Development of hydroxyapatite bone cement for controlled drug release via tetracycline hydrochloride

The purpose of this work was to study the preparation and characterization of drug–hydroxyapatite cement. The hydroxyapatite (HA) cement has been synthesized by using tricalcium phosphate, calcium carbonate and dicalcium phosphate anhydrous with sodium hydrogen phosphate as liquid phase. The effect of added tetracycline hydrochloride (TCH) as drug on final phases, microstructure, setting behaviour and compressive strength has been studied. The drug release rate was first order within the first day and then was zero order. No obvious difference could be detected in XRD patterns of the TCH–HA cement with various amounts of drug. By increasing the drug concentration, mechanical strength of cement was decreased and its setting time was increased. The results of this study demonstrate the potential of using HA cement as a carrier for drug delivery.     

Injectable suspensions for prolonged release nalbuphine

There is a need for parenteral opioid analgesics with longer durations of action. Suspensions of nalbuphine were formulated by buffering the HCI salt to pH 9-9.2 in the presence of the commonly used suspending agents, methylcellulose, sodium carboxymethylcellulose, and PEG. Each of these suspensions prolonged nalbuphine release, relative to a nalbuphine HCI solution, after intramuscular administration to rats. Peak plasma concentrations were lower, and the half-life was increased more than 2-fold. The methylcellulose suspension had the smallest particle size and gave the highest plasma nalbuphine concentrations. This was also evaluated in dogs, and as in rats, the half-life was approximately doubled. These suspensions can be lyophilized and readily resuspended, and do not appear to be irritating. This is a simple, practical approach to a prolonged release injectable.     

Injectable PLA-based in situ forming implants for controlled release of Ivermectin a BCS Class II drug: solvent selection based on physico-chemical characterization

In situ forming implants (ISI) prepared from biodegradable polymers such as poly(d,l-lactide) (PLA) and biocompatible solvents can be used to obtain sustained drug release after parenteral administration. The aim of this work was to study the effect of several biocompatible solvents with different physico-chemical properties on the release of ivermectin (IVM), an antiparasitic BCS II drug, from in situ forming PLA-based implants. The solvents evaluated were N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2P), triacetine (TA) and benzyl benzoate (BB). Hansen’s solubility parameters of solvents were used to explain polymer/solvent interactions leading to different rheological behaviours. The stability of the polymer and drug in the solvents were also evaluated by size exclusion and high performance liquid chromatography, respectively. The two major factors determining the rate of IVM release from ISI were miscibility of the solvent with water and the viscosity of the polymer solutions. In general, the release rate increased with increasing water miscibility of the solvent and decreasing viscosity in the following order NMP>2P>TA>BB. Scanning electron microscopy revealed a relationship between the rate of IVM release and the surface porosity of the implants, release being higher as implant porosity increased. Finally, drug and polymer stability in the solvents followed the same trends, increasing when polymer-solvent affinities and water content in solvents decreased. IVM degradation was accelerated by the acid environment generated by the degradation of the polymer but the drug did not affect PLA stability.     

Gelatin manipulation of latent macropores formation in brushite cement

Macroporous brushite cement was prepared from a mixture of -tricalcium phosphate (-TCP) and monocalcium phosphate monohydrate (MCPM) using gelatin powder as a latent templates. In a setting reaction coexisting with gelatin, closed packed, open-pore structure with 100–200 m macropores are obtained after immersion of the set cement into PBS buffer (pH 7.4) at 37 °C for 1–4 weeks. The macroporous brushite cement has compressive strength of 15 MPa originally, which reducing to 5.5 MPa with macropore formation gradually in comparison to that of cancellous bone (5–10 MPa).     

药物控、缓释体系的缓释同步性研究

通过插层技术合成了醋酸洗必泰-盐酸特比萘芬/蒙脱土(CA-TBNF/MMT)药物控、缓释纳米中间体,利用XRD对其结构进行了表征,结果表明CA-TBNF已进入MMT层间,层间距变化明显。最小抑菌浓度与缓释浓度匹配,从层间解析出的CA与TB-NF在协同作用下对细菌和真菌都有较好的杀菌效果。实验证明两种药物可实现同步缓释。     

Hybrid nanostructured drug carrier with tunable and controlled drug release

We describe here a transformative approach to synthesize a hybrid nanostructured drug carrier that exhibits the characteristics of controlled drug release. The synthesis of the nanohybrid architecture involved two steps. The first step involved direct crystallization of biocompatible copolymer along the long axis of the carbon nanotubes (CNTs), followed by the second step of attachment of drug molecule to the polymer via hydrogen bonding. The extraordinary inorganic–organic hybrid architecture exhibited high drug loading ability and is physically stable even under extreme conditions of acidic media and ultrasonic irradiation. The temperature and pH sensitive characteristics of the hybrid drug carrier and high drug loading ability merit its consideration as a promising carrier and utilization of the fundamental aspects used for synthesis of other promising drug carriers. The higher drug release response during the application of ultrasonic frequency is ascribed to a cavitation-type process in which the acoustic bubbles nucleate and collapse releasing the drug. Furthermore, the study underscores the potential of uniquely combining CNTs and biopolymers for drug delivery.     

Carboxylates and sulfates of polysaccharides for controlled internal water release during cement hydration

Calcium and aluminium carboxylates and sulfates of polysaccharides form hydrogels. Four Al- and three Ca-salt hydrogels of such polysaccharides, which were found to be stable enough to be mixed into fresh Portland cement pastes of low initial water-to-cement ratio of 0.275, were compared with respect to their water retardation potential using non-destructively operating low-field ¹H NMR relaxometry. All of the investigated hydrogels release their water to the cement mainly during the accelerated period of cement hydration. At a degree of hydration of about 0.7 the water in the hydrogels is consumed completely by the hydration reactions. Based on Powers’ hydration model the development of the volumetric phase distribution of the investigated hydrating cement with internal curing by the hydrogels was quantified. Within the hardening cement the Ca-salt hydrogels are more stable than the Al-hydrogels which is concluded from the changes of the T₂ relaxation times during the cement hydration.     

Dithiocarbamate chitosan as a potential polymeric matrix for controlled drug release

Objective: To develop a polymer matrix for controlled release of drugs, chitosan, a linear aminopolysaccharide, was chemically modified to dithiocarbamate chitosan (DTCC) to afford a matrix where metal–drug complexes could be attached and released in a controlled manner depending on the binding nature between the drugs and the metals.

Materials and methods: DTCC was treated with metal-tetracycline (Tc) complexes to prepare DTCC–Ca(II)–Tc, DTCC–Mg(II)–Tc, DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc.

Results: The binding amount of Tc was in the order of DTCC–Zn(II)–Tc?≈?DTCC–Mg(II)–Tc?≈ DTCC–Ca(II)–Tc?>?DTCC–Cu(II)–Tc. The biphasic binding profiles, where Tc binding increased initially and then decreased, were shown for DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc. In a flow method, Tc was released slowly from DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc compared with Tc release from DTCC–Tc. In parallel with the results of the release experiment, DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc presented a prolonged antibacterial activity in an antibacterial test. The antibacterial activity of DTCC–Ca(II)–, –Mg(II)– and –Zn(II)–Tc complexes lasted for 28–44 days, while free Tc and DTCC–Tc lasted for 7–12 days.

Discussion and conclusion: Taken together, our data suggest that DTCC could be used for a polymeric matrix for controlled release of drugs such as Tc, which possess functional groups for ionic and/or coordinate bond with metals.     

Low temperature fabrication of spherical brushite granules by cement paste emulsion

Secondary protonated calcium phosphates such as brushite (CaHPO₄·2H₂O) or monetite (CaHPO₄) have a higher resorption potential in bone defects than sintered ceramics, e.g. tricalcium phosphate or hydroxyapatite. However, processing of these phosphates to monolithic blocks or granules is not possible by sintering due to thermal decomposition of protonated phosphates at higher temperatures. In this study a low temperature technique for the preparation of spherical brushite granules in a cement setting reaction is presented. These granules were synthesized by dispersing a calcium phosphate cement paste composed of β-tricalcium phosphate and monocalcium phosphate together with a surfactant to an oil/water emulsion. The reaction products were characterized regarding their size distribution, morphology, and phase composition. Clinically relevant granule sizes ranging from 200?μm to 1?mm were obtained, whereas generally smaller granules were received with higher oil viscosity, increasing temperature or higher powder to liquid ratios of the cement paste. The hardened granules were microporous with a specific surface area of 0.7?m²/g and consisted of plate-like brushite (>95?% according to XRD) crystals of 0.5–7?μm size. Furthermore it was shown that the granules may be also used for drug delivery applications. This was demonstrated by adsorption of vancomycin from an aqueous solution, where a load of 1.45–1.88?mg drug per g granules and an almost complete release within 2?h was obtained.     

Injectable iron-modified apatitic bone cement intended for kyphoplasty: cytocompatibility study

In this study, the cytocompatibility of human ephitelial (HEp-2) cells cultured on new injectable iron-modified calcium phosphate cements (IM-CPCs) has been investigated in terms of cell adhesion, cell proliferation, and morphology. Quantitative MTT-assay and scanning electron microscopy (SEM) showed that cell adhesion and viability were not affected with culturing time by iron concentration in a dose-dependent manner. SEM-cell morphology showed that HEp-2 cells, seeded on IM-CPCs, were able to adhere, spread, and attain normal morphology. These results showed that the new injectable IM-CPCs have cytocompatible features of interest to the intended kyphophasty application, for the treatment of osteoporotic vertebral compression fractures.     

Synthesis strategies for disulfide bond-containing polymer-based drug delivery system for reduction-responsive controlled release

Tumor micro-environment responsive drug delivery systems (DDSs) have been developed as a potential approach to reduce the side effects of cancer chemotherapy. Glutathione (GSH) has been supposed to the most significant signal of the difference between the normal tissue and the tumor cells, besides the media pH and temperature. In recent years, the reduction-responsive DDSs have attracted more and more attention for delivery of anti-cancer drugs, based on such physiological signal. Among them, disulfide bond-containing polymers have been designed as the main tool for the purpose. The recent progress in the synthesis strategies for the disulfide bond-containing polymer-based DDS is focused in the present review.     

Injectable and fast resorbable calcium phosphate cement for body-setting bone grafts

In this work a calcium phosphate (CPC)/polymer blend was developed with the advantage of being moldable and capable of in situ setting to form calcium deficient hydroxyapatite under physiological conditions in an aqueous environment at body temperature. The CPC paste consists in a mix of R cement, glycerol as a liquid phase carrier and a biodegradable hydrogel such as Polyvinyl alcohol, which acts as a binder. Microstructure and mechanical analysis shows that the CPC blend can be used as an injectable implant for low loaded applications and fast adsorption requirements. The storage for commercial distribution was also evaluated and the properties of the materials obtained do not significantly change during storage at −18°C.     

A remotely triggered drug release system with dot array-like configuration for controlled release of multiple drugs

Near-infrared (NIR) light as noninvasive external stimuli to trigger on-demand drug release has attracted great attention in recent years. However, the current existing NIR-related drug delivery systems (DDSs) still have difficulty in controlling the release of the individual drug separately. In the present work, a dot array-like DDS was developed for accurately controlling the release of multiple drugs. Each dot had a drug core and an outer protective layer. The outer protective layer consisted of lauric acid (LA) and polylactic acid (PLA). LA is a kind of phase-change material (PCM) with melting point of 43.8 °C. When loaded with polypyrrole nanoparticles (PPy NPs) that acted as photothermal transducers, the outer protective layer became NIR light responsive and was able to convert light into heat to melt the LA. As a result, the drugs stored inside were released. By changing the PPy loading, NIR light power density, and mass ratio of LA to PLA, the drug release profile could be carefully controlled. Such a NIR-responsive DDS may find great potential applications in treating diseases that require long-term therapies using more than one drug.     

Preparation and characterization of acrylic bone cement with high drug release

Drug-loaded bone cement is used as an application method to prevent and treat prosthesis-related infection. Despite the commercial availability of drug-loaded bone cement, low release rate of drugs from drug-loaded bone cement may result in the emergence of drug-resistant coagulase-negative staphylococci in subsequent deep infection. This work presents a method to control and increase both the drug release rate and total release amounts of drugs for drug-loaded bone cement without losing the mechanical properties of cement. A novel drug-loaded bone cement is also developed by introducing cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles into bone cement. Capable of increasing the hydrophilicity of the cement and allowing fluids to pass into the cement, the bone cement developed here supplements both the drug release rate and total release amounts of drugs.     

Gold nanorods mediated controlled release of doxorubicin: nano-needles for efficient drug delivery

Use of cysteamine hydrochloride (Cys-HCl) protected gold nanorods (GNRs) as efficient carrier of widely used anti-cancer drug doxorubicin using folic acid as navigational molecule is presented in this work. GNRs were found to have excellent drug loading capacity of >97 %. A detailed comprehension of in vitro drug release profile under ideal physiological condition was found to obey 1st order kinetics at pH 6.8, 5.3 and 7.2, an ideal milieu for drug delivery to solid tumours.     

Fabrication and dissolution behavior of hollow hydroxyapatite microspheres intended for controlled drug release

Hollow hydroxyapatite (HA) microspheres were fabricated by a simple spray drying method in this study. Moreover, the dissolution behavior of these hollow HA microspheres after immersion in simulated body fluid (SBF) was also studied. The results indicated that the dissolution of the HA microspheres in SBF is not homogeneous in a layer-by-layer fashion but was preferential at different locations of the particle surface. Generically, dissolution preferentially occurs on the location with looser structure and high porosity of the microspheres. The degradable HA microspheres are expected to have potential applications in bone local drug delivery systems.     

Effect of diluents on tablet integrity and controlled drug release

The objective of this study was to evaluate the effect of diluents and wax level on tablet integrity during heat treatment and dissolution for sustained-release formulations and the resultant effect on drug release. Dibasic calcium phosphate dihydrate (DCPD), microcrystalline cellulose (MCC), and lactose were evaluated for their effect on tablet integrity during drug dissolution and heat treatment in wax matrix formulations. A newly developed direct compression diluent, dibasic calcium phosphate anhydrous (DCPA), was also evaluated. Compritol® 888 ATO was used as the wax matrix material, with phenylpropanolamine hydrochloride (PPA) as a model drug. Tablets were made by direct compression and then subjected to heat treatment at 80°C for 30 min. The results showed that MCC, lactose, and DCPA could maintain tablets intact during heat treatment above the melting point of wax (70°C-75°C). However, DCPD tablets showed wax egress during the treatment. MCC tablets swelled and cracked during drug dissolution and resulted in quick release. DCPD and lactose tablets remained intact during dissolution and gave slower release than MCC tablets. DCPA tablets without heat treatment disintegrated very quickly and showed immediate release. In contrast, heat-treated DCPA tablets remained intact through the 24-hr dissolution test and only released about 80% PPA at 6 hr. In the investigation of wax level, DCPD was used as the diluent. The drug release rate decreased as the wax content increased from 15% to 81.25%. The dissolution data were best described by the Higuchi square-root-of-time model. Diluents showed various effects during heat treatment and drug dissolution. The integrity of the tablets was related to the drug release rate. Heat treatment retarded drug release if there was no wax egress.     

Electrically controlled drug release from nanostructured polypyrrole coated on titanium

Previous studies have demonstrated that multi-walled carbon nanotubes grown out of anodized nanotubular titanium (MWNT-Ti) can be used as a sensing electrode for various biomedical applications; such sensors detected the redox reactions of certain molecules, specifically proteins deposited by osteoblasts during extracellular matrix bone formation. Since it is known that polypyrrole (PPy) can release drugs upon electrical stimulation, in this study antibiotics (penicillin/streptomycin, P/S) or an anti-inflammatory drug (dexamethasone, Dex), termed PPy[P/S] or PPy[Dex], respectively, were electrodeposited in PPy on titanium. The objective of the present study was to determine if such drugs can be released from PPy on demand and (by applying a voltage) control cellular behavior important for orthopedic applications. Results showed that PPy films possessed nanometer-scale roughness as analyzed by atomic force microscopy. X-ray photoelectron spectroscopy confirmed the presence of P/S and Dex encapsulated within the PPy films. Results from cyclic voltammetry showed that 80% of the drugs were released on demand when sweep voltages were applied for five cycles at a scan rate of 0.1 V s(-1). Furthermore, osteoblast (bone-forming cells) and fibroblast (fibrous tissue-forming cells) adhesion were determined on the PPy films. Results showed that PPy[Dex] enhanced osteoblast adhesion after 4 h of culture compared to plain Ti. PPy-Ti (with or without anionic drug doping) inhibited fibroblast adhesion compared to plain Ti. These in vitro results confirmed that electrodeposited PPy[P/S] and PPy[Dex] can release drugs on demand to potentially fight bacterial infection, reduce inflammation, promote bone growth or reduce fibroblast functions, further implicating the use of such materials as implant sensors.