Sustained release system for highly water-soluble radiosensitizer drug etanidazole: irradiation and degradation studies

Etanidazole (one nitro-imidazole hypoxic radiosensitizer) is formulated as polymer matrix type controlled release devices in this study. A novel double polymer drug carrier, unlike the double wall microparticles, is fabricated for the purpose of drug delivery, with the following objectives in mind: (1) to have a high encapsulation efficiency, (2) to achieve a pusatile release profile suitable for the radiation schedule of radiotherapy, (3) to elucidate the degradation profile of these microparticles. Irradiation of the microparticles were also studied to investigate effects on release and degradation. At a dosage of 50 Gy (total dosage during a radiotherapy treatment period) showed no apparent effects on the tri-phase release profile. It consists of an initial burst in the first 72 h, followed by a slow and steady drug release phase, and finally a faster degradation controlled phase corresponding to the degradation state of the different microparticles. At 25 kGy (sterilization dosage), the release profiles of the drug carrier were drastically modified. The faster erosion of the polymer with high dosage irradiation hastened the drug release and shortened the release time span, accompanied by decreases in the polymer molecular weight and glass transition temperatures, which was not apparent from SEM imaging. Degradation studies suggested a heterogeneous degradation process, with the outer layer and inner matrix degrading at different rates. The modifiable tri-phase release profile using microparticles of different polymer blends implies that the release properties of the drug carriers can be modified for different treatment regimes.     

Dissolution behaviour of hydrophilic matrix tablets containing two different polyethylene oxides (PEOs) for the controlled release of a water-soluble drug. Dimensionality study.

Hydrophilic matrix tablets containing polyethylene oxides as the retarding polymer have been successfully employed in the controlled release of drugs. To evaluate the relative influence of drug diffusion and polymer erosion mechanisms in the drug delivery process, we studied the hydration behaviour of matrix tablets containing a water-soluble drug and PEOs of two different molecular weights: Polyox WSRN 1105 (Mw = 0.9 x 10(6)) and Polyox WSRN 301 (Mw = 4 x 10(6)). The hydration rate, the extent of swelling, and the erosion rate of matrices containing the polymer, the drug and tableting excipients were evaluated in comparison to tablets made of pure polymer. The results of these studies on function of the release behaviour were then discussed. The results show that the higher molecular weight PEO swells to a greater extent and tends to form, upon hydration, a stronger gel, which is therefore less liable to erosion, if compared to the lower molecular weight PEO. This difference in the erosion behaviour can explain the different efficiencies of the two polymeric products in modulating the delivery rate of the water-soluble drug. Moreover, the presence of other soluble components (drug and excipients) in the dosage form enhances the erosion trend of the tablets with a consequent reduction of the efficiency of the polymer in drug release control.     

Release of propranolol and diclofenac from low Mw DL-poly(lactic acid)

The controlled release of two drugs, i.e. the sodium salt of diclofenac and propranolol was studied, by using low molecular weight D,L-Poly(lactic acid) as a matrix. Tablets of the above polymer containing those drugs were immersed into buffers with various pH values and delivery was recorded as a function of time, via UV-spectroscopy. The results showed that the polymer is appropriate for such biomedical applications, as generally, it ensures complete drug delivery within 45-60 days, which is acceptable for most cases. On the other hand, the release rate depends on many parameters including the interactions among drug, matrix and the surrounding liquid, which adds complexity to the process and requires careful investigation for proper design of a controlled release system.     

An efficient method for computer-aided dosage form design

It is desirable to have slow-release dosage form to be taken once daily, or at most twice daily, as compared to three or four times in a single day. However, the existing computer-aided dosage form design method requires a large amount of computer time when applied to nonlinear disposition drugs. This large commitment of computer time makes it inconvenient to study the feasibility for prolonged-release products containing such drugs. Instead of evaluating all possible combinations of the amount of dose and release rates that produce acceptable steady-state plasma concentrations, only the contour of the dose-release rate domain needs to be determined. An image boundary tracking method has been used to determine such contours. When combined with several modifications of the numerical solution process, the acceptable dose and release rate constants can be determined efficiently. When this modified boundary tracking method was applied to phenytoin, which exhibits nonlinear disposition, the required computer time was reduced to about 5% of the previous method, making the dosage form feasibility assessment practical.     

聚氨基酸材料在药物控释系统中的应用

聚氨基酸材料是一类具有良好生物相容性的高分子材料,在控释药物领域有独特的用途,我们就氨基酸材料在控释药物中类型,侧链修饰性,剂型,结构及生物相容性等方面作一简要的综述。     

Diffuse-interface theory for structure formation and release behavior in controlled drug release systems

A common method of controlling drug release has been to incorporate the drug into a polymer matrix, thereby creating a diffusion barrier that slows the rate of drug release. It has been demonstrated that the internal microstructure of these drug–polymer composites can significantly impact the drug release rate. However, the effect of processing conditions during manufacture on the composite structure and the subsequent effects on release behavior are not well understood. We have developed a diffuse-interface theory for microstructure evolution that is based on interactions between drug, polymer and solvent species, all of which may be present in either crystalline or amorphous states. Because the theory can be applied to almost any specific combination of material species and over a wide range of environmental conditions, it can be used to elucidate and quantify the relationships between processing, microstructure and release response in controlled drug release systems. Calculations based on the theory have now demonstrated that, for a characteristic delivery system, variations in microstructure arising due to changes in either drug loading or processing time, i.e. evaporation rate, could have a significant impact on both the bulk release kinetics and the uniformity of release across the system. In fact, we observed that changes in process time alone can induce differences in bulk release of almost a factor of two and typical non-uniformities of ±30% during the initial periods of release. Because these substantial variations may have deleterious clinical ramifications, it is critical that both the system microstructure and the control of that microstructure are considered to ensure the device will be both safe and effective in clinical use.     

The degradation, swelling and erosion properties of biodegradable implants prepared by extrusion or compression moulding of poly(lactide-co-glycolide) and ABA triblock copolymers

In the design of parenteral delivery systems the modulation of the biodegradation of a polymer matrix represents a promising strategy to control drug release. We have investigated the degradation of ABA triblock copolymers, consisting of poly(lactide-co-glycolide) A-blocks and poly(oxyethylene) B-blocks, and PLG, poly(lactide-co-glycolide), with respect to swelling behaviour, molecular weight loss and polymer erosion. Implants were prepared by either compression moulding or extrusion using a laboratory ram extruder. Insertion of an elastoplastic B-block did not lower the processing temperature, but the entanglement of the polymer chains was significantly reduced as can be seen from the diameters of the extruded rods. The swelling of the rods showed a volume extension of 130% for an ABA containing 50% PEO and 20% for an ABA containing 20% PEO. Using 1H-NMR it was found that protons in the B-blocks of the swollen ABA copolymers were mobile, while the A-blocks remained rigid during incubation. The analysis of the pH inside ABA rods using electron paramagnetic resonance, EPR, gave a pH of 5.2 after incubation with a subsequent increase to pH 6.0 during the first day, approaching the pH of the medium after nearly 33 d. Acidic degradation products did not accumulate inside the ABA rods. Degradation and erosion started immediately upon incubation. By contrast, PLG rods showed the typical profile of degradation and erosion. In this case, the influence of the geometry of the device was insignificant. Consequently, ABA triblock copolymers may widen the spectrum of parenteral drug delivery with regard to release of pH-sensitive drugs as well as erosion-controlled release kinetics.     

Modelling of drug release kinetics from a laminated device having an erodible drug reservoir

The purpose of this communication is to present a preliminary analysis to demonstrate the effect of laminating a drug-containing erodible polymer matrix with a second barrier membrane. A mathematical model for the diffusive release of the drug from an erodible polymer device undergoing surface erosion has been extended to similar devices with a secondary membrane to allow a comparison of the results. The results indicate that the constant rate of release characteristic of erodible devices is not sacrificed with the addition of the secondary membrane; moreover, the membrane provides additional controllable parameters at the disposal of the device designer.     

Optimization of a novel bioerodible device based on auto-catalyzed poly(ortho esters) for controlled delivery of tetracycline to periodontal pocket

Local delivery of antimicrobial agents in inflamed periodontal pocket has been shown to be effective in reducing periodontopathic microorganisms. This research focuses on developing and characterizing bioerodible formulations based on auto-catalyzed poly(ortho esters) (POExLAy) for modulated release of tetracycline over 2 weeks. POExLAy are a new versatile family of POE-containing lactoyl lactyl dimers in the polymer backbone. By modifying the proportion of lactic acid in the polymer, viscous or solid materials having different degradation rate can be produced. The formulations can be either injected or placed as a solid device directly into the periodontal pocket. Tetracycline-free base incorporated into these materials was released within 10-14 days depending on polymer structure. Increase in lactic acid content in the polymer tended to increase the drug release rate and to reduce the initial lag time. Tetracycline release from such bioerodible delivery system occurs predominantly by surface erosion of the polymeric matrix, leading to kinetics which can be zero order. This periodontal drug delivery system is designed to be used as an adjunct in the treatment of periodontal diseases. Clinical studies are currently in progress.     

Controlled release of biologically active compounds from bioerodible polymers

This article reviews the controlled release of biologically active agents by the erosion or chemical degradation of a polymer matrix into which the agent is incorporated. Chemically bound active agents and work on steroid release from cholesterol implants are not covered. The mechanisms of polymer erosion discussed are: cross-linked scission; hydrolysis, ionization or protonation of pendant groups; backbone cleavage. Drug release studies are dealt with under each of these headings.     

Bioerodible system for sequential release of multiple drugs

Because many complex physiological processes are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the objective of the present research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. The polymers used were cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule.     

A mathematical model for predicting drug release from a biodurable drug-eluting stent coating

Drug-eluting stents (DESs) are drug-device combination products that have been commercialized and demonstrated to be safe and efficacious in treating coronary artery disease. They have been very effective in reducing the extent of neointimal hyperplasia and therefore in preventing or minimizing the occurrence of in-stent restenosis. In order to develop a successful DES, it is imperative that the coating be designed so as to deliver, after stent implantation, a therapeutic dose of the drug for the desired time duration at the site of the arterial blockage. Mathematical models are very valuable tools that can be used to study the effect of different coating parameters on drug delivery and can therefore help in coating design. We have developed a bimodal lumped-parameter mass transport model to describe the release of the drug everolimus from a biodurable fluoropolymer-based DES coating. We assume that the dispersed drug phase contributes to two discrete modes of drug transport through the coating. These are the fast mode (mode I) which is the release of the drug from a highly percolated structure of drug phase within the polymer, and the slow mode (mode II) which is the release of the drug from a nonpercolated, polymer-encapsulated phase of the drug within the coating. The three coefficients in the governing equations describing the model, i.e. the two effective diffusivities corresponding to each of the two modes and the fraction of the drug in one of the two modes, were determined by fitting with available DES release data. The predictive power of the model is demonstrated by comparing the release rate from different coating configurations (thickness and drug to polymer ratios) with experimental data. Also, it is demonstrated that if limited experimental data are available at early time points, the model can be used to predict drug release at subsequent time points.     

Mathematical modeling of drug release from nanostructured porous Si: Combining carrier erosion and hindered drug diffusion for predicting release kinetics

A novel, empirical, macroscopic model is developed to describe the release of a model anticancer drug, Mitoxantrone, from native and chemically modified porous Si (PSi) thin films. Drug release from these carriers results from a combination of two mechanisms, i.e. out-diffusion of the drug molecules and erosion of the Si scaffold. Thus, the proposed mathematical model adapts the Crank model to lump the effects of temporal changes in molecular interactions and carrier scaffold erosion into a comprehensive model of hindered drug diffusion from nanoscale porous systems. Careful characterization of pore size, porosity, surface area, drug loading, as well as Si scaffold degradation profiles, measured over the same time-scale as drug release, are incorporated into the model parameter estimation. A comparison of the experimental and model results shows accurate representation of the data, emphasizing the reliability of the model. The proposed model shows that drug diffusivity values significantly vary with time for the two studied carriers, which are ascribed to the distinctive role of the prevailing physical mechanisms in each system. Finally, secondary validation of the proposed model is demonstrated by showing adequate fit to published data of the release of dexamethasone from similar mesoporous Si carriers.     

Formulation and characterization of modified release tablets containing isoniazid using swellable polymers

The aim of this work was to develop swellable modified release (MR) isoniazid tablets using different combinations of polyvinyl acetate (PVAc) and sodium-carboxymethylcellulose (Na-CMC). Granules were prepared by moist granulation technique and then compressed into tablets. In vitro release studies for 12 hr were carried out in dissolution media of varying pH i.e. pH 1.2, 4.5, 7.0 and 7.5. Tablets of all formulations were found to be of good physical quality with respect to appearance (width and thickness), content uniformity, hardness, weight variation and friability. In vitro release data showed that increasing total polymer content resulted in more retarding effect. Formulation with 35% polymer content exhibited zero order release profile and it released 35% of the drug in first hr, later on, controlled drug release was observed upto the 12(th) hour. Formulations with PVAc to Na-CMC ratio 20:80 exhibited zero order release pattern at levels of studied concentrations, which suggested that this combination can be used to formulate zero order release tablets of water soluble drugs like isoniazid. Korsmeyer-Peppas modeling of drug release showed that non-Fickian transport is the primary mechanism of isoniazid release from PVAc and Na-CMC based tablets. The value of mean dissolution time decreased with the increase in the release rate of drug clearly showing the retarding behavior of the swellable polymers. The application of a mixture of PVAc to Na-CMC in a specific ratio may be feasible to formulate zero order release tablets of water soluble drugs like isoniazid.     

In vitro degradation of insulin-loaded poly (n-butylcyanoacrylate) nanoparticles

Poly (n-butyl cyanoacrylate) (PBCA) nanoparticles were prepared by a dispersion polymerisation process in water at pH 3 and using dextran as a stabilising agent. The drug insulin was introduced during the latter stages of particle synthesis and was found not to interfere with the polymer structure, molecular weight, and the particle size. Nanoparticles were exposed to the enzyme esterase in phosphate buffered saline solution at 37 degrees C for time periods up to 4h. Esterase catalyses the degradation of the PBCA through hydrolysis of the side chain on the repeat unit with the release of butanol, and this was monitored as an indicator of degradation. The release of both butanol and insulin occurred via similar biphasic processes, with an initial burst release from the surface, followed by a slower diffusionally hindered release associated with particle erosion. Hydrolysis of the nanoparticle polymer was confirmed by infrared spectroscopy. Particle size reduces with time of exposure to esterase, but is greatest in the first 30 min of exposure. Despite the hydrolysis reaction, and reduction in particle size, there was no reduction in residual polymer molecular weight suggesting a progressive loss of entire chains from the active surface. Polymer loss is thought to occur through either solvation of degradation residue or through complete depolymerisation of hydrolysed chains.     

Magnetically Guided Release of Ciprofloxacin from Superparamagnetic Polymer Nanocomposites

Tailored with superparamagnetic properties the magnetic nanocomposites have been thoroughly investigated in recent past because of their potential applications in the fields of biomedicine and bioengineering such as protein detection, magnetic targeted drug carriers, bioseparation, magnetic resonance imaging contrast agents and hyperthermia. Magnetic drug targeting has come up as a safe and effective drug-delivery technology, i.e., with the least amount of magnetic particles a maximum of drug may be easily administered and transported to the site of choice. In the present work novel magnetic drug-targeting carriers consisting of magnetic nanoparticles encapsulated within a smart polymer matrix with potential of controlled drug release is described. To make such magnetic polymeric drug-delivery systems, both the magnetic nanoparticles and antibiotic drug (ciprofloxacin) were incorporated into the hydrogel. The controlled release process and release profiles were investigated as a function of experimental protocols such as percent loading of drug, chemical composition of the nanocomposite, pH of release media and strength of magnetic field on the release profiles. The structure, morphology and compositions of magnetic hydrogel nanocomposites were characterized by FT-IR, TEM, XRD and VSM techniques. It was found that magnetic nanocomposites were biocompatible and superparamagnetic in nature and could be used as a smart drug carrier for controlled and targeted drug delivery.     

Combining Ultra‐High Drug‐Loaded Micelles and Injectable Hydrogel Drug Depots for Prolonged Drug Release

Hydrogel‐based drug depot formulations are of great interest for therapeutic applications. While the biological activity of such drug depots is often characterized well, the influence of incorporated drug or drug‐loaded micelles on the gelation properties of the hydrogel matrix is less investigated. However, the latter is of great importance from fundamental and application points of view as it informs on the physicochemical interactions of drugs and water‐swollen polymer networks and it determines injectability, depot stability, as well as drug‐release kinetics. Here, the impact of incorporated drug, neat polymer micelles, and drug‐loaded micelles on the viscoelastic properties of a cytocompatible hydrogel is investigated systematically. To challenge the hydrogel with regard to the desired application as injectable drug depot, curcumin (CUR) is chosen as a model compound due to its very low‐water solubility and limited stability. CUR is either directly solubilized by the hydrogel or pre‐incorporated into polymer micelles. Interference of CUR with the temperature‐induced gelation process can be suppressed by pre‐incorporation into polymer micelles forming a binary drug delivery system. Drug release from a collagen matrix is studied in a trans‐well setup. Compared to direct injection of drug formulations, the hydrogel‐based systems show improved and extended drug release over 10 weeks.     

Controlled degradation of multilayered poly(lactide-co-glycolide) films using electron beam irradiation

The ability to undergo predictable and controlled degradation allows biopolymers to release prescribed dosages of drugs locally over a sustained period. However, the bulk or homogeneous degradation of some of these polymers like poly(L-lactide) (PLLA) and poly(lactide-co-glycolide) (PLGA) work against a better controlled release of the drugs. Inducing the polymers to undergo surface erosion or layer-by-layer degradation could provide a better process of controlled drug release from the polymers. This study has demonstrated that surface erosion degradation of PLGA is possible with the use of a multilayer film system, with PPdlLGA [plasticized poly(D,L-lactide-co-glycolide) (PdlLGA)] as the surface layers and poly(L-lactide-co-glycolide) as the center layer. The use of the more hydrophilic PPdlLGA as the surface layer resulted in a faster degradation of the surface layers compared to the center layer, thus giving a surface erosion degradation effect. The rate of surface degradation could also be controlled with electron beam (e-beam) radiation, where e-beam irradiation was shown to alter the degradation time and onset of polymer mass loss. It was also shown that the more highly irradiated PPdlLGA surface layers had an earlier onset of mass loss, which resulted in a faster reduction in overall film thickness. The ability to control the rate of film thickness reduction with different radiation dose promises a better controlled release of drugs from this multilayer PLGA film system.     

A unified mathematical model for the prediction of controlled release from surface and bulk eroding polymer matrices

A unified model has been developed to predict release not only from bulk eroding and surface eroding systems but also from matrices that transition from surface eroding to bulk eroding behavior during the course of degradation. This broad applicability is afforded by fundamental diffusion/reaction equations that can describe a wide variety of scenarios including hydration of and mass loss from a hydrolysable polymer matrix. Together, these equations naturally account for spatial distributions of polymer degradation rate. In this model paradigm, the theoretical minimal size required for a matrix to exhibit degradation under surface eroding conditions was calculated for various polymer types and then verified by empirical data from the literature. An additional set of equations accounts for dissolution- and/or degradation-based release, which are dependent upon hydration of the matrix and erosion of the polymer. To test the model's accuracy, predictions for agent egress were compared to experimental data from polyanhydride and polyorthoester implants that were postulated to undergo either dissolution-limited or degradation-controlled release. Because these predictions are calculated solely from readily attainable design parameters, it seems likely that this model could be used to guide the design controlled release formulations that produce a broad array of custom release profiles.     

In vitro release of clomipramine HCl and buprenorphine HCl from poly adipic anhydride (PAA) and poly trimethylene carbonate (PTMC) blends

Controlled drug-delivery technology is concerned with the systematic release of a pharmaceutical agent to maintain a therapeutic level of the drug in the body for modulated and/or prolonged periods of time. This may be achieved by incorporating the therapeutic agent into a degradable polymer vehicle, which releases the agent continuously as the matrix erodes. In this study, poly trimethylene carbonate (PTMC), an aliphatic polycarbonate, and poly adipic anhydride (PAA), an aliphatic polyanhydride, were synthesized via melt condensation and ring-opening polymerization of trimethylene carbonate and adipic acid, respectively. The release of clomipramine HCl and buprenorphine HCl from discs prepared with the use of PTMC-PAA blends in phosphate buffer (pH 7.4) are also described. Clomipramine HCl and buprenorphine HCl were both used as hydrophilic drug models. Theoretical treatment of the data with the Peppas model revealed that release of clomipramine HCl (5%) in devices containing 70% PTMC or more followed a Fickian diffusion model. However, the releases of buprenorphine HCl (5%) in the same devices were anomalous. For devices containing 50% and more PAA, surface erosion may play a significant role in the release of both molecules.