A new oral microsphere drug delivery system

A new oral proteinoid microsphere drug delivery system is discussed with respect to its unique dependence on pH. Extensive evidence indicate that this technique not only can be used to deliver the protein and polar macromolecular drugs which are currently administered via injection, but also can be used to administer antigens and vaccines. Future work has been proposed to study the physical interaction of specific drugs with specifically designed oligopeptides structures.     

Design and optimization of a new self-nanoemulsifying drug delivery system

To improve the dissolution rate of ibuprofen, a model poorly water soluble drug, self-nanoemulsifying drug delivery systems (SNEDDS) were developed. Various surfactants and oils were screened as candidates for SNEDDS on the basis of droplet size of the resulting emulsions. The influence of the constituent structure, concentration and the composition of SNEDDS formulations, and the emulsifier HLB value, on the properties of the resulting emulsions was systematically investigated. Several SNEDDS formulations were employed to study the relationship between the emulsion droplet size and the dissolution rate of ibuprofen. The dissolution rate was accelerated by decreasing the nanoemulsion droplet size, and was significantly faster than that from a conventional tablet. The optimal SNEDDS formulation had a mean nanoemulsion droplet diameters of 58 nm in phosphate buffer, pH 6.8 (simulated intestinal fluid), and released ibuprofen more than 95% within 30 min. Therefore, these novel SNEDDS carriers appear to be useful for controlling the release rate of poorly water soluble drugs.     

Green amorphous nanoplex as a new supersaturating drug delivery system

The nanoscale formulation of amorphous drugs represents a highly viable supersaturating drug-delivery system for enhancing the bioavailability of poorly soluble drugs. Herein we present a new formulation of a nanoscale amorphous drug in the form of a drug-polyelectrolyte nanoparticle complex (or nanoplex), where the nanoplex is held together by the combination of a drug-polyelectrolyte electrostatic interaction and an interdrug hydrophobic interaction. The nanoplex is prepared by a truly simple, green process that involves the ambient mixing of drug and polyelectrolyte (PE) solutions in the presence of salt. Nanoplexes of poorly soluble acidic (i.e., ibuprofen and curcumin) and basic (i.e., ciprofloxacin) drugs are successfully prepared using biocompatible poly(allylamine hydrochloride) and dextran sulfate as the PE, respectively. The roles of salt, drug, and PE in nanoplex formation are examined from ternary phase diagrams of the drug-PE complex, from which the importance of the drug's charge density and hydrophobicity, as well as the PE ionization at different pH values, is recognized. Under the optimal conditions, the three nanoplexes exhibit high drug loadings of ~80-85% owing to the high drug complexation efficiency (~90-96%), which is achieved by keeping the feed charge ratio of the drug to PE below unity (i.e., excess PE). The nanoplex sizes are ~300-500 nm depending on the drug hydrophobicity. The nanoplex powders remain amorphous after 1 month of storage, indicating the high stability owed to the PE's high glass-transition temperature. FT-IR analysis shows that functional groups of the drug are conserved upon complexation. The nanoplexes are capable of generating prolonged supersaturation upon dissolution with precipitation inhibitors. The supersaturation level depends on the saturation solubility of the native drugs, where the lower the saturation solubility, the higher the supersaturation level. The solubility of curcumin as the least-soluble drug is magnified 9-fold upon its transformation to the nanoplex, and the supersaturated condition is maintained for 5 h.     

Design and gamma-scintigraphic evaluation of a floating and pulsatile drug delivery system based on an impermeable cylinder

A blend of floating and pulsatile principles of drug delivery system seems to present the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release. The objective of this study was to develop and evaluate a floating and pulsatile drug delivery system based on an impermeable cylinder. Pulsatile capsule was prepared by sealing the drug tablet and the buoyant material filler inside the impermeable capsule body with erodible plug. The drug delivery system showed typical floating and pulsatile release profile with a lag time followed by a rapid release phase. The lag time prior to the pulsatile drug release correlated well with the erosion properties of plugs and the composition of the plug could be controlled by the weight of the plug. The buoyancy of the whole system depended on the bulk density of the dosage form. Gamma-scintigraphic evaluation in humans was used to establish methodology capable of showing the subsequent in vivo performance of the floating and pulsatile release capsule. Developed formulations showed instantaneous floating with no drug release during the lag time followed by a pulse drug release. From the gamma-scintigraphic results, the pulsatile release capsule we prepared could achieve a rapid release after lag time in vivo, which was longer than that in vitro. The scintigraphic evaluation could confirm qualitatively that the system with in vitro lag time of 4.0 h provided, with relatively high reproducibility, a pulsatile release occurred around 5.0 h after administration.     

Absorption of diltiazem in beagle dog from pulsatile release tablet.

An orally applicable pulsatile drug delivery system in dry-coated tablet form was prepared using diltiazem hydrochloride as the model drug, and a polyvinyl chloride-hydrogenated castor oil-polyethyleneglycol mixture as the outer shell of the tablet. In vitro drug release from the prepared tablet exhibited a typical pulsatile pattern with a 7 h lag phase (non-drug release period). This dosage form was orally administered to three beagle dogs under non-fasting and fasting conditions, and the plasma concentration level of diltiazem was determined according to time after administration. The result of the in vivo study in non-fasting dogs suggested that the drug could be released in the gastrointestinal tract as in the in vitro test. However, under the fasting condition, a large difference in the plasma concentration profile was found, suggesting that the disintegration time of the tablet tended to be influenced by the feeding condition of subject.     

A new drug delivery system using plasma-irradiated pharmaceutical aids. VIII. Delayed-release of theophylline from double-compressed tablet composed of eudragit as wall material.

The rapid release from a double-compressed tablet containing theophylline as a core drug with the pH-dependent water-soluble polymers, Eudragit L100, S100 or L100-55 used as a wall material was suppressed by argon plasma-irradiation due to an effect of inter-segmental cross-link reactions on the decrease in the surface polymer solubility of outer layer. In addition, the rapid theophylline release from the double-compressed tablet of Eudragit L100-55 with a lower glass transition temperature (Tg) has converted into the delayed-release system under a set of plasma operational conditions due to an additional effect of plasma heat flux on softening of Eudragit L100-55 surface resulting in the formation of the film-like surface with a particle-particle interlinking of the outer layer.     

A novel biocompatible drug carrier for oral delivery and controlled release of antibiotic drug: loading and release of clarithromycin as an antibiotic drug model

In this work, a novel biocompatible carrier was designed by modification of nanoporous carbon material and synthesized by hydrothermal condensation of d-Fructose, as the carbon source, in the presence of Pluronic^® F127, as the surfactant. The prepared material is completely biocompatible and suitable for oral drug delivery. As this nanoporous carbon has surface decorated hydroxyl groups, they are able to react with 3-aminopropyltriethoxysilane agent and produce amino-functionalized nanoporous carbon. The synthesis of amine-modified carbon nanoporous material was confirmed by X-ray powder diffraction, IR spectroscopy, elemental analysis, thermal analysis and nitrogen adsorption analysis. Clarithromycin as an active drug molecule with carbonyl and hydroxyl functional groups in chemical structure was chosen as the drug model and stored in pores of the amine-modified nanoporous carbon. Release of clarithromycin from modified nanoporous carbon was investigated in mouth and stomach pH values. The results showed that this drug carrier can transfer the drug up to stomach without any leak or release. The release time was investigated, and the results showed that the carrier is also successful for the controlled-release delivery.     

Numerical study of a drug release profile in the transdermal drug delivery system

Drug release by diffusion from an unstressed thin polymer film with a dissolved crystallizable component was simulated using a kinetic Monte Carlo model. This model was used previously to study Ostwald ripening in a high crystallizable component regime and was shown to correctly simulate solvation, diffusion, and precipitation. In this study, the same model with modifications was applied to the drug transportation and release in the low concentration regime of interest to the transdermal drug delivery system (TDS) community. We demonstrate the model's utility by simulating diffusion, crystal precipitation, growth and shrinkage during storage, and drug release from the thin TDS to a surface under different conditions. The simulation results provide a first approximation for the drug release profile occurring from TDS to skin. It has been reported that growth of drug crystals in TDS occurs mainly in the middle third of the polymer layer at relatively higher temperatures. The results from the simulations showed that the release rate and concentration profile of a TDS depend on the dissolution process of the crystal. At low storage temperature, the drug precipitates to form small evenly distributed crystals throughout the thickness of the TDS patch. The release rate of these small, evenly distributed crystals most closely matched that of a completely dissolved drug.     

A new drug delivery system using plasma-irradiated pharmaceutical aids. IX. Controlled-release of theophylline from double-compressed tablet composed of cellulose derivatives as wall material.

The rapid release from a double-compressed tablet containing theophylline with the water-soluble polymer, hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose phthalate (HPMCP), used as a wall material can be suppressed by argon plasma-irradiation and changed into the sustained-release system due to a decrease in solubility of the outer layer. It was shown that the release profiles can be varied so as to cause theophylline release at different rates, depending on the set of conditions chosen for tablet manufacture and for plasma operation.     

Preparation and in vivo studies of a new drug delivery system

Polyhexylcyanoacrylate nanoparticles have been prepared with vincamine as the model drug. These particles had an average size of 200 nm and adsorbed approximately 435 of vincamine. The adsorption of vincamine to nanoparticles modified the distribution of vincamine in tissues. After iv injection the distribution volumes were increased in comparison with an aqueous solution of drug. In comparison with an aqueous solution of drug, the absolute bioavailability of vincamine was also increased after an oral administration of nanoparticles.     

Design of a rate- and time-programming drug release device using a hydrogel: pulsatile drug release from kappa-carrageenan hydrogel device by surface erosion of the hydrogel

We have found that a repetitive pulsatile drug release with a certain time interval is observed from a monolithic hydrogel device by surface erosion of the hydrogel. As a model system of pulsatile drug release, dibucaine hydrochloride and kappa-carrageenan hydrogel were chosen as a drug and a device, respectively. Electrostatic interactions between dibucaine hydrochloride and kappa-carrageenan polymer segments are strong, since dibucaine hydrochloride is positively charged and each disaccharide repeating unit of kappa-carrageenan chains has one sulfate group. Dibucaine hydrochloride was loaded into the hydrogel by immersing dry kappa-carrageenan hydrogel disks in a dibucaine hydrochloride solution for 24 h. The pulsed release of dibucaine hydrochloride from the device was observed every 50 min between 30 and 250 min after the release starts. The weight of kappa-carrageenan hydrogel decreases in an oscillatory manner with time in distilled water. The oscillatory changes observed in the hydrogel weight in distilled water are considered to be caused by influx and efflux of water molecules into and from the surface and core of the hydrogel and by polymer liberation from the hydrogel. This phenomenon was well explained by our kinetic model [Colloids and Surfaces B 8 (1996) 93-100]. The time interval between pulses observed in drug release coincides with that observed in the oscillatory weight change of the hydrogel. From these, it was concluded that the pulsatile release of dibucaine hydrochloride from the device was caused by the pulsatile liberation of swollen kappa-carrageenan hydrogel from the surface of the device.     

Chitosan modified with terephthaloyl diazide as a drug delivery system

Russian Chemical Bulletin - pH- and thermo-sensitive hydrogels based on chitosan cross-linked with terephthaloyl diazide were synthesized. A new formulation of the polysaccharide modified with...     

Novel modified nanoporous silica for oral drug delivery: loading and release of clarithromycin

Nanoporous silica SBA-15 was prepared to evaluate its application as an oral drug delivery system. A series of surface-functionalized nanopore materials as efficient clarithromycin delivery carriers was investigated. An efficient pH-responsive carrier system was constructed by hydrogen bond interaction between carboxyl and hydroxyl groups in the clarithromycin and the amine group in modified SBA-15. HPLC analyses of clarithromycin were run on a C₁₈ column using a mobile phase comprised of potassium dihydrogen phosphate, acetonitrile and methanol (30:40:30, v/v/v). Active molecules such as clarithromycin could be stored and released from the pore voids of SBA-15 by changing the pH. The amount of clarithromycin stored in the pores of nanoporous silica based on TREN [tris(2-aminoethyl) amine]-modified SBA-15 rods was up to 46 ± 4.8 wt% at pH 8. In addition, when the pH was below 4, clarithromycin was steadily released from the pores of SBA-15 (up to 97 wt% in simulated gastric medium).     

Towards site-specific nanoparticles for drug delivery application: preparation,characterization and release performance

Due to the uncontrollable drug release, traditional chemotherapies could cause great side-effects and are detrimental to normal tissue or organs. Therefore, to avoid those side-effects, drug delivery system (DDS) which is capable of releasing drug molecules at target area with controllable rate according to the development of the disease or to certain functions of the organism/biological rhythm, has attracted especially focus in recent years. In this research, we devoted our efforts in constructing a core–shell nanocomposite to meet the above requirements. The superparamagnetic Fe₃O₄ nanoparticles were chosen as the core to introduce the magnetic guiding as well as site-specific properties in this novel drug carrier. The core was further encapsulated by silica-based molecular sieve MCM-41 (briefly denoted as MS in this research), which was consisted by immense highly ordered hexagonal tunnels to offer plenty cavity for molecules of drug. A light stimuli-responsive ligand, which is a derivative from light-responsive precursor 4,5-diazafluoren-9-one (indicated in the paper as DAFO), was further connected to the MCM-41 tunnels. The ligand can be excited by light and will flip over, making the tunnels of MCM-41 switch from close to open with light on and light off. The nanocomposite thus became capable of releasing drug molecules at certain wavelength of light. In the final, the nanoparticles were tested via SEM/TEM, XRD, FT-IR spectra, thermogravimetry and N₂ adsorption/desorption to verify the structure. The MTT testing of our nanocomposite reveals no obvious cytotoxicity with non-morbid L929 murine fibroblast cells line, indicating that it could be used as a DDS candidate. The cargo releasing behaviors were studied on cytarabine loaded composite: DAFO@MS@Fe₃O₄ in simulated body fluids.     

Synthesis of biocompatible nanocomposite hydrogels as a local drug delivery system

Nanocomposite biocompatible hydrogels (NCHG) were synthesised as model systems for in situ cured potentially local drug delivery devices for curing periodontal infections. The composite consists of the following components: nanoparticles (NPs), matrix gel, and chlorhexidine (CHX) as antibacterial drug. The NPs were obtained by free radical initiated copolymerization of the monomers, 2-hydroxyethyl methacrylate (HEMA) and polyethyleneglycol dimethacrylate (PEGDMA), in aqueous solution. The same monomers were used to prepare crosslinked matrices by photopolymerization. NCHGs were obtained by mixing NPs, monomers, and drug in an aqueous solution then crosslinked by photopolymerization. Mechanical properties, swelling behavior, and the kinetics of drug release have been investigated. It was found that compression strength values increased with increasing ratio of the crosslinker PEGDMA. Incorporation of NPs into the matrix resulted similar compression strength as the matrix hydrogel. The hydrated NCHGs swelled more slowly but admitted more water. The drug was incorporated in NPs by swelling in CHX aqueous solution or added to the solution of monomer mixture followed by photopolymerization. Studies of release kinetics revealed that on average 60% of the loaded drug was released. The most rapid release was observed over a 24 h period for matrix gels with low crosslinking density. For NCHGs, the release period exceeded 48 h. An unexpected result was observed for NCHGs without drug in the NPs. In this case, increasing release was observed for the first 24 h. Thereafter, however, the apparent quantity of detectable drug decreased dramatically.     

Design and synthesis of a series of novel, cationic liposaccharide derivatives as potential penetration enhancers for oral drug delivery

Oral delivery remains a challenge for a number of drug candidates with low absorption profile (poor membrane permeability, lack of stability, solubility issues or susceptibility to enzymatic degradation) and various methodologies have been investigated to overcome it. The approach presented here consists of associating, by ion-pairing, a hydrophilic, ionizable model drug to a series of synthetic counter-ionic entities with a controlled degree of lipophilicity in order to enhance its penetration of biomembranes and offer some protection against in situ degradation, while preserving its biologically active chemical structure. We report herein the synthesis of a series of positively charged potential penetration enhancers designed from d-glucose, 2-aminododecanoic acid, and additional lipophilic amino acids, and converted afterward into quaternary ammoniums in an optimized, innovative one-step reaction. Each liposaccharide derivative synthesized was fully characterized and their ability to generate micelles in solution was assessed by isothermal titration calorimetry.     

Design and preparation of pH-responsive curdlan hydrogels as a novel protein delivery vector

New pH-responsive saccharide hydrogels were designed and prepared using curdlan derivatives(curdlan-Bochistidine, CUR-HIS). The CUR-HIS hydrogels possessed highly porous structures. The swelling ratios of CUR-HIS hydrogels increased with the degree of substitution of Boc-histidine groups. And the addition of 0.5 mol/L Na Cl provoked a sharp reduction of swelling ratio of CUR-HIS hydrogels. Bovine serum albumin(BSA) can be efficiently encapsulated into CUR-HIS hydrogels. Moreover, the release profiles of BSA at different p H values from CUR-HIS hydrogels were significantly different. These hydrogels showed good biocompatibility in the cytotoxicity assays. The CUR-HIS hydrogels are of great potential in biomedical applications such as protein delivery systems.     

Synthesis and characterization of a pH responsive and mucoadhesive drug delivery system for the controlled release application of anti-cancerous drug

In this work a novel pH sensitive composite, polyacrylamide grafted succinyl chitosan intercalated bentonite (AAm-g-NB/SC) was prepared as a drug carrier system for the controlled delivery of paclitaxel. Characterization of the drug delivery system was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal analysis etc. The equilibrium swelling behaviour of the composite was studied and the result showed a maximum at pH 7.4. The in vitro drug release study of paclitaxel indicated that about 15.6% of drug release was found to be occurred at pH 1.2 within 16 h, whereas about 82.5% of drug release was occurred at the intestinal pH condition of 7.4. In vitro biocompatibility study was performed and the result showed good biocompatibility of the composite in the concentration range 6.25–100 µg/mL. The cytotoxicity assay was carried out in cancerous cell line of Human colorectal Adenocarcinoma. Mucous glycoprotein assay study showed that the drug delivery system having good apparent adhering property towards mucin. The investigation indicated that paclitaxel, an anticancer drug can be successfully entrapped in the AAm-g-NB/SC composite for the controlled and targeted delivery for colorectal cancer therapy.     

Modified MCM-41 as a drug delivery system for acetylsalicylic acid

The modification of prepared MCM-41 by different groups (amino, chloro and oxo) was studied. Prepared materials were treated by acetylsalicylic acid and hybrid materials were characterized, compared from the point of view of immobilized amount of active substance. The highest amount of acetylsalicylic acid was detected using methyl-tert- butyl ether as a solvent and MCM-41 without modification after 1 h (0.35 g per 1 g of the support) or MCM modified by amino group after 5 h (0.37 g per 1 g of the support) as a support. Using amino modified MCM, the longer treatment by acetylsalicylic acid converged to the equilibrium and after 24 h the immobilized amount was 0.3 g per 1 g. A dissolution in vitro study was carried out, comparing the stability of formed interactions. The slowest dissolution was detected using non-modified MCM-41 and oxo modified material.