Decrease In Drug Release Rate Research Articles

Antitumor activity of sorafenib-incorporated nanoparticles of dextran/poly(dl-lactide-co-glycolide) block copolymer

Sorafenib-incoporated nanoparticles were prepared using a block copolymer that is composed of dextran and poly(DL-lactide-co-glycolide) [DexbLG] for antitumor drug delivery. Sorafenib-incorporated nanoparticles were prepared by a nanoprecipitation-dialysis method. Sorafenib-incorporated DexbLG nanoparticles were uniformly distributed in an aqueous solution regardless of the content of sorafenib. Transmission electron microscopy of the sorafenib-incorporated DexbLG nanoparticles revealed a spherical shape with a diameter < 300 nm. Sorafenib-incorporated DexbLG nanoparticles at a polymer/drug weight ratio of 40:5 showed a relatively uniform size and morphology. Higher initial drug feeding was associated with increased drug content in nanoparticles and in nanoparticle size. A drug release study revealed a decreased drug release rate with increasing drug content. In an in vitro anti-proliferation assay using human cholangiocarcinoma cells, sorafenib-incorporated DexbLG nanoparticles showed a similar antitumor activity as sorafenib. Sorafenib-incorporated DexbLG nanoparticles are promising candidates as vehicles for antitumor drug targeting.

Adriamycin-Incorporated Nanoparticles of Deoxycholic Acid-Conjugated Dextran: Antitumor Activity Against CT26 Colon Carcinoma

In this study, we prepared adriamycin (ADR)-encapsulated nanoparticles using deoxycholic acid-conjugated dextran (DexDA). Its antitumor activity was evaluated using CT 26 tumor cells in vitro and in vivo. ADR-incorporated DexDA nanoparticles have spherical shapes and their particle sizes were ranged about 50-200. Their particle sizes were changed according to the preparation conditions, i.e., the higher substitution degree (DS) of deoxycholic acid (DA) and higher drug feeding ratio induced increased particle size and zeta potential. Furthermore, the higher DS of DA and higher drug feeding ratio induced increased drug contents and loading efficiency of drug. The higher DS of DA and higher drug feeding ratio induced decreased drug release rate. Futhermore, acidic pH of release media accelerated the drug release rate compared to alkaline pH. At in vitro cytotoxicity test using CT26 tumor cells, the nanoparticles showed higher antitumor activity than free ADR. In fluorescence microscopic observation, nanoparticles were properly entered into tumors cells and maintained in the cells compared to ADR itself. At in vivo animal tumor model using CT-26 cells, nanoparticles resulted in survivability increase of mice even though free ADR showed higher effectiveness to inhibit tumor growth. These results suggested that ADR-incorporated DexDA nanoparticles are promising vehicles for anti-tumor drug delivery.

Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica

The aim of the present study was to evaluate the effect of release rate from ordered mesoporous silica materials on the rate and extent of absorption of the poorly soluble drug fenofibrate. Three ordered mesoporous silica materials with different pore diameter (7.3 nm, 4.4 nm and 2.7 nm) were synthesized and loaded with fenofibrate via impregnation. Release experiments were conducted under sink conditions and under supersaturating conditions in biorelevant media, simulating the fasted and the fed state. Subsequently, all silica-based formulations were evaluated in vivo (rat model). The release experiments under sink conditions indicated a clear increase in release rate with increasing pore size. However, under supersaturating conditions (FaSSIF), the, pharmaceutical performance (in terms of both the degree and duration of supersaturation), increased with decreasing pore size. The same trend was observed in vivo (fasted state): the area under the plasma concentration–time profile amounted to 102 ± 34 μM h, 86 ± 19 μM h and 20 ± 13 μM h for the materials with pore diameter of 2.7 nm, 4.4 nm and 7.3 nm, respectively. The results of this, study demonstrate that a decrease in drug release rate – and thus, a decrease of the rate at which supersaturation is created – is beneficial to the absorption of fenofibrate.

Influence of an Acrylic Polymer Blend on the Physical Stability of Film-Coated Theophylline Pellets

The purpose of this study was to investigate the physical stability of a coating system consisting of a blend of two sustained release acrylic polymers and its influence on the drug release rate of theophylline from coated pellets. The properties of both free films and theophylline pellets coated with the polymer blend were investigated, and the miscibility was determined via differential scanning calorimetry. Eudragit RS 30 D was plasticized by the addition of Eudragit NE 30 D, and the predicted glass transition temperature (T(g)) of the blend was similar to the experimental values. Sprayed films composed of a blend of Eudragit NE 30 D/Eudragit RS 30 D (1:1) showed a water vapor permeability six times greater than films containing only Eudragit NE 30 D. The presence of quaternary ammonium functional groups from the RS 30 D polymer increased the swellability of the films. The films prepared from the blend exhibited stable permeability values when stored for 1 month at both 25 degrees C and 40 degrees C, while the films which were composed of only Eudragit NE 30 D showed a statistically significant decrease in this parameter when stored under the same conditions. Eudragit NE 30 D/Eudragit RS 30 D (1:1)-sprayed films decreased in elongation from 180% to 40% after storage at 40 degrees C for 1 month, while those stored at 25 degrees C showed no change in elongation. In coated pellets, the addition of Eudragit RS 30 D to the Eudragit NE 30 D increased the theophylline release rate, and the pellets were stable when stored at 25 degrees C for a period of up to 3 months due to maintenance of the physico-mechanical properties of the film. Pellets stored at 40 degrees C exhibited a decrease in drug release rate over time as a result of changes in film physico-mechanical properties which were attributed to further coalescence and densification of the polymer. When the storage temperature was above the T(g) of the composite, instabilities in both drug release rate and physical properties were evident. Stabilization in drug release rate from coated pellets could be correlated with the physico-mechanical stability of the film formulation when stored at temperatures below the T(g) of the polymer.

Evaluation of the release rate of bioactive recombinant human epidermal growth factor from crosslinking collagen sponges

The purpose of this study was to prepare recombinant human epidermal growth factor (rhEGF) collagen sponges for topical applications and investigate the effects of different types of crosslinked collagen sponges as platforms for the controlled release of rhEGF. The microstructure and the drug release rates of collagen sponges were modified through treatment with different types (glutaraldehyde (GTA), genipin and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)), different concentrations of crosslinking agents and various preparation conditions. A controlled release profile was observed for the crosslinked collagen sponges as compared to the non-crosslinked ones. The results indicated that the GTA crosslinked sponges have the most potent controlling effect. As the amount of GTA increased, a greater rigidity of the collagen sponge structure combined with a lower hydrophilicity was observed, leading to a decreased drug release rate and an increased water uptake. This study also demonstrated that a good correlation was obtained for in vitro release rates of rhEGF using the power model. The crosslinked rhEGF collagen sponges showed a successful delivery of rhEGF in bioactive form to stimulate cell proliferation.

Influence of sulfobutyl ether β-cyclodextrin (Captisol ®) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion

The aim of this study was to investigate the influence of sulfobutyl ether β-cyclodextrin (SBE 7-β-CD; Captisol ®) on the dissolution properties of a poorly water-soluble drug from extrudates prepared by hot-melt extrusion. Ketoprofen was employed as a model drug. Extrudates containing the parent β-cyclodextrin (β-CD) were also produced for comparative evaluation to assess the benefits of SBE 7-β-CD. Hot-melt extrudates were produced at 100 °C, which was close to the melting point of ketoprofen. The physiochemical properties and the in vitro drug release properties of ketoprofen from extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying and heat-treatment. The solubilizing effects and the interactions of ketoprofen with SBE 7-β-CD and β-CD were investigated using phase solubility and NMR studies, respectively. The dissolution rate of ketoprofen from samples prepared by hot-melt extrusion with SBE 7-β-CD was significantly faster than both the physical mixture and the hot-melt extrudates prepared with the parent β-CD. Moisture absorption studies revealed that the hygroscopic nature of SBE 7-β-CD led to particle aggregation and a corresponding decrease in drug release rate for all samples. However, the samples prepared by melt extrusion were least affected by exposure to elevated humidity.

Use of Proteins to Minimize the Physical Aging of EUDRAGIT® Sustained Release Films

ABSTRACTThe objective of this study was to investigate the influence of two proteins, albumin and type B gelatin, on the physical aging of EUDRAGIT® RS 30 D and RL 30 D coated theophylline pellets. The physicomechanical properties of sprayed films, thermal properties of cast films, influence of proteins on the zeta potential and particle size of the dispersion, and the release of proteins from cast films under simulated dissolution conditions were investigated. The release rate of theophylline decreased significantly over time from pellets coated with an acrylic dispersion containing 10% albumin when there was no acidification of the acrylic dispersion; however, when pellets were coated with an acidified EUDRAGIT®/albumin dispersion, the theophylline release rate was stable for dosage forms stored in the absence of humidity. The drug release rate was faster for pellets coated with acrylic dispersions containing 10% gelatin compared to the albumin–containing formulations. When sprayed films were stored at 40°C/75% RH, the water vapor permeability decreased significantly for both EUDRAGIT® films and those containing EUDRAGIT® and albumin; however, there was no significant change in this parameter when 10% gelatin was present. Albumin was released from the acrylic films when the pH of the dissolution media was below the isoelectric point of the protein while no quantitative release of gelatin was observed in pH 1.2 or 7.4 media. The effect of gelatin to prevent the decrease in drug release rate was due to stabilization in water vapor permeability of the film. Acidification of the polymeric dispersion resulted in electrostatic repulsive forces between albumin and the acrylic polymer, which stabilized the drug release rate when the dosage forms were stored in aluminum induction sealed containers at both 40°C/75% RH and 25°C/60% RH.

Evaluation of gum damar as a novel microencapsulating material for ibuprofen and diltiazem hydrochloride

A natural gum, damar was investigated as a novel microencapsulating material for sustained drug delivery. Microparticles were prepared by oil-in-oil emulsion solvent evaporation method. Ibuprofen and diltiazem hydrochloride were used as model drugs. Microparticles were evaluated for particle size, encapsulation efficiency and in vitro drug release kinetics. Images of the microparticles were obtained by bright field microscopy. The effect of different gum:drug ratios and solubility of drug on microparticle properties was principally investigated. Gum damar could produce discrete and spherical microparticles with both drugs. With a freely water soluble drug (diltiazem hydrochloride), gum damar produced bigger (45-50 µm) and fast drug releasing microparticles with low encapsulation efficiencies (44-57%). Contrary, with a slightly water soluble drug (ibuprofen), gum damar produced small (24-33 µm) microparticles with better drug encapsulation (85-91%) and sustained drug delivery. The increase in gum:drug ratio showed an increase in particle size, encapsulation efficiency and decrease in drug release rate in all cases. Drug release profiles of all microparticles followed zero order kinetics. In conclusion, gum damar can be used successfully to produce discrete and spherical microparticles of ibuprofen and diltiazem hydrochloride.

Cross-linked starch microspheres: Effect of cross-linking condition on the microsphere characteristics

Cross-linked starch microspheres were prepared using different kinds of cross-linking agents. The influence of several parameters on morphology, size, swelling ratio and drug release rate from these microspheres were evaluated. These parameters included cross-linker type, concentration and the duration of cross-linking reaction. Microspheres cross-linked with glutaraldehyde had smooth surface compared with those prepared with epichlorhydrine or formaldehyde. The particle size increased with increasing the cross-linking time and increasing the drug loading. Swelling ratio of the particles was a function of cross-linker type but not the concentration or time of cross-linking. Drug release from starch microspheres was measured in phosphate buffer and also in phosphate buffer containing alpha-amylase. Results showed that microspheres cross-linked with epichlorhydrine released all their drug content in the first 30 minutes. However, cross-linking of the starch microspheres with glutaraldehyde or formaldehyde decreased drug release rate. SEM and drug release studies showed that cross-linked starch microspheres were susceptible to the enzymatic degradation under the influence of alpha-amylase. Changing the enzyme concentration from 5000 to 10,000 IU/L, increased drug release rate but higher concentration of enzyme (20,000 IU/L) caused no more acceleration.

Effect of Chemical Enhancers on In Vitro Release of Salbutamol Sulphate from Transdermal Patches

The effect of combination of PG with DMSO, BC, IPM, Tween 80 and SLS on drug release rate was studied in vitro. The mechanism of drug release was also studied by using power law. Significant difference (One way ANOVA; p&lt;0.05) in release rate among the 16 formulations was seen in the study. The release profiles of various formulations also showed that the added enhancers in individual batches affect the release rate of the drug. The concentration of DMSO and Tween 80 showed directly proportional where as concentration of BC and SLS showed inversely proportional relationship with drug release rate. The increase followed by decrease in drug release rate was seen with increase in IPM concentration. In most of the formulations, drug release occurred by diffusion partially through a swollen matrix and water-filled pores.

Controlled delivery achieved with bi-layer matrix devices produced by co-injection moulding.

The aim of this study was to design new soy protein-based bi-layered co-injection moulded matrix systems aimed to achieve controlled drug delivery. The devices consisted of a drug-free outer layer (skin) and a drug-containing core. The systems overcame the inherent disadvantage of non-linear release associated with diffusion-controlled single-layer matrix devices by providing additional releasing area with time to compensate for the decreasing release rate. As expected, the bi-layer devices presented a significant decrease in drug release rate when compared with a correspondent single layer matrix system. The skin thickness and the degree of crosslinking of the core appeared to be very important tools to tailor the release patterns. Furthermore, due to the amphoteric nature of the soy protein, the developed devices evidenced a pH-dependent behaviour. The mechanisms of drug release were also elucidated at two different pH values: i) pH 5.0, near the isoelectric point of soy (low matrix solubility); and ii) pH 7.4, physiological pH (high matrix solubility). Consequently, changing the release medium from pH 5.0 to pH 7.4 after two hours, led to an abrupt increase in drug release and the devices presented a typical controlled drug delivery profile: slow release/fast release. These evidences may provide for the development of individual systems with different release onsets that in combination may exhibit drug releases at predetermined times in a pre-programmed way. Another possibility is the production of three-layer devices presenting bimodal release profiles (fast release/slow release/fast release) by similar technologies. Scanning electron micrograph of a developed bi-layer device.

Development, characterization and preliminary clinical evaluation of mucoadhesive vaginal gels containing chlorhexidine digluconate

Gels containing chlorhexidine, based on hydroxyethylcellulose or its mixtures with either hydroxypropylmethylcellulose or chitosan, were prepared and characterized by in vitro drug release, swelling, mucoadhesion and rheological studies. All formulations provided a controlled drug delivery showing in general a decrease in drug release rate with the increase of the total polymer concentration. Formulations containing either hydroxyethylcellulose or its mixtures with hydroxypropylmethylcellulose presented similar strength of gel network that was markedly higher compared to gels based on mixtures with chitosan at the same total polymer concentration. Drug release was more sustained when gel components were mixtures of hydroxyethylcellulose and hydroxypropylmethylcellulose. Mucoadhesion was similar for all preparations. Viscosity measurements gave higher values in correspondence to higher total polymer concentrations. A candidate vaginal gel formulation containing hydroxyethylcellulose at 2.5% (w/w) induced a clinical remission in 93% of patients affected by bacterial vaginosis compared to 76% of patients belonging to a metronidazole treatment group, and in 84% of subjects with Candida infections compared to 83% receiving clotrimazole. No adverse events were reported during the trial in any patient. Patient compliance with the mucoadhesive gel was good.

Investigation of Cyclobenzaprine Hydrochloride Release from Oral Osmotic Delivery Systems Containing a Water-Swellable Polymer

ABSTRACTOral osmotic delivery systems containing polyethylene oxide (PEO, a water-swellable polymer) were designed and the release of cyclobenzaprine hydrochloride (model drug) from the devices was investigated. The systems consisted of model drug, mannitol (osmotic agent), and increasing amounts of PEO surrounded by a semipermeable membrane drilled with a delivery orifice. There was a decrease in drug release rate with PEO in the core. This may be due to solubility-modulating properties of the polymer. Visual inspection of the devices with PEO showed significant swelling during dissolution testing. Swelling (internal pressure) may influence water imbibition rate into the core and subsequently drug release rate. The release rates were a function of membrane thickness. The release rates were independent of orifice size (range of 150–510 μm diameter) and hydrodynamic conditions for the devices. This would be advantageous in the delivery of drugs in man.

Release of Cyclobenzaprine Hydrochloride from Osmotically Rupturable Tablets

ABSTRACTOsmotically rupturable systems were developed and the release of cyclobenzaprine hydrochloride (model drug) from the systems was investigated. Systems were designed using mannitol (osmotic agent) and increasing amounts of polyethylene oxide (PEO, a water-swellable polymer) surrounded by a semipermeable membrane. When placed in an aqueous environment, osmotic water imbibition into the systems distended and swelled the systems until the membrane ruptured and released the active compound to the outside environment. Tablets with increasing amount of PEO exhibited longer rupture times. This may be due to osmotic pressure-modulating properties of the polymer, changing the rate of water imbibition into the systems.The integrity of the membranes was investigated using high-pressure mercury intrusion porosimetry. Minimal mercury intrusion into the membrane structure and core tablet indicated membrane integrity and lack of defective areas or pinholes. The results were in agreement with the release profiles where no drug release was detected prior to membrane rupture. Mercury intrusion porosimetry appears to be a promising technique for evaluation of membrane integrity.Once the systems ruptured, drug was released by osmotic pumping and diffusion mechanisms through the ruptured area. There was a decrease in drug release rate with inclusion of PEO in the core.The effects of film thickness on rupture and release times were also investigated. Devices with thicker films produced longer rupture times. This is in agreement with the theoretical prediction.

The study of gelation kinetics and chain-relaxation properties of glutaraldehyde-cross-linked chitosan gel and their effects on microspheres preparation and drug release

The effects of gelation kinetics and chain-relaxation properties of glutaraldehyde-cross-linked chitosan gel on microspheres preparation or drug release were studied. The rate of gelation is zero order corresponding to the chitosan concentration but non-zero order corresponding to the glutaraldehyde concentration. It was suggested that the cross-linking reaction was mainly dominated by the concentration of small molecule reactant, glutaraldehyde. The relaxation of an entangled polymer chain in a gel network as a result of the swelling of cross-linked chitosan hydrogel was investigated by the stress–strain determination. The higher the cross-linking density of chitosan hydrogel, the lower the swelling ability of chitosan hydrogel due to the slower relaxation rate of polymer chain, which then results in the decreased drug-release rate.

Development and biopharmaceutical evaluations of a new press-coated prolonged-release salbutamol sulphate tablet in man

The aim of the study described was to develop prolonged-release press-coated tablets of salbutamol sulphate from which drug release would increase with time. The bioavailability of the formulation considered best was then studied in man. The tablets, each consisting of a core and a coat, were prepared using a compression-coating technique. Salbutamol sulphate was divided between the core and the coat in the ratio 2:1 or 1 : 2. Different viscosity grades and amounts of hydroxypropylmethylcellulose (HPMC) were used in the coat. When HPMC K100 was used, release of salbutamol sulphate from tablets with 2/3 of the drug in the core increased with time. The release patterns obtained with 1/3 of the drug in the core were biphasic. With other HPMC grades, the release patterns were best described by zero-order kinetics with 2/3 of the drug in the core and square-root-of-time kinetics with 1/3 of the drug in the core. For all formulations, an increase in the amount of HPMC decreased drug release rate. In man the only statistically significant difference in bioavailability parameters between the test formulation and the commercial reference preparation related to C max values.

Instability of drug release from anhydrous theophylline-imcrocrystalline cellulose formulations

In the production of anhydrous theophylline-microcrystalline cellulose pellets, extrusion is preceded by wet granulation. Wet granulation also used in the tablet production causes a remarkable decrease in drug release rate accompanied by a conversion of anhydrous theophylline into theophylline monohydrate. Oven drying at 40° C does not seem sufficient to restore this conversion. The formation of additional bindings may be responsible for the decrease in drug release rate instead of the crystal transition. The degree of the further decrease in drug release rate during storage depends on the humidity conditions and the packaging. This instability in pharmaceutical availability seems specific for the combination of theophylline and microcrystalline cellulose. A decrease in dissolution rate is also seen for dry compressed anhydrous theophylline-microcrystalline cellulose blends when stored at high humidity levels. Storage at low humidity levels or the use of another diluent seem to overcome this unpredictable change in drug dissolution rate.

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, II. Combination Resin Formulations

AbstractTheophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness betw...