Estradiol sustained release from high affinity cyclodextrin hydrogels.

Hydrogels for loading estradiol and controlling its release were prepared cross-linking various cyclodextrins with ethyleneglycol diglycidylether. To select the more adequate cyclodextrins, estradiol solubility diagrams in water with beta-cyclodextrin (betaCD), methyl-beta-cyclodextrin (MbetaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD), and sulfobutyl-beta-cyclodextrin (SBbetaCD) were made in absence and presence of hydroxypropyl methylcellulose (HPMC) applying or not autoclaving. Although all cyclodextrins showed enough complexation capability, the low solubility of betaCD and the high anionic character of SBbetaCD hindered the cross-linking process, and these cyclodextrins were discarded for preparing hydrogels. Hydrogels prepared with MbetaCD (20%, 25%) or HPbetaCD (20%, 25%, and 30%), with or without HPMC 0.25%, absorbed 4-10 times their weight in water and loaded up to 24 mg estradiol per gram, which is 500 times greater than the amount of drug that can be dissolved in their aqueous phase. Positive linear correlation was found between the stability constant and the network/water partition coefficients of drug. The hydrogels sustained the release up to one week; the affinity of estradiol for the cyclodextrin units controlling the process, as shown by the negative correlation with the release rate constants. These results highlight the potential of cyclodextrin complexation for the development of hydrogels useful in loading hydrophobic drugs and controlling their release.     

Characterisation and controlled drug release from novel drug-loaded hydrogels.

Hydrogel based devices belong to the group of swelling controlled drug delivery systems. Temperature responsive poly(N-isopropylacrylamide)-poly(vinylpyrrolidinone) random copolymers were produced by free radical polymerisation, using 1-hydroxycyclohexylphenyketone as an ultraviolet-light sensitive initiator, and poly(ethylene glycol) dimethacrylate as the crosslinking agent (where appropriate). The hydrogels were synthesised to have lower critical solution temperatures (LCST) near body temperature, which is favourable particularly for 'smart' drug delivery applications. Two model drugs (diclofenac sodium and procaine HCl) were entrapped within these xerogels, by incorporating the active agents prior to photopolymerisation. The properties of the placebo samples were contrasted with the drug-loaded copolymers at low levels of drug integration. Modulated differential scanning calorimetry (MDSC), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and atomic force microscopy (AFM) were used to investigate the influence of the drugs incorporated on the solid-state properties of the xerogels. MDSC and swelling studies were carried out to ascertain their effects on the LCST and swelling behaviour of the hydrated samples. In all cases, drug dissolution analysis showed that the active agent was released at a slower rate at temperatures above the phase transition temperature. Finally, preliminary in vitro cytotoxicity evaluations were performed to establish the toxicological pattern of the gels.     

Sustained release of lidocaine from Poloxamer 407 gels

In this work, we show that alteration of P407 gel content can affect drug release rates. The inorganic salts and PEG 400 commonly included in the formulation of P407 gels can also change the rate at which a drug is released. Lidocaine was selected as a model drug because, although widely used in the treatment of pain, its use is limited by short duration of its effects. The use of P407 gels prolongs the residence time of the lidocaine at the injection site, sustains drug release and increases therapeutic efficacy. Release studies were performed in a diffusion system. During release, data followed the Higuchi square root law time kinetic (r>0.98). Increased polymer concentration in the gel increases viscosity and reduces lidocaine release rates and diffusion coefficients via extended gel dissolution time and prolonged drug diffusion through the gel matrix. Lidocaine release rates and diffusion coefficients increased in gels composed of NaCl or PEG 400 aqueous solution. Because these additives are hydrophilic, they reduce gel dissolution time, thereby accelerating drug diffusion. Poloxamer is biocompatible and the results support the possibility of using Poloxamer gel as a sustained release injectable formulation.     

Pulsatile drug release control using hydrogels.

Current research in the field of drug delivery devices, by which pulsed and/or pulsatile release is achieved, has been intensified. In this article several types of drug delivery systems using hydrogels are discussed that showed pulsed and/or pulsatile drug delivery characteristics. As is frequently found in the living body, many vital functions are regulated by pulsed or transient release of bioactive substances at a specific site and time. Thus it is important to develop new drug delivery devices to achieve pulsed delivery of a certain amount of drugs in order to mimic the function of the living systems, while minimizing undesired side effects. Special attention has been given to the thermally responsive poly(N-isopropylacrylamide) and its derivative hydrogels. Thermal stimuli-regulated pulsed drug release is established through the design of drug delivery devices, hydrogels, and micelles. Development of modified alginate gel beads with pulsed drug delivery characteristic is also described in this article.     

Cyclodextrin controlled release of poorly water-soluble drugs from hydrogels

The effect of 2-hydroxypropyl-β-cyclodextrin and γ-cyclodextrin on the release of ibuprofen, ketoprofen and prednisolone was studied. Stability constants calculated for inclusion complexes show size dependence for complexes with both cyclodextrins. Hydrogels were prepared by ultraviolet irradiation and release of each model drug was studied. For drugs formulated using cyclodextrins an increase in the achievable concentration and in the release from hydrogels was obtained due to increased solubility, although the solubility of all γ-cyclodextrin complexes was limited. The Load also was increased by adjusting pH for the acidic drugs and this exceeds the increase obtained with γ-cyclodextrin addition.     

Kinetic analysis of drug release from hydrogels containing amphoteric surfactants

A one compartment open model was used in order to describe chloramphenicol release from hydrogels containing amphoteric surfactants as gelling agents. Such interpretation seems to be more profitable than that based on Higuchi's root square equation. Using the proposed model it is possible to consider that drug release takes place from the water phase near the surface of membrane, rather than from the micellar phase in which drug seems to be immobilized.     

Surface crosslinking for delayed release of proxyphylline from PHEMA hydrogels

Delayed release systems find applications in chronotherapeutics and colon-specific delivery. They have also been considered suitable carriers for the oral delivery of peptides and proteins. In prior work, our research group has reported surface crosslinking as an effective technique to modify drug release profiles for poly(vinyl alcohol) (PVA) hydrogels, reducing the early burst effect in particular. Here, we demonstrate the feasibility of delayed release of proxyphylline from poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels via surface crosslinking. Studies on in vitro drug release and the morphology changes of PHEMA hydrogels during swelling and drug release showed that the highly surface crosslinked layers and the ruptures occurring in these layers during swelling were likely responsible for the delayed release. In addition, the initial burst was significantly reduced or even eliminated from the drug release profile for PHEMA to achieve near zero-order release by judicious selection of two surface crosslinking parameters: crosslinking reagent concentration and exposure time used for the surface crosslinking treatment.     

In vitro release of lidocaine from pluronic F-127 gels

The release of lidocaine from aqueous, crystal clear and colorless gels of Pluronic F-127 (a polyoxyethylene-polyoxypropylene surface-active block polymer) has been studied in an in vitro release model which did not utilize a membrane. Pluronic F-127 forms micelles in aqueous systems and the gels are believed to be viscous isotropic liquid crystals. Due to their reverse thermal gelation behavior, good solubilization capacity, optical properties and low toxicity, they appear to have potential application as topical drug delivery systems. It has been found that the rate of lidocaine release was inversely proportional to its concentration, the concentration of Pluronic F-127 and electrolyte concentration (sodium chloride). Release of lidocaine was maximal at pH values close to its pK_a; however, release of the more water-soluble benzocaine (included for comparison purposes) was relatively pH-independent over the pH range studied. Since the apparent diffusion coefficient of lidocaine increased with increasing temperature, in spite of increasing macro-viscosity of the gel, it is apparent that drug is released by diffusion through the extramicellar aqueous channels of the gel matrix. Hence, the rate of drug release was determined by the micro-viscosity of the extramicellar fluid, the dimensions of the aqueous channels, and the equilibrium relationship of drug between the micelles and the external aqueous phase.     

Controlled release of proteins and peptides from hydrogels synthesized by gamma ray-induced polymerization.

Hydrogels prepared by radiation-induced polymerization at a low temperature have been used as carriers for the controlled release of peptides and proteins. It was found that polymerization of 2-hydroxyethyl methacrylate in the presence of poly (ethylene glycol) methyl ether (MPEG) enabled the more porous and swellable matrics to be obtained, the higher the molecular weight of MPEG. As a consequence, protein release took place at an increasing extent and, provided that MPEG molecular weight was high enough, high molecular weight proteins could also be released. Such a state of affairs was not met in the case of hydrogels based on poly (2-hydroxyethyl acrylate). SEM analysis revealed that even high molecular weight MPEG did not give rise to any porosity, even though the degree of swelling was very high. As a result, no protein release was observed. It was therefore concluded that control of hydrogel porosity for the controlled release of large proteins is of overwhelming importance.     

Theoretical model for the diclofenac release from PEGylated chitosan hydrogels

Controlled drug delivery systems are of utmost importance for the improvement of drug bioavailability while limiting the side effects. For the improvement of their performances, drug release modeling is a significant tool for the further optimization of the drug delivery systems to cross the barrier to practical application. We report here on the modeling of the diclofenac sodium salt (DCF) release from a hydrogel matrix based on PEGylated chitosan in the context of Multifractal Theory of Motion, by means of a fundamental spinor set given by 2 × 2 matrices with real elements, which can describe the drug-release dynamics at global and local scales. The drug delivery systems were prepared by in situ hydrogenation of PEGylated chitosan with citral in the presence of the DCF, by varying the hydrophilic/hydrophobic ratio of the components. They demonstrated a good dispersion of the drug into the matrix by forming matrix-drug entities which enabled a prolonged drug delivery behavior correlated with the hydrophilicity degree of the matrix. The application of the Multifractal Theory of Motion fitted very well on these findings, the fractality degree accurately describing the changes in hydrophilicity of the polymer. The validation of the model on this series of formulations encourages its further use for other systems, as an easy tool for estimating the drug release toward the design improvement. The present paper is a continuation of the work ‘A theoretical mathematical model for assessing diclofenac release from chitosan-based formulations,’ published in Drug Delivery Journal, 27(1), 2020, that focused on the consequences induced by the invariance groups of Multifractal Diffusion Equations in correlation with the drug release dynamics.     

Slow release of two antibiotics of veterinary interest from PVA hydrogels

Two antibiotics, tylosin tartrate and oxytetracycline hydrochloride, were entrapped in poly(vinyl alcohol) (PVA) hydrogels (MW 31,000-50,000) by a cryogen procedure obtaining a controlled release system suitable for veterinary application. It was found that at a low drug matrix loading (10 mg/ml), the in vitro release rate of both antibiotics could be reduced by a previous freeze drying of the gel, while no reduction in drug rate took place in heavily loaded matrices (300 mg/ml). When PVA hydrogels containing tylosin were administered to rats per os the drug could not be detected in the blood, but it was found in organs,: liver, kidneys, and muscles, for up to 120 h. On the other hand, when the same amount of drug was administered orally as powder, no appreciable organ accumulation was detected, while the drug was found in faeces and urine. These data show that PVA hydrogels can be a suitable slow release system for tylosin administration. Oxytetracycline could also be quantitatively entrapped and released from PVA hydrogels, but once administered per os to rats, it was not detected in blood or organs.     

Loading into and electro-stimulated release of peptides and proteins from chondroitin 4-sulphate hydrogels.

Chondroitin 4-sulphate (CS) hydrogels were examined as potential matrices for the electro-controlled delivery of peptides and proteins. A CS hydrogel, cross-linked with ethylene glycol diglycidyl ether, and with a swelling ratio of 20, was used to study the influence of molecular size and shape of guest molecules on loading and release rates. Three positively charged molecules of different molecular weights (vasopressin MW 1084, aprotinin MW 6512 and lysozyme MW 14,400), and one negatively charged protein (bovine serum albumin MW 67,000) were used as model solutes. The hydrogels were loaded by equilibrium swelling. As a result, the three positively charged peptide and proteins were found to be concentrated in the gels, most likely due to ionic attraction between the negative charges in the gel polymeric backbone and the positively charged solutes. No such concentration of solute in the gel was seen for the negatively charged albumin. The latter is presumably loaded passively by diffusing in the water phase of the gel. The loading efficiency (indicated by the loading rate and the total amount of solute loaded in the gel) was found to increase with decreasing molecular size of solute. Electro-stimulated release of the loaded peptide and proteins was followed for 3 h during which an electric field was applied in pulses of 5 V (pulse duration and pulse interval were both of 20 min). The release of lysozyme and aprotinin from CS hydrogels responded to electrical pulses. On the other hand, vasopressin and albumin were largely released by passive diffusion and their release could not be electrically controlled. This work shows that the size of the guest molecule is an important parameter when electrically-stimulated drug release is desired, but further work obviously needs to be carried out with a larger range of molecular weights and conformations.     

Modifying the release of proxyphylline from PVA hydrogels using surface crosslinking

Drug release profiles were altered to prevent the initial burst effect or introduce a lag phase by creating surface crosslinked layers in poly(vinyl alcohol) (PVA) hydrogels. Confocal laser scanning microscopy (CLSM) confirmed the successful introduction of these surface crosslinked layers. The thickness and crosslinking density of the surface crosslinked layer were highly dependent on the surface crosslinking conditions (i.e., exposure time and glutaraldehyde (GTA) concentration used). By judicious selection of these parameters, the initial burst release could be eliminated and a reproducible delayed release could be achieved. Highly surface crosslinked layers had a tendency to rupture during the swelling process of PVA hydrogels; these raptures were found to coincide with delayed release of proxyphylline from surface crosslinked PVA hydrogels.     

注射用蜂毒多肽温度敏感型缓释凝胶的制备及体外释放研究

目的制备注射用蜂毒多肽的温度敏感型缓释凝胶制剂并对其体外释药进行考察。方法以新型温度敏感聚丙交酯乙交酯聚乙二醇嵌段共聚物(PLGAPEGPLGA)为载体材料制备注射用蜂毒多肽缓释凝胶制剂,采用福林酚试剂法测定制剂在磷酸盐缓冲溶液中(pH7.4)的体外释放度,并对体外释放数据用KorsmeyerPeppas方程进行拟合。结果蜂毒多肽体外持续释放36d,其释药速率随聚合物的质量分数增加而降低,且聚合物分子结构中丙交酯比例增大对释药速率几乎没有影响。蜂毒多肽从凝胶中的释放初期以扩散为主,体外释放行为符合KorsmeyerPeppas方程,后期为凝胶溶蚀和药物扩散结合的作用机制。结论注射用蜂毒多肽的温度敏感型缓释凝胶制剂制备工艺简便,药物释放达到预期要求,同时说明温度敏感PLGAPEGPLGA嵌段共聚物作为注射用缓释给药系统的载体材料具有很好的应用前景。     

Modeling of caffeine release from crosslinked water-swellable gelatin and gelatin-maltodextrin hydrogels

Research from this group has recently led to the development of a genipin-crosslinked gelatin gel that may be used as a controlled release matrix for bioactive compounds. This study presents a model that simulates the release of entrapped caffeine from the hydrogel and the ingress of water into these gels. Fick's second law of diffusion is used to describe the water penetration and bioactive release in the system. To validate the model, caffeine release experiments from the gel were carried out. The predicted bioactive release profiles are in very good agreement with experimental data at different gel compositions. The model may also be used for a wide range of bioactive molecules and hydrogels with different cylindrical dimensions.     

Equilibrium properties and mechanism of kinetic release of metoclopramide from carbomer hydrogels

Equilibrium properties and kinetics of metoclopramide release of carbomer-metoclopramide (C-M) hydrogels are reported. A set of (C-M)(X) (x=moles percent of M=50, 75, 100) that covers a pH range between 6.49 and 8.40 was used. Hydrogels exhibited a high negative electrokinetic potential (zeta). Concentrations of ion pair [R-COO(-)MH(+)] and free species [M] and [MH(+)] were determined by the selective extraction of M with 1,2-dichloroethane (DCE) together with pH measurements. The system (C-M) is characterized by a high proportion of drug present in the form of ion pairs and a negative zeta potential that attracts MH(+) and H(+) and repeals OH(-), providing a microenvironment of higher acidity than the bulk medium. Delivery rates of M were measured in a Franz type bi-compartmental device using water and NaCl 0.9% solution as receptor media. (C-M) hydrogels behave as a reservoir that releases the drug at a slow rate to water; the rate increases 14 times as water is replaced by NaCl solution. The pH effect on delivery rate suggests that, under the main conditions assayed, the rate of dissociation of R-COO(-)MH(+) together with the low change of pH in the polyelectrolyte environment are the factors that control releasing rates.     

Effect of gelatin on heparin regulation of cytokine release from hyaluronan-based hydrogels

The hypothesis that incorporation of small amounts (0.3% w/w) of modified heparin in thiol-modified hyaluronan or HA and gelatin hydrogels would regulate release of cytokine growth factors (GFs) from those gels has been investigated in vitro. In addition, the physiologic response to gel implantation has been evaluated in vivo. Tests were performed with 6 GFs: basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), keratinocyte growth factor, platelet-derived growth factor-AA (PDGF), and transforming growth factor-beta 1. Release profiles for all 6 over several weeks were well fit by first order exponential kinetics (R(2) > 0.9 for all cases). The most remarkable result of the experiment was a dramatic variation in the total mass ultimately released, which varied from as much as 90.2% of the initial load for bFGF to as little as 1.8% for PDGF, a 45-fold difference. Furthermore, gels containing either VEGF of Ang-1 produced twice the vascularization response in vivo as gels not containing a growth factor. Thus, those GFs maintained strong physiologic effectiveness.     

Single-layer transdermal film containing lidocaine: modulation of drug release.

We have recently described an innovative drug delivery system, a water-based and vapor permeable film intended for dermal and/or transdermal delivery. The aim of this work was to modulate the delivery of the model drug lidocaine hydrochloride from the transdermal film across rabbit ear skin. The effect of drug loading, of film-forming polymer type and content, of adhesive and plasticizer on lidocaine transport across the skin was evaluated. Additional objective was to evaluate the effect of occlusion on the kinetics of lidocaine transport, by applying an occlusive backing on the surface of the transdermal film. From the data obtained it can be concluded that the transdermal film acts as a matrix controlling drug delivery. The film-forming polymer molecular weight had a negligible effect on drug penetration, while its content was more effective. The choice of the adhesive seems to be the most important variable governing drug transport. In particular, the presence of lauric acid combined with a basic drug, such as lidocaine, can produce a relevant improvement in permeation, because of the formation of an ion pair. Concerning the kinetics, drug depletion is responsible for the declining permeation rates observed in the late times of permeation.     

Investigation of active substance release from poly(ethylene oxide) hydrogels

The uptake and controlled release of model active substances from poly(ethylene oxide), (PEO), hydrogels synthesized by irradiation were investigated. For the characterization of network structure of PEO hydrogels, swelling properties in water and the number average molecular weight between crosslinks were determined. Salicylic acid, phthalic acid and resorcinol were used as model substances for their controlled release from PEO hydrogels. The effects of dose rate, total dose and chemical structure of active substance on the uptake and release have been studied. The active substance uptake capacity of hydrogels was found to be lowest for phthalic acid and highest for resorcinol in the gel system obtained by irradiation both at low and high dose rates. The release was lowest both in rate and in total amounts in hydrogels containing phthalic acid, more in those with salicylic acid and highest in those with resorcinol. The physical and chemical factors affecting the release of model compounds such as the network structure of hydrogels and hydrogen bond formation between the adsorbent and PEO chains were discussed.     

Controlled release of dexamethasone from PLGA microspheres embedded within polyacid-containing PVA hydrogels

The development of zero-order release systems capable of delivering drug(s) over extended periods of time is deemed necessary for a variety of biomedical applications. We hereby describe a simple, yet versatile, delivery platform based on physically cross-linked poly(vinyl alcohol) (PVA) microgels (cross-linked via repetitive freeze/thaw cycling) containing entrapped dexamethasone-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for controlled delivery over a 1-month period. The incorporation of polyacids, such as humic acids, Nafion, and poly(acrylic acid), was found to be crucial for attaining approximately zero-order release kinetics, releasing 60% to 75% of dexamethasone within 1 month. Microspheres alone entrapped in the PVA hydrogel resulted in negligible drug release during the 1-month period of investigation. On the basis of a comprehensive evaluation of the structure-property relationships of these hydrogel/microsphere composites, in conjunction with their in vitro release performance, it was concluded that these polyacids segregate on the PLGA microsphere surfaces and thereby result in localized acidity. These surface-associated polyacids appear to cause acid-assisted hydrolysis to occur from the surface inwards. Such systems show potential for a variety of localized controlled drug delivery applications such as coatings for implantable devices.