

Highly Porous and Drug-Loaded Amorphous Solid Dispersion Microfiber Scaffolds of Indomethacin Prepared by Melt Electrowriting

Melt electrowriting (MEW) is an additive manufacturing technology enabling the production of highly porous microfiber scaffolds, suggested in particular for use in biomedical applications, including drug delivery. Indomethacin (IND) is a nonselective anti-inflammatory drug, for which sublingual delivery could offer advantages such as rapid absorption by the veins in the mouth floor while overcoming the side effects of peroral delivery such as damage to the gastrointestinal mucosa barrier. This study introduces MEW as a processing method to obtain rapid-dissolving drug-releasing scaffolds, containing IND as a model drug, for sublingual drug delivery applications. For this, an amorphous solid dispersion (ASD) of IND in combination with a poly(2-oxazoline)-based amphiphilic triblock copolymer excipient is introduced, enabling ultra-high drug loading. We prepared highly porous, melt electrowritten drug-loaded scaffolds with different polymer/IND w/w ratios up to 1:2 and assessed their morphology, amorphicity, and IND release rate. The results show completely amorphous dispersion of the polymer and drug after MEW processing resulting in smooth and uniform fibers and rapid dissolution of the drug-loaded scaffold. These first water-soluble melt electrowritten IND-loaded microfiber scaffolds break ground as a model for rapid sublingual delivery of ultra-high drug-loaded ASDs.

Spray drying encapsulation of CD-MOF nanocrystals into Eudragit® RS microspheres for sustained drug delivery

Sustained release microspheres containing γ-cyclodextrin metal-organic frameworks (CD-MOF) was designed to improve oral bioavailability and control the release of indomethacin (IMC). The CD-MOF nanocrystals were encapsulated with Eudragit® RS by spray drying technology to regulate the release rate of indomethacin. The morphology, physical states and pore structure of the CD-MOF nanocrystals and CD-MOF@Eudragit® RS microspheres were investigated by scanning electron microscopy, X-ray diffraction, and nitrogen adsorption. Fourier infrared transform spectroscopy revealed the presence of intermolecular interactions between the CD-MOF and indomethacin. Drug-loaded CD-MOF nanocrystals exhibited significantly higher dissolution rate compared with raw IMC during the in vitro release studies. And the encapsulation of CD-MOF nanocrystals with Eudragit® RS significantly reduced the initial burst release of the loaded drug. Pharmacokinetic studies in SD rats showed both IMC/CD-MOF nanocrystals and IMC/CD-MOF@Eudragit® RS microspheres increased oral bioavailability of IMC compared with raw IMC. Meanwhile, the IMC/CD-MOF@Eudragit® RS microspheres achieved a significantly prolonged Tmax value than the raw IMC and IMC/CD-MOF nanocrystals, indicating sustained release of the loaded drug. The strategy of spray drying composite microspheres of CD-MOF nanocrystals and organic polymer for sustained drug release can be applied to the design of oral drug delivery systems of other poorly soluble drugs.

Poly(alkylene sebacate ether)urethane hydrogels for indomethacin delivery formulations

A series of aliphatic polyurethane hydrogels based on poly(alkylene sebacate) diols was developed by polyaddition reaction. The chemical structures of unloaded and indomethacin-loaded poly(alkylene sebacate ether)urethane hydrogels were characterized using ATR-FT-IR spectroscopy. The aim of this research was to study the influence of the long alkylene chains on the indomethacin release rate. The swelling kinetics was analyzed using power law and second-order equation and it was found that both diffusion and polymer relaxation mechanisms control the overall rate of water uptake. The release mechanism follows the same behavior as swelling, but the interaction of the drug with the hydrophobic matrix influences the release kinetics. The surface properties and the influence of the surface configuration on the indomethacin release kinetics were also investigated using contact angle measurements. The mechanical properties of the dry samples were affected by the crosslinker, while, for the swollen samples, the stress–strain curves were overlapping and the mechanical parameter values decrease. The swelling of these hydrogels was also attributed to the network porosity, which was revealed by scanning electron microscopy (SEM) on freeze-dried specimens. The results prove the importance of the polyurethane matrix structure in the development of new drug releasing systems.

Smart nanoparticles based on pullulan-g-poly(N-isopropylacrylamide) for controlled delivery of indomethacin

Double hydrophilic thermo-responsive pullulan-g-poly(N-isopropylacrylamide) (P-g-pNIPAM) copolymers with two different molecular weight of thermosensitive grafts were synthesized and used for preparation of indomethacin-loaded nanoparticles by dialysis and nanoprecipitation method. The polymers form aggregates in aqueous solution at a concentration of 10g/L, above their critical aggregation concentration (3.36g/L) and below the lower critical solution temperature (LCST). After indomethacin loading, nanoparticles with compact and uniform structure were formed below the LCST. The effects of copolymer composition, concentration, and the feed polymer/drug ratio on the particle size, drug loading content (DLC) and entrapment efficiency (EE) were investigated. DLC increased with drug feeding, reaching a maximum value of 40% at the ratios of 1/1. Smaller particles (145nm) with narrower size distribution were obtained from polymer with a higher molecular weight of pNIPAM grafts.FT-IR and 1H NMR spectra proved that the main driven force for the aggregation was the hydrogen bonding between indomethacin and the pNIPAM side chains of copolymer.The indomethacin release rate from nanoparticles was influenced by temperature, because of the dissociation of the hydrogen bonds at high temperatures, the degree of drug loading, and the pH of the release media.

Development and Evaluation of Indomethacin Controlled Release Press Coated Tablets

In the present work, several batches of indomethacin press coated tablets were prepared with drug and Avicel PH 102 utilizing the press coating technology. The core tablet was compression coated with minimal compression pressure. The compression coating mixture was formulated using various amount of lactose and xanthan gum which was used as the release retarding agent. Three formulations (IX-1, IX-2 and IX-3) were designed to evaluate the release profile as function of xanthan gum load. In vitro drug release testing demonstrated that the drug release was inversely proportional to the amount of xanthan gum in the coating formulations. In addition, formulation IX-2 was modified by incorporating hydroxypropyl methyl cellulose (HPMC) 15 cps into the compression coating formulation to understand their effects on drug release. The formulation was evaluated for its properties and correlated with in vitro and kinetic release studies. Incorporation of HPMC caused the highest fraction of drug to be released in the dissolution fluid. The physico-chemical properties of the excipients can be held responsible for the discrepancy in release rate of indomethacin. From kinetic analysis drug release was found to follow Higuchi mechanism for all the formulations. Overall, the study concluded that excipients present in the coating formulations make a significant impact on drug release.Dhaka Univ. J. Pharm. Sci. 14(2): 187-192, 2015 (December)

Polysaccharide-based nanocapsules for controlled release of indomethacin

Indomethacin (IMC) nanoparticles are encapsulated through layer-by-layer self-assembly of natural polysaccharides chitosan (CHI) and pectin (PEC). The adsorption of both polymers is realized in aqueous solutions containing 10−2M NaCl and pH 4.5, where the drug particles are practically insoluble. The stoichiometry of charges and the thickness of the polymer coating on the IMC particles, as well as the stability of their suspensions, are identified using electric light scattering. We found linear increase in the coating thickness with the number of deposited layers. Correspondingly, the electric light scattering is found to increase with increasing number of the layers, showing small excess of positive charges when the coating is terminated with the more highly charged CHI. The release rate of IMC from the nanocapsules is monitored with UV-absorbance in buffer at close to physiological pH 7, when the solubility of IMC increases several times. We found that the encapsulation of the IMC nanoparticles prolong the release time of the drug to about 5h. The released amount of IMC is also found to depend on the concentration of NaCl in the dipping polysaccharide solutions.

English

This study aimed to investigate the efficacy of both xanthan gum (XG) and guar gum (GG) controlling the release rate of the poorly water soluble drug, indomethacin (IDM) from colon target drug delivery systems. Binary mixtures of the drug and the hydrophilic carrier (XG) in the ratios of 1:1 and 1:2 and tertiary mixture in the ratio of 1:1:1 IDM: XG: GG were prepared using three different approaches namely, physical mixture, co-grinding and solid dispersion. The prepared binary and tertiary systems were compressed into core tablets. The core tablets were evaluated for their drug content, weight variation, hardness, friability and in-vitrodissolution rate study. The dissolution profiles in pH 6.8 buffer solutions revealed that increasing the gum content in the core tablet resulted in a decrease in the IDM release rate. The core tablets were then coated with two different type of coat (inner and outer). The inner coat consisted of guar gum solutions of different concentrations (0.2, 0.4, 0.6, 0.8% w/v) to prevent the drug release in pH 7.4. Tablets were then coated with an enteric coat by dipping in 5% Eudragit (ER L100) ethanolic solution to inhibit the drug release in pH 1.2. The coated tablets were then dried using hot air. The prepared coated tablets were subjected to release rate study which indicated that the release of the drug was inhibited in pH 1.2 whereas; a low percentage of the drug was released in pH 7.4. In pH 6.8, the release profiles showed a sustained release of the drug over 18 h. The coated tablets that showed the promising sustained release profiles were further evaluated in pH 6.8 buffer solution containing rat cecal content to study the effect of bacterial degradation on the polysaccharide gums. Key words: Indomethacin, xanthan gum, guar gum, co-grinding, solid dispersion, dissolution rate, colon target drug delivery systems.

Pectin and charge modified pectin hydrogel beads as a colon-targeted drug delivery carrier

The physical and chemical properties of commercial low methoxyl citrus pectins, CP 28 and CP 55, and a pectinmethylesterase (PME) charge modified citrus pectin (MP 38) were compared, and the differences in ability to encapsulate indomethacin in hydrogel beads was determined at 0.5 or 1.0% (w/v) indomethacin ratio, and 100, 200 or 300mM CaCl2 solution. In order to investigate the drug release characteristics, indomethacin loaded dried hydrogel beads were immersed in simulated gastric fluids (pH 1.2) for 2h, followed by immersing in simulated intestinal fluids (pH 7.4) for 3h. Pectin type was highly significant (p<0.0001) for encapsulation efficiency and in vitro release assay. Encapsulation efficiency was also highly affected (p<0.0001) by indomethacin ratio and CaCl2 concentration. The accumulative release rate of indomethacin from pectin hydrogel bead was less than 15% in simulated gastro-intestinal fluids. MP 38 beads showed significantly higher entrapment efficiency and lower release rate than beads formed from CP 28 or CP 55. MP 38 hydrogel formulated with 300mM CaCl2 and 0.5% indomethacin ratio showed the highest entrapment efficiency. These studies suggest that charge modification of pectin improves encapsulation efficiency of drugs for colon targeted drug delivery system through oral administration.

Hot melt mixing and foaming of soluplus® and indomethacin

AbstractThe hot melt mixing (HMM) process was used to dissolve 30 wt% of a model drug, indomethacin (INM), in Soluplus® a water soluble polymer excipient. Comprehensive characterization of the HMM‐prepared samples, using differential scanning calorimetry, X‐ray diffraction, Fourier Transform Infrared spectroscopy, and optical microscopy, strongly suggests that INM was in amorphous state, forming a solid solution with the polymer. Furthermore, to understand the impact of foaming on INM's release profile, the HMM product was foamed in a batch process using supercritical carbon dioxide (CO2). Dissolution tests of HMM and reference samples were conducted in aqueous solutions with pH 7.4 and 1.2. In all cases INM's release showed strong pH‐dependency; faster release and a greater amount of INM was released at pH 7.4 than at pH 1.2. For pure INM and the physical mixture, the drug's ionizable character results in the observed pH‐dependency. While for the HMM samples it is also a consequence of theformation of hydrogen bonds between Soluplus® and INM which hinder polymer dissolution at pH 1.2. It was observed that the release rate of INM from different sample types at pH 7.4 decreased in the following sequence: foamed HMM &gt; unfoamed HMM &gt; crystalline INM &gt; physical mixture. POLYM. ENG. SCI., 2012. © 2012 Society of Plastics Engineers

Synthesis and Drug Release from a PH/Temperature Sensitive Bead of Poly(N-Acryloylglycinate) and Alginate

In this paper, a new pH/temperature sensitive beads with core-shelled structure, composed of sodium alginate and poly(N-acryloylglycinate), were prepared using as drug delivery carrier. Selecting indomethacin as a model drug, in vitro drug release behaviors were investigated at different temperatures, phosphate buffer solutions (PBS) and polymer content. At pH=2.1, the release amount of indomethacin loaded in the beads was only 2.46% while this value approached to 95.23% in pH=7.4 PBS. In addition, the release rate of indomethacin at 37°C is much higher than at 18°C.

Influence of indomethacin-loading on the micellization and drug release of thermosensitive dextran-graft-poly(N-isopropylacrylamide)

The influence of loading indomethacin (IMC) on the thermosensitive aggregation of a double hydrophilic graft copolymer dextran- graft-poly(N-isopropylacrylamide) (DgP) was studied. Before IMC-loading, DgP forms loose aggregates of unimers in aqueous solution below the lower critical solution temperature (LCST), while compact nanoparticles appear above the LCST because of the phase transition of the poly(N-isopropylacrylamide) (PNIPAAm) side chains (Topp, 1997 [31]; Motokawa, 2005 [32]; Zhao, 2006 [25]). After the loading of IMC, however, uniform nanoparticles were formed even below the LCST. The hydrogen bonding between IMC and the PNIPAAm side chains is proposed as the driving force for the aggregation. The IMC release rate was accelerated at a higher temperature because of the dissociation of the hydrogen bonds.

Influence of Excipient Hydroxyl Value on the In‐vitro Release of Indomethacin Suppositories

The release rates of indomethacin from suppositories prepared with excipients of different hydroxyl values were examined by the Muranishi dialysis method. All the excipients tested had an inhibitory effect on the indomethacin release in comparison with the original powder. However, the greatest inhibition of the indomethacin release was observed when excipients of very low (OH 45) hydroxyl values were used. Excipients of an optimal range of hydroxyl values at about 15–30 are suggested to be most appropriate for the preparation of indomethacin suppositories.

Drug release behaviors of a pH/temperature sensitive core-shelled bead with alginate and poly(N-acryloyl glycinates)

In this study, a pH/temperature sensitive bead with core-shelled structure, as a drug carrier, was prepared by grafting of N-acryloylglycinates on the surface of sodium alginate beads. The pH and temperature sensitivity of the beads originate from sodium alginate (SA) and copoly(N-acryloylglycinates), respectively. Here, indomethacin (IMC) was selected as a drug model molecule and loaded in SA beads. The release of IMC was systematically investigated as a function of temperature, pH, and SA concentration. The amount of IMC released from beads was as high as 61.6%in pH = 7.4 phosphate buffer solution (PBS) over 620 min, whereas only 27.9% IMC diffused into the pH = 2.1 PBS. In addition, the release rates of IMC at 37.5°C were faster than that at 20.0°C and decreased with increasing SA concentration in the beads. The result indicates that the sensitive beads have the potential to be used as an effective pH/temperature-controlled delivery system in the biomedical fields.

Thermosensitive Poly(N‐isopropylacrylamide)‐g ‐Polyamidoamine Dendrimer Derivatives: Preparation and the Drug Release Behaviors

AbstractSummary: A series of thermally responsive dendritic core‐shell polymers were prepared based upon dendritic polyamidoamine (PAMAM), modified with carboxyl end‐capped linear poly(N‐isopropylacrylamide) (PNIPAAm‐COOH) in different ratios via an esterification process to obtain PNIPAAm‐g‐PAMAM. The graft ratio of PNIPAAm could be adjusted by changing the feed ratio of PAMAM‐OH to PNIPAAm‐COOH and was verified by 1H NMR and gel penetration chromatography (GPC). The lower critical solution temperature (LCST) of PNIPAAm‐g‐PAMAM evaluated by UV‐vis spectrophotometer was about 32 °C. Indomethacin (IMC) as a model drug was loaded in the thermosensitive polymer‐grafted dendrimer derivative and its release behavior was studied below and above its LCST (27 °C vs 37 °C). Results showed that the LCST of PNIPAAm‐g‐PAMAM was around 32 °C compared with that of the pure PNIPAAm. The release behavior of the indomethacin entrapped in the internal cavities of the PNIPAAm‐g‐PAMAM showed that almost 77% of the drug was cumulatively released at 27 °C after 10 hours, whereas only 20% was released at 37 °C. The release rate of IMC from the IMC/PNIPAAm‐g‐PAMAM complex at 37 °C is significantly slower than that at 27 °C, which indicates that the PNIPAAm chains grafted on the surface of PAMAM dendrimer could act as a channel switching on‐off button through expending or contracting in response to the temperature variation and could control the drug release by varying the surrounding temperature.

Drug Release Behaviors of a pH/Temperature Sensitive Hydrogel Bead with Core-Shelled Structure

As a drug delivery carrier, a novel pH/temperature sensitive bead (pTSB) with core-shelled structure from poly(N-acryloylglycine) (PAG), copoly(N-acryloylglycine methyl este and N-acryloylglycine ethyl ester) was prepared by two steps. In pH=7.4 phosphate buffer solution (PBS), the cumulative release amount of indomethacin loaded in the pTSB was about 60.1 % within 500 mins, but this value only reached to 22.3 % in pH=2.1 PBS. The release behaviors of indomethacin from pTSB also exhibited a remarkable dependence on PAG content in the core. Additionally, the release rate of indomethacin was much faster at 18 oC than that at 37 oC due to the temperature sensitivity of poly(N-acryloylglycinates). The experimental results indicate that pTSB seems to have a potential application in the drug release system controlled via pH or temperature in the biomedical fields.

A pH/Temperature-Sensitive Semi-IPN Bead for Drug Release Carrier

A series of pH/temperature sensitive hydrogel beads with semi-interpenetrating polymer network (semi-IPN), composed of sodium alginate and poly(N-acryloylglycinate) were prepared as drug delivery carrier. In pH=2.3 phosphate buffer solution (PBS), the release amount of indomethacin incorporated into the beads was about 9% within 610 min, while this value approached to 68% in pH=7.4 PBS. The release rate of indomethacin was higher at 37 than that at 20 . In addition, the release amount of indomethacin was increased with increasing poly(N-acryloylglycinate) content. These results suggest that the stimuli-sensitive beads have the potential to be used as an effective pH/temperature delivery system in bio-medical fields.

Drug release behavior of a pH/temperature sensitive calcium alginate/poly(N-acryloylglycine) bead with core-shelled structure

In this study, a novel pH/temperature sensitive hydrogel bead with core-shelled structure, composed of calcium alginate (Ca-alginate) and poly(N-acryloylglycine) (PAG), was prepared using as a drug delivery system. The equilibrium swelling has indicated the distinct sensitivities of the beads to pH value and temperature. In pH = 7.4 phosphate buffer solu- tion (PBS), the cumulative release amount of indomethacin loaded in the core of the beads was about 83.5% within 650 min, whereas this value only reached 16.6% in pH = 2.1 PBS. In addition, the release rate of indomethacin was much faster at 37°C than that at 24°C. The experimental results have showed that the Ca-alginate/PAG beads have a potential application for the pH/temperature-controlled drug release carrier in the biomedical field.

Sustained release properties of arborescent polystyrene-graft-poly(2-vinylpyridine) copolymers

The release kinetics of small molecules from dendritic graft copolymer micelles incorporating an arborescent polystyrene (PS) core and a poly(2-vinylpyridine) (P2VP) shell were investigated in dilute HCl solutions by fluorescence and UV spectroscopies. The redistribution of pyrene and perylene among arborescent micelles was studied by the fluorescence resonance energy transfer (FRET) technique, and was characterized by an initial burst in exchange followed by gradual equilibration of the probes. Fluorescence quenching experiments demonstrated that the diffusion coefficient of pyrene increased for copolymer micelles of higher generations, suggesting a more porous shell structure for the higher generation arborescent PS-g-P2VP copolymers. In vitro release tests for indomethacin and lidocaine monitored by UV spectroscopy showed that sustained release characteristics were achieved, the release rate being higher for lidocaine due to its higher water solubility at low pH. The release rate of indomethacin increased for lower generation micelles and for higher micelle loadings, in agreement with a diffusion-controlled release mechanism. An increasing fraction of the indomethacin molecules loaded in the micelles remained trapped for higher generation copolymers. The diffusion coefficient and the release rate of indomethacin were calculated by fitting the solution of Fick's second law of diffusion to the experimental data. While the initial release rate decreased for higher generations, the trends observed for the diffusion coefficients were similar to those determined for pyrene in the fluorescence quenching experiments. This result is again consistent with a more diffuse shell structure for higher generation micelles, possibly due to the enhanced electrostatic repulsions between the charged P2VP chains.

Preparation and characterization of temperature-sensitive poly(N-isopropylacrylamide)-g-poly(L-lactide-co-ε-caprolactone) nanofibers

Biodegradable and elastic poly(L-lactide-co-e-caprolactone) (PLCL) was electrospun to prepare nanofibers, andN-isopropylacrylamide (NIPAAm) was then grafted onto their surfaces under aqueous conditions using60Co-γ irradiation. The graft yield increased with increasing irradiation dose from 5 to 10 kGy and the nanofibers showed a greater graft yield compared with the films. SEM confirmed that the PLCL nanofibers maintained an interconnected pore structure after grafting with NIPAAm. However, overdoses of irradiation led to the excessive formation of homopolymer gels on the surface of the PLCL nanofibers. The equilibrium swelling and deswelling ratio of the PNIPAAm-g-PLCL nanofibers (prepared with 10 kGy) was the highest among the samples, which was consistent with the graft yield results. The phase-separation characteristics of PNIPAAm in aqueous conditions conferred a unique temperature-responsive swelling behavior of PNIPAAm-g-PLCL nanofibers, showing the ability to absorb a large amount of water at < 32 °C, and abrupt collapse when the temperature was increased to 40 °C. In accordance with the temperature-dependent changes in swelling behavior, the release rate of indomethacin and FITC-BSA loaded in PNIPAAm-g-PLCL nanofibers by a diffusion-mediated process was regulated by the change in temperature. Both model drugs demonstrated greater release rate at 40 °C relative to that at 25 °C. This approach of the temperature-controlled release of drugs from PNIPAAm-g-PLCL nanofibers using gamma-ray irradiation may be used to design drugs and protein delivery carriers in various biomedical applications.

Synthesis and Characterization of pH-Sensitive Thiol-Containing Chitosan Beads for Controlled Drug Delivery Applications

The aim of this study was to develop chitosan-based materials in drug delivery systems possessing covalent attachment of thiol moieties. Thiol-containing chitosan (TCS), found to be soluble in water, was synthesized by graft copolymerization technique. The TCS beads were prepared by using tripolyphoshate, at pH 4.0. The morphology of TCS beads was examined by scanning electron microscopy. The in vitro drug release behavior was studied in phosphate buffer solution at various pH, using indomethacin as a model drug at two different concentrations (0.3 and 0.6% w/w). The release amounts of indomethacin from TCS beads were higher increasing pHs in the dissolution medium. The release rate of indomethacin at pH 7.4 was higher than the release rate at pH 1.4 due to ionization of thiol groups and high solubility of indomethacin in an alkaline medium. These results indicated that the TCS beads may become a delivery system for the controlled release of different drugs wherever pH sensitive mechanics might be useful. This is especially applicable in cases when it is important to minimize drug release in acidic sites, such as in the stomach.