Delayed Drug Delivery Research Articles

Shifting from sustained to delayed drug delivery systems: Encapsulated mesoporous silica-chitosan grafted polylactic acid-based composite approach

The current study demonstrates a desired drug delivery-controlled system with a wide range of release parameters. It illustrates the feasibility of carriers in the systems for extended and short drug release. Herein, mesoporous silica nanoparticles (MSNs) coated with chitosan (Cs) grafted polylactic acid (PLA) composite were fabricated by a sol-gel method in the form of micrometric porous particles (∼270 nm) with ζ-potential of −17.7 ± 1.7 mV and a specific surface area and total pore volume of 122700 cm2/g and 0.057 cm3/g, respectively. The prepared template of polymer-silica composite pores proved to be essential in the incorporation of Doxorubicin (Dox) drug molecules with adsorption capacity of 83.33 mg/g and encapsulation efficiency of 88 %. Dox was incorporated via the solvent diffusion method into the polymer-silica composites at suitable pH and concentration, resulting in solid drug dispersions. The silica-Cs-g-PLA composites showed greater effectiveness in the delayed release of the Dox with complete release after 10 days as compared to pristine MSNs and silica-Cs, which were completed after 12 h and 24 h, respectively. The drug release profiles were studied at different pH (2, 7, and 8), with maximum results obtained at pH 2. Both pristine MSNs and silica-Cs suffered from the burst effect, which was overcome by the grafting of PLA. The functionalized silica-Cs with PLA shows a significant change in the drug release properties from a sustained release process for pristine MSNs and silica-Cs to an enhanced delayed process for the silica-Cs-g-PLA composite, which makes this composite attractive for oral multi-particulate formulations of modified release.

The effect of patient's body weight, infusion connection point, and infusion pump position on intravenous multi-infusion drug delivery at low infusion rates suitable for premature neonates.

Parenteral drug administration in the neonatal intensive care involves complex pharmacotherapy adjusted for the patient's weight, fluid allowance, and complex multi-infusion systems. We investigated the delivery rate of a model drug through a multi-infusion system consisting of six intravenous infusions. Delivery rate of the model drug was determined after infusion initiation and termination. Measurements were collected spectrophotometrically in real time. Time to drug delivery and the amount of drug delivered were measured. The longest time to drug delivery was observed for a 500 g neonate model with a distal infusion connection point and neutral pump position (337 ± 30 min, P < 0.001). The shortest time was observed for a 1000 g neonate model in the combination of proximal infusion connection point and neutral pump position (18 ± 12 min, P < 0.05). The expected 100% of the drug was delivered only in two combinations: 500 g and 1000 g neonate models, proximal infusion connection point and neutral pump position (100.4 ± 4.7%, P = 0.819 and 100.2 ± 2.7%, P = 0.874, respectively). While the least drug was delivered to a 500 g neonate model in the combination of distal infusion connection point and neutral pump position (27.5 ± 5.8%, P < 0.001). Delayed drug delivery to premature neonates due to multi-infusion systems may compromise accurate drug administration and lead to dosing errors.

10 clinical tips for advancing patient safety when using syringe pump systems for microinfusion intravenous drug therapy.

10 clinical tips for advancing patient safety when using syringe pump systems for microinfusion intravenous drug therapy.

3D printing and enteric coating of a hollow capsular device with controlled drug release characteristics prepared using extruded Eudragit® filaments

This work focuses on the extrusion of a brittle, tacky, cationic copolymer i.e. Eudragit® E-100 to prepare filament and subsequent 3D printing of hollow capsular device using the extruded filament. An optimum amount of talc and triethyl citrate was used for the possible extrusion of the polymer. There was no thermal and chemical degradation of the polymer observed after extrusion confirmed by DSC and FTIR analysis. Microscopic analysis of the printed capsule showed the layer-by-layer manner of 3D printing. Capsule parts were printed according to the set dimensions (00 size) with minimal deviation. Printed capsule showed the soluble behaviour in gastric fluid pH 1.2 where within 15 min the encapsulated drug encounters with the dissolution medium and almost 70% drug was dissolved within 4 hr. In case of phosphate buffer pH 6.8, the printed capsule showed a longed swelling behaviour up to 12 hr and then gradually bursting of capsule occurred wherein more than 90% encapsulated drug was dissolved within 36 hr. Enteric coating of the printed capsule showed similar behaviour in alkaline medium that observed with non-enteric capsule. This indicates the potential application of this printed capsules for both gastric and intestinal specific delayed drug delivery by a single step enteric coating process.

Gel Formulation of Nabumetone and a Newly Synthesized Analog: Microemulsion as a Photoprotective Topical Delivery System.

Photostability studies were performed on topical formulations containing the anti-inflammatory drug Nabumetone and an analog newly synthesized in order to achieve better photostability and pharmacokinetic profile. Stability tests, according to the International Conference on Harmonization rules, were applied on ethanol solutions and topical gel formulations of both compounds. The photodegradation profiles were monitored by Multivariate curve resolution applied to the UV spectral data. The inclusion of the compounds in microemulsion was investigated to improve light stability and, at the same time, to ensure a sustained release system for skin delivery. All the formulations in solution, gel, microemulsion, and microemulsion-in-gel were exposed to a forced irradiation of 350 W/m2, corresponding to a 21 kJ/m2 min, for up to 300 min. Photostability increased significantly for both drugs in the liquid microemulsion and microemulsion-in-gel, compared to the ethanol solution and plain gel, reaching a residual drug of 97% and 98% for Nabumetone and analog in microemulsion-in-gel, respectively. Permeation experiments on the microemulsion-in-gel showed a better performance of the analog formulated at 0.2%, compared to the same formulation of Nabumetone at 0.7%. These results highlight the potential of the designed matrices as delayed drug delivery systems along with the use of lower drug doses leading to reduced side effects.

Optimization of Ethyl Cellulose Microspheres Containing Satranidazole Using 32 Factorial Design

Intestinal amoebiasis is an infection of the large intestine caused by microscopic one-celled parasites, Entamoeba histolytica. Intestinal amoebiasis has a worldwide distribution and many drugs are available for the same. For better management of intestinal amoebiasis, satranidazole is a potent drug. For its successful delivery to colon, satranidazole must be protected in gastrointestinal tract and then released later in colon. This delayed drug delivery can be achieved using microspheres of satranidazole. Thus the aim of the study is to prepare a multi-particulate system for colonic delivery of satranidazole for better management of intestinal amoebiasis. It is proposed to formulate satranidazole microspheres using emulsion-solvent evaporation technique with ethyl cellulose as a polymer. Since particle size plays an important role in drug release from microspheres, it was optimized using 32 full factorial design in 2 stage. Prepared microspheres were evaluated for particle size, yield, drug loading, encapsulation efficiency, cumulative percentage release in 10 hrs and 24 hrs. The best batch was selected and further evaluated. The release of drug from best batch was compared with dissolution of pure drug. These results suggest that multi-particulate system of ethyl cellulose microspheres could successfully be utilized for colon delivery of satranidazole for better management of intestinal amoebiasis.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp

Modified pH independent/ time controlled explosion system (TES) for targeted drug delivery in the lower intestinal tract: Formulation and pharmacokinetic evaluation in healthy volunteers

The current work aimed to formulate a modified pH independent/time controlled release tablet for delayed drug delivery. The effect of different coating levels and polymer combination on drug release was investigated. Propranolol HCl (PRO) was chosen as a freely water soluble model drug. Statistical analysis of data revealed the significant (P < 0.05) influences of (i) coating level of swelling layer (SL), (ii) Different ethyl cellulose/hydrophilic polymer combination in rupturable layer and (iii) coating level of the rupturable layer (RL) on tL (lag time) and t90 (time for 90% drug release). The best achieved system; formed of 10% coating level croscarmellose sodium as inner swelling layer, 7% coating level of ethylcellulose/polyethylene oxide 205 (50:50) as an outer rupturable layer showed a tL of (10 h) followed by 90% drug release in the following 2 h. The in vivo pharmacokinetics of PRO following oral administration of the best achieved system (PF8) and Inderal® were assessed in healthy volunteers. The in vivo studies showed drug release of PRO following a tLof 6 h and a tmax of 8 h. The developed systems pave the way for delayed pulsatile release of other water soluble drugs for pH independent delayed drug delivery.

Small Molecule-Based Fluorescent Organic Nanoassemblies with Strong Hydrogen Bonding Networks for Fine Tuning and Monitoring Drug Delivery in Cancer Cells.

Bright supramolecular fluorescent organic nanoassemblies (FONs), based on strongly polar red-emissive benzothiadiazole fluorophores containing acidic units, are fabricated to serve as theranostic tools with large colloidal stability in the absence of a polymer or surfactant. High architectural cohesion is ensured by the multiple hydrogen-bonding networks, reinforced by the dipolar and hydrophobic interactions developed between the dyes. Such interactions are harnessed to ensure high payload encapsulation and efficient trapping of hydrophobic and hydrogen-bonding drugs like doxorubicin, as shown by steady state and time-resolved measurements. Fine tuning of the drug release in cancer cells is achieved by adjusting the structure and combination of the fluorophore acidic units. Notably delayed drug delivery is observed by confocal microscopy compared to the entrance of hydrosoluble doxorubicin, demonstrating the absence of undesirable burst release outside the cells by using FONs. Since FON-constituting fluorophores exhibit a large emission shift from red to green when dissociating in contact with the lipid cellular content, drug delivery could advantageously be followed by dual-color spectral detection, independently of the drug staining potentiality.

Electrosprayed hydrophilic nanocomposites coated with shellac for colon-specific delayed drug delivery

Advanced medicated nanomaterials that provide time- and target-specific drug release profiles are highly desired for efficacious drug delivery. In this study, a structural nanocomposite (P2) consisted of tamoxifen citrate (TC) and polyvinylpyrrolidone (PVP) (2:8, w:w) as core and shellac as shell was designed and fabricated using a modified coaxial electrospraying process. Shellac solution, which could not be converted into solid particles individually, was explored as a shell working fluid to encapsulate the core TC-PVP blending solution, which could be electrosprayed into solid particles (P1) all alone. SEM and TEM evaluations demonstrated that the quality of the core-shell particles P2 was higher than that of the monolithic particles P1 in terms of particle diameter, size distribution and number of satellites. XRD results suggested that TC was similarly present in an amorphous state in particles P1 and P2 due to its fine compatibility with PVP, which was verified through FTIR tests. In vitro dissolution experiments suggested that P2 could provide the designed drug colon-specific delayed release characteristics, passing through acidic conditions of pH2.0 dissolution media and freeing all of the loaded TC within 5min at pH7.4 dissolution media.

Prevention of Chronic Post-Thoracotomy Pain in Rats By Intrathecal Resolvin D1 and D2: Effectiveness of Perioperative and Delayed Drug Delivery.

In studies of rats, the injection of the proresolving compounds of the resolvin-D series into spinal fluid, before or just after thoracotomy surgery, prevents the occurrence of acute and chronic pain. If these chemicals, which have shown no side-effects, were used in humans it might greatly reduce chronic postoperative pain.

Carboxymethyl Starch Excipients for Drug Chronodelivery.

Carboxymethyl starch (CMS) is a pH-responsive excipient exhibiting also interesting properties for applications in delayed drug delivery systems. This work was aimed to investigate the release properties of monolithic and dry-coated tablets based on ionic sodium CMS and on protonated CMS, formulated with three model tracers: acetaminophen, acetylsalicylic acid (ASA), and sodium diclofenac. The sodium or protonated CMS were obtained from the same CMS synthesis by controlling the final pH of reaction media. The two forms of CMS were confirmed by the Fourier transform infrared spectroscopy. The in vitro dissolution profiles for monolithic and double core tablets were different and allowed a better understanding of characteristics of the two excipient forms. It was found that the protonated CMS exhibited a better stability in simulated gastric fluid in comparison to its sodium salt in monolithic dosage forms, whereas both excipients afforded a complete gastric protection of drugs when formulated as dry-coated dosages. Determination of water uptake and erosion rate of monolithic matrices based on the two CMS forms showed different mechanisms involved in the delivery of the three model active molecules in simulated intestinal media. When pancreatic enzymes were added in dissolution media, the drug release was accelerated showing that CMS is still a substrate for alpha-amylase. Both sodium and protonated starch excipients, formulated as dry-coated dosages, afforded a good gastro-protection and allowed a drug chronodelivery at various intervals up to 4-5h. They could be considered as an alternative for delayed delivery and a solvent-free coating procedure.

Homogeneous carboxymethylated orange pulp cellulose: Characterization and evaluation in terms of drug delivery

The aim of the present study is to develop an environment-friendly method to convert orange pulp wastes to Carboxymethyl cellulose (CMC) by homogeneous substitution. Carboxymethylation of Orange pulp treated with alkaline PEG solutions was investigated and characterized by means of TGA, DSC, XRD and SEM and compared with commercial CMC. The TGA data reveals that shifting of peaks was observed towards lower temperature with increase in monochloroacetic acid (MCA). SEM studies showed greater blending of particulate powder with increasing MCA content. The crystallinity of synthesized CMC was found to be lower than the commercial CMC. Finally, the cellulosic materials were evaluated for the formulation and dissolution studies of prepared tablets. Dissolution release studies shows that synthesized cellulose (CMCOP5, CMCOP8, CMCOP11) release up to 70.1±0.04%, whereas the commercial CMC 78.184±0.07% in 8h respectively and thereby suggests that it may be used in delayed drug delivery and targeting drugs to the colon. The synthesized CMC from orange pulp may be used as substitute for the commercial CMC.

Physicochemical properties and release characteristics of starches from seeds of Indian Shahi Litchi

Many conventional sources of starches are from staple foods. Non-conventional and cheap sources of starch are being explored. Starch was isolated from Shahi Litchi seeds using two extraction media; acidic (citric acid 0.3%, w/w; LC) and alkaline (NaOH 0.5%, w/w; LN). Each starch was investigated for various properties such as structural, morphological and functional. The percentage yield of LN and LC was 11% and 12.6%, respectively. Morphological properties of both starches show same structural makeup, but compound granules were in LN starch. Moisture content, amylose content was found to be higher LC starch than in LN starch, which indicates that extraction media affects the properties of starch. FTIR confirmed the carbohydrate nature of the both isolated starches. TGA data of both starches reveal slight difference in stability with temperature. In vitro release of both starches shows the release up to 58.95±0.04% and 67.184±0.07% in 5h for LN and LC, respectively, that indicates that these starches can be used in delayed drug delivery and targeting drugs to the colon.

Illustrative neonatal cases regarding drug delivery issues.

Illustrative neonatal cases regarding drug delivery issues.

Controlled drug release from antibiotic‐loaded layered double hydroxide coatings on porous titanium implants in a mouse model

As an alternative to degradable organic coatings the possibility of using layered double hydroxides (LDHs) to generate implant coatings for controlled drug delivery was evaluated in vivo and in vitro. Coatings prepared from LDH suspensions dissolved slowly and appeared compatible with cultured cells. LDH coatings loaded with an antibiotic resulted in antibacterial effects in vitro. The LDH coating prolonged the drug release period and improved the proliferation of adherent cells in comparison to pure drug coatings. However, during incubation in physiological solutions the LDH coatings became brittle and pieces occasionally detached from the surface. For stress protection porous titanium implants were investigated as a substrate for the coatings. The pores prevented premature detachment of the coatings. To evaluate the coated porous implants in vivo a mouse model was established. To monitor bacterial infection of implants noninvasive in vivo imaging was used to monitor luminescently labeled Pseudomonas aeruginosa. In this model porous implants with antibiotic-loaded LDH coatings could antagonize bacterial infections for over 1 week. The findings provide evidence that delayed drug delivery from LDH coatings could be feasible in combination with structured implant surfaces.

Novel co-axial prilling technique for the development of core–shell particles as delayed drug delivery systems

In this study, biocompatible double layered beads consisting of pectin core and alginate shell were prepared through a single step manufacturing process based on prilling apparatus equipped with co-axial nozzles. The core was loaded with piroxicam (PRX) as model non-steroidal anti-inflammatory drug (NSAID). Morphology, size distribution and shape of the double layered beads varied depending on the operative conditions and polymer concentrations. Co-axial nozzles size, applied vibration frequency, gelling conditions and, mainly, polymers mass ratio were identified as critical variables. Particularly, the relative viscosity of polymeric feed solutions inside the nozzle was the key parameter to obtain homogeneous and well-formed coated particles. The produced beads were investigated for the release kinetic in different media. Once PRX was encapsulated within the pectin core, a controlled release pattern was observed. Particularly, beads produced with 4:1 core/shell ratio (F4) released less than 30% of PRX in simulated gastric fluid (SGF) while total liberation of the drug was achieved during the next 3h in simulated intestinal fluid (SIF). More interesting, F4 tested in SIF was able to release drug in a delayed and sustained manner at established time points (2h_8.2%, 3h_32.2%, 4h_70.1% and 5h_about 100%). Based on the above results, co-axial prilling approach is expected to provide success in manufacturing systems with delayed drug release profiles. Such systems may be potentially useful in targeting diseases which are affected by the circadian rhythm, such as chronic inflammation.

Recirculatory Pharmacokinetic Modeling

Recirculatory Pharmacokinetic Modeling

Design and evaluation of succinylated soy protein tablets as delayed drug delivery systems

The impact of succinylation on soy proteins as excipients for delayed delivery of drugs in the gastrointestinal tract was studied. Succinylation decreased protein solubility and protein charge density at pH 1.2 and increased solubility and zeta potential at pH above 4.5. Tablet erosion and swelling were decreased at pH 1.2 and increased at pH 7.5. FTIR analysis indicated polypeptide chain unfolding as a result of succinylation. Tablets of protein succinylated 50% or 100% released less than 10% of loaded riboflavin or rifampicin in 2 h at gastric pH in the presence of pepsin but released these compounds rapidly at intestinal pH. Succinylated soy protein tablets were thus gastroresistant, suggesting their use as excipients for controlled release of medicinal or nutraceutical agents.

PREPARATION OF ETHYLCELLULOSE COATED GELATIN MICROSPHERES AS A MULTIPARTICULATE COLONIC DELIVERY SYSTEM FOR 5-AMINOSALICILIC ACID

In the long-term management of ulcerative colitis patients, repeat dosing maybe required. Since 5-ASAis largely absorbed from the upper intestine, selective delivery of drugs into the colon may be regarded as a better method of drug delivery with fewer side effects and a higher efficacy. The aim of this study was to prepare and evaluate a double coated multiparticulate system for 5-ASAdelivery using gelatin and ethylcellulose as the primary and secondary polymer respectively. Gelatin microspheres containing 5-aminosalicylic acid was produced using the solvent evaporation method. Prepared gelatin microspheres were spherical, free flowing, non-aggregated and showed no degradation in the acidic medium. Entrapment efficacy of microspheres was about 50%. Results showed that drug release was fast and complete and is affected by the amount of core material entrapped. Gelatin microspheres were then coated by ethylcellulos e using a coacervation phase separation technique. The idea for this approach was to prepare a delayed drug delivery system, in which, ethylcellulose protects particles for the first 6 h transit through the gastrointestinal tract. However, it was shown that this system could provide a suitable drug release pattern for colonic delivery of active agents, as 30% of the drug was released from the ethylcellulose-coated microcapsules within 6 h, while this amount was 90% of the loaded drug for gelatin microspheres under the same condition.