In-situ forming chitosan implant-loaded with raloxifene hydrochloride and bioactive glass nanoparticles for treatment of bone injuries: Formulation and biological evaluation in animal model.

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing.

Preparation, Characterization and Pharmacokinetics Evaluation of the Compound Capsules of Ibuprofen Enteric-Coated Sustained-Release Pellets and Codeine Phosphate Immediate-Release Pellets.

The objective of this study was to prepare ibuprofen enteric-coated sustained-release pellets (IB-SRPs) and codeine phosphate immediate-release pellets (CP-IRPs) to play a synergistic role in analgesia. The pellets were developed by extrusion-spheronization and fluidized bed coating technology. The single-factor investigation was used to determine the optimal prescription and process. The sustained-release membrane of IB-SRPs was water-insoluble ethyl cellulose (EC), triethyl citrate (TEC) was used as plasticizer, and hydroxypropyl methylcellulose (HPMCP) was chose as porogen. Besides, the immediate-release layer of CP-IRPs was gastric-soluble coating film. The ibuprofen and codeine phosphate compound capsules (IB-CP SRCs) were prepared by IB-SRPs and CP-IRPs packed together in capsules with the optimum doses of 200 and 13 mg, respectively. The prepared pellets were evaluated by scanning electron microscopy and dissolution test. Pharmacokinetic studies in beagle dogs indicated that the optimized IB-CP SRCs had smaller individual differences and better reproducibility comparing with commercial available tablets. Additionally, IB-CP SRCs achieved consistency with in vivo and in vitro tests. Therefore, IB-CP SRCs could play a great role in rapid and long-term analgesic.

Preparation, Characterization and In Vitro / In Vivo Evaluation of Oral Time-Controlled Release Etodolac Pellets.

The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis.

Mucoadhesive Properties of Thiolated Pectin-Based Pellets Prepared by Extrusion-Spheronization Technique.

The aim of this study was to develop mucoadhesive pellets on a thiolated pectin base using the extrusion-spheronization technique. Thiolation of pectin was performed by esterification with thioglycolic acid. The molecular weight and thiol group content of the pectins were determined. Pellets containing pectin, microcrystalline cellulose, and ketoprofen were prepared and their mucoadhesive properties were evaluated through a wash-off test using porcine intestinal mucosa. The in vitro ketoprofen release was also evaluated. Thiolated pectin presented a thiol group content of 0.69 mmol/g. Thiolation caused a 13% increase in polymer molecular weight. Pellets containing thiolated pectin were still adhering to the intestinal mucosa after 480 min and showed a more gradual release of ketoprofen. Conversely, pellets prepared with nonthiolated pectin showed rapid disintegration and detached after only 15 min. It can be concluded that thiolated pectin-based pellets can be considered a potential platform for the development of mucoadhesive drug delivery systems for the oral route.

Comparison of Borate Bioactive Glass and Calcium Sulfate as Implants for the Local Delivery of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus-Induced Osteomyelitis in a Rabbit Model.

There is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TEC in vitro and to cure methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC.

Preparation and evaluation of enteric-coated delayed-release pellets of duloxetine hydrochloride using a fluidized bed coater.

In this study, the enteric-coated delayed-release pellets of duloxetine hydrochloride (DLX) were formulated using a fluidized bed coater. Three separate layers, the drug layer, the barrier layer, and the enteric layer, were coated onto inert core pellets. Among the three formulations (F1-F3), the dissolution profiles of formulation F2 were most similar to those of the marketed product, with similarity and difference factors of 83.99 and 3.77, respectively. In addition, pharmacokinetic parameters of AUC, C(max), T(max), t(1/2), K(el), and MRT of DLX for the developed formulation (F2) did not differ significantly from those for the marketed product in beagle dogs, suggesting that they were bioequivalent. Our results demonstrated that the in vitro dissolution data resembled the in vivo performance of the drug. Therefore, this study has a positive scope for further scale up and development of the formulation for achievement of the generic product.

Synthesis of a disulfide cross-linked polygalacturonic acid hydrogel for biomedical applications.

Polygalacturonic acid (PGA) hydrogel cross-linked via disulfide bonds was synthesized using a thiol oxidation reaction. PGA was grafted with cysteine to yield thiolated PGA (denoted PGAcys). Per gram, PGA-conjugated cysteine was 725 ± 77 µmol, and the degree of modification was 16.24 %. A PGAcys hydrogel film was fabricated under physiological conditions, with gel content 91.6 % and water content 43.3 %. The PGAcys hydrogel was used as a drug carrier for rosmarinic acid (RA) (denoted PGAcys/RA) and to prevent postsurgical adhesion. The in vitro dynamic release behavior of RA from the PGAcys hydrogel was analyzed. The profiles showed that 80 % of the total RA was released from the hydrogel within 15 min, followed by zero-order kinetic release. Animal implant studies showed that PGAcys and PGAcys/RA hydrogel films reduced adhesion incidence by over 90 %, significantly higher than did Hyaluronate/Carboxymethylcellulose (analogous Seprafilm™) (42 %). The PGAcys/RA hydrogel film also reduced the early inflammatory reaction.

Biodegradable IPN hydrogel beads of pectin and grafted alginate for controlled delivery of diclofenac sodium.

A novel diclofenac sodium (DS) loaded interpenetrating polymer network (IPN) beads of pectin and hydrolyzed polyacrylamide-graft-sodium alginate (PAAm-g-SA) was developed through ionotropic gelation and covalent cross-linking. The graft copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The grafting, alkaline hydrolysis, and characterization of beads were confirmed by Fourier transforms infrared spectroscopy. The crystalline structure of drug after encapsulation into IPN beads were evaluated by differential scanning colorimetry and X-ray diffraction analyses. DS encapsulation was up to 96.45 %. The effect of hydrolyzed graft copolymer/pectin ratios and glutaraldehyde concentration on drug release in acidic and phosphate buffer solutions were investigated. The release of drug was significantly increased with increase of pH. The release of drug depends on the extent of cross-linking. The results indicated that IPN beads of hydrolyzed PAAm-g-SA and pectin could be used for sustained release of DS.

Metronidazole-loaded bioabsorbable films as local antibacterial treatment of infected periodontal pockets.

BACKGROUND: Periodontal disease is infectious in nature and leads to an inflammatory response. It arises from the accumulation of subgingival bacterial plaque and leads to the loss of attachment, increased probing depth, and bone loss. It is one of the world's most prevalent chronic diseases. In this study we developed and studied metronidazole-loaded 50/50 poly(DL-lactide-co-glycolide) (PDLGA), 75/25 PDLGA, and poly(DL-lactic acid) (PDLLA) films. These films are designed to be inserted into the periodontal pocket and treat infections with controlled-release metronidazole for >or=1 month. METHODS: The structured films were prepared using the solution-casting technique. Concentrated solutions and high solvent-evaporation rates were used to get most of the drug located in the bulk, i.e., in whole film's volume. The effects of copolymer composition and drug content on the release profile, cell growth, and bacterial inhibition were investigated. RESULTS: The PDLLA and 75/25 PDLGA films generally exhibited a low- or medium-burst release followed by a moderate release at an approximately constant rate, whereas the 50/50 PDLGA films exhibited a biphasic release profile. The drug released from films loaded with 10% weight/weight metronidazole resulted in a significant decrease in bacterial viability within several days. When exposed to human gingival fibroblasts in cell culture conditions, these films maintained their normal fibroblastic features. CONCLUSIONS: This study enabled the understanding of metronidazole-release kinetics from bioabsorbable polymeric films. The developed systems demonstrated good biocompatibility and the ability to inhibit Bacteroides fragilis growth; therefore, they may be useful in the treatment of periodontal diseases.

Do in situ forming PLG/NMP implants behave similar in vitro and in vivo? A non-invasive and quantitative EPR investigation on the mechanisms of the implant formation process.

Electron paramagnetic resonance (EPR) spectroscopy was applied to monitor non-invasively the formation of in situ forming implants in vitro and in vivo after the administration of poly(lactide-co-glycolide) (PLGA)/N-methyl-pyrrolidone (NMP) solutions. The nitroxide spin probe 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TB) was incorporated in polymer solutions and samples were incubated in 0.1 M phosphate buffer (pH 7.4) at 37 degrees C or injected subcutaneously in the femoral of BALB/c mice. EPR permitted the direct and continuous determination of the NMP-water exchange during implant formation both in vitro and in living mice. The formation of the implant structure followed a two phase mechanism: over 75% of the polymer precipitated immediately after injection within the first 30 min and formed a solid shell. The subsequent moderate solidification of the implants was governed by diffusion and was completed after 24 h. The replacement of the organic solvent NMP by water was determined by polarity shifts within the implant and could be quantified. Both the kinetic of NMP-water exchange and polymer precipitation showed good in vitro-in vivo correlation.

Immobilization of Chinese herbal medicine onto the surface-modified calcium hydrogenphosphate.

To accelerate the healing of bone defects or for healing to take place, it is often necessary to fill them with suitable substance. Various artificial materials defects have been developed. Among these, calcium phosphates and bioactive glass have been proven to be biocompatibile and bioactive materials that can chemically bond with bone, and have been successfully used clinically for repair of bone defects and augmentation of osseous tissue. However, those bioceramics have only the property of osteoconduction without any osteoinduction. Many ligands have been physicochemically absorbed onto substrates to enhance cell-substrate interactions. Although widely developed, they are still limited to use in long-term implantation because of their half-life period. Thus, some interfacial modification will be required for enhancing the efficacy of the delivery system. These models involve the immobilization of biologically active ligands of natural and synthetic origin onto various substrates to produce an interface with stronger chemical bond between ligand and substrate. The advantage of covalently immobilizing a ligand is that a chemical bond is present to prevent ligand or medicine from desorption. In our study, a two-step chemical immobilization was performed to surface-modified calcium hydrogenphosphate powders. The first was to modify the surface of calcium hydrogen-phosphate (CHP) with a coupling agent of hexanmethylene diisocyanate (HMDI). CHP surface modified by HMDI is abbreviated as MCHP. The linkage between CHP and HMDI will be characterized by FTIR. The second step was to immobilize chemically Gusuibu onto MCHP. Moreover, the sorption and desorption of Gusuibu was evaluated and quantitatively analyzed by spectrophotometer and HPLC. Bioceramic CHP was surface-modified by a two-step chemical immobilization. First, the surface of calcium hydrogen-phosphate (CHP) was successfully modified with coupling agent of hexanmethylene diisocyanate (HMDI). The first step was also activated the surface of CHP to induce primary amine terminator. The reaction of this functional group with Gusuibu was the second step. We confirmed simultaneously that Gusuibu could be immobilized chemically onto the surface of MCHP. Although some immobilized Gusuibu was also released rapidly at the first 12h, the degree of the released Gusuibu was lower than both by Gusuibu-adsorbing MCHP and Gusuibu-adsorbing CHP.

Preparation and evaluation of a melt pelletised paracetamol/stearic acid sustained release delivery system.

The potential of a sustained release formulation for paracetamol produced by melt pelletisation was investigated. The chosen formulation was based on the combination of stearic acid as a melting binder and anhydrous lactose as a filler. After determination of the size distribution, the pellet characterisation included scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), specific surface area and true density determination. Hence, the in vitro release from every single size fraction (2000, 1250, 800, 630, <630 microm) was evaluated and the release mechanism was analysed with the help of an appropriate mathematical model. The results of drug content and superficial atomic composition were found to be constant in all pellets size fractions, attesting the ability of melt pelletisation in a high shear mixer to form a product with homogeneous composition. The mathematical model is built on the hypotheses that drug diffusion and solid drug dissolution in the release environment are the key phenomena affecting drug release kinetics. Smaller classes apart (particles are not perfectly spherical), the comparison between model best fitting and experimental data indicated the reasonability of these hypotheses. Moreover, model reliability is proved by its ability of predicting drug release from a known mixture of the above mentioned particles classes.