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.     

Controlled release of hepatocyte growth factor from gelatin hydrogels based on hydrogel degradation

This paper investigates the controlled release of hepatocyte growth factor (HGF) by biodegradable gelatin hydrogels and their HGF-induced angiogenic effect. Hydrogels of different degradabilities were prepared through chemical crosslinking gelatin with varied amounts of glutaraldehyde. When the gelatin hydrogels were radioiodinated and subcutaneously implanted into the back of mice, the remaining radioactivity of the hydrogels decreased with time. However, the remaining period became longer when the concentration of glutaraldehyde used for hydrogel preparation increased. Following implantation of gelatin hydrogels incorporating 125I-labeled HGF, the HGF radioactivity retained in the mouse subcutis for longer time periods as the glutaraldehyde concentration becomes higher. The time profile of HGF remaining in every gelatin hydrogel was in good accordance with that of hydrogel degradation, indicating HGF release as a result of hydrogel biodegradation. The gelatin hydrogel incorporating HGF histologically induced angiogenic change around the implanted hydrogel. Gelatin hydrogels incorporating 5 and 10 microg HGF significantly enhanced the number of capillaries newly formed around the implanted site. This was in marked contrast to free HGF of same dose form and HGF-free, empty gelatin hydrogel. The gelatin hydrogel incorporating HGF induced VEGF around the implanted site. In vitro bioassay revealed that HGF molecules interacting with gelatin, still exhibited the biological activity. The interacted HGF would be released from gelatin hydrogels only when they were degraded to generate water-soluble gelatin fragments. It is possible that the HGF associating gelatin fragments of bioactivating, results in induced angiogenic effect.     

Effect of plasticization on heparin release from biodegradable matrices

Heparin-loaded polymer films of poly-L-lactide (PLLA) and poly-L-lactide-co-glycolide (PLLGA) as well as poly-DL-lactide-co-glycolide (PLGA) were produced. A plasticizer, PEG, was added to the polymers. It was found that the release profile in general consisted of a burst effect, a diffusion-controlled phase and a degradation-controlled phase. The plasticizer accelerated the onset of degradation in all cases, but its effect on the release profile differed significantly depending on the polymer. The plasticizer depressed the burst effect for PLLA, and accelerated the kinetics of the diffusion-controlled phase. For the PLLGA 80/20, however, the plasticizer had no significant effect on the release profile or kinetics. We explain these observations in terms of hydrophilicity and crystallinity effects.     

Preparation of gelatin hydrogels incorporating small interfering RNA for the controlled release

The objective of this study is to design biodegradable hydrogels of gelatin for the controlled release of bioactive small interfering RNA (siRNA). Gelatin was cationized by chemically introducing ethylene diamine into the carboxyl groups in different conditions to obtain cationized gelatins (CGs). The CG was mixed with siRNA at various mixing ratios of amino groups of gelatin to the phosphate groups of siRNA in aqueous solution to form the siRNA–CGnano-complex. Gelatin together with the complex of siRNA and CG was chemically crosslinked to prepare the gelatin hydrogel incorporating the complex. The hydrogel incorporating the siRNA–CG complex was hardly degraded in phosphate-buffered saline solution (PBS) at 37°C and did not release the siRNA complex after initial siRNA release. When placed in PBS containing collagenase, the hydrogel was enzymatically degraded to release the siRNA complex. In this release system, the siRNA was released as a result of hydrogel degradation. The siRNA released showed an activity to specifically suppress the expression of the corresponding gene. The hydrogel is promising to release siRNA and also elicit biological activity for a longer time.     

Protein release from gelatin matrices

Gelatin is a denatured, biodegradable protein obtained by acid and alkaline processing of collagen. This processing affects the electrical nature of collagen, yielding gelatin with different isoelectric points (IEPs). When mixed with positively or negatively charged gelatin, an oppositely charged protein will ionically interact to form a polyion complex. This review article describes protein release from charged gelatin matrices on the basis of this polyion complexation. The biodegradable hydrogel matrices are prepared by chemical crosslinking of acidic or basic gelatin and are enzymatically degraded in the body with time. The degradation is controllable by changing the extent of crosslinking, which, in turn, produces hydrogels with different water contents. The time course of protein release is in good accordance with the rate of hydrogel degradation. It is very likely that the protein drug complexed with gelatin hydrogel is released as a result of its biodegradation. This gelatin hydrogel system releases the protein drug under maintenance of biological activity. This article will focus on experimental data that sustained release of growth factor from the gelatin hydrogels is very effective in exerting the biological functions of the growth factor.     

Effect of cross-linking on the in vitro release kinetics of doxorubicin from gelatin implants

Doxorubicin is one of the most potent anti-tumor agents used generally in the treatment of bone cancer. Like other cancer chemotharepeutics, it produces undesirable side effects such as cardiotoxicity, which is especially severe when administrated via the conventional intravenous route. In order to minimize the systemic toxicities and to make this drug more suitable for the treatment of bone cancer, an implantable delivery system with cross-linked gelatin as the biodegradable matrix material was developed. This delivery system could possibly improve targeting of the drug as well as sustain the rate of release of the drug to the tumor. Glutaraldehyde was used as a cross-linking agent. Incorporation of glutaraldehyde in the matrix was needed to maintain the mechanical strength of the implant and to sustain the rate of release of the drug from the implant. Besides cross-linking the gelatin matrix, glutaraldehyde was found to cross-link the free amino group of doxorubicin. The effect of cross-linker concentration on the stability of the drug in the implant and on the rate and extent of release were also evaluated. In conclusion, cross-linked gelatin implants were developed for the local delivery of doxorubicin.     

Release of growth factors, cytokines and therapeutic molecules by hyaluronan-based hydrogels

Hyaluronan (HA) is a highly biocompatible biopolymer that is widely used for a variety of therapeutic purposes including surgical preparations, adhesion prevention, viscosupplementation and drug and cytokine delivery. Delivery can be accomplished effectively when HA-based carriers are synthesized in the form of hydrogels, though doing so normally requires chemical modification of the native HA structure. Solute delivery from HA-based gels can be either "simple", that is from a gel not including separate components intended to control release, or "regulated" when specific components are included for that purpose. A variety of modified forms of HA have been developed and used for delivery of desired molecules in therapeutic, clinical, veterinary and laboratory research environments, and the number of such applications is likely to grow in future years.     

Effect of chitosan on the release of protein from thermosensitive poly(organophosphazene) hydrogels

Poly(organophosphazenes) have been suggested as a potential thermosensitive hydrogel for use in the development of an injectable gel-depot system. Under biological conditions, hydrophilic model protein drugs, including bovine serum albumin (BSA), gelatin type B (MW 20,000) (GB20), and fluorescein isothiocyanate albumin (FITC-albumin) loaded in the hydrogels were released for 1-2 weeks, showing an initial burst release. However, this initial burst release could be suppressed when the proteins were couched in a complex with chitosan, and under these conditions evidenced a prolonged release period. BSA, GB20, and FITC-albumin, all of which are negatively charged at a pH of 7.4, interacted with chitosan harboring positive amine groups. The formation of these protein/chitosan complexes were confirmed via measurements of changes in zeta-potential and high-performance liquid chromatography. We determined the appropriate ratio of proteins to chitosan for suppression of the initial burst to be 1:5 to 1:10. From these findings, we were able to conclude that both the release rate and release period could be controlled via the formation of protein/chitosan complex.     

Mechanism of lidocaine release from carbomer-lidocaine hydrogels.

Rheology, acid-base behavior, and kinetics of lidocaine release of carbomer-lidocaine (C-L) hydrogels are reported. A series of (C-L)(x) (x = mol% of L = 25, 50, 75, 100) that covers a pH range between 5.33 and 7.96 was used. Concentrations of ion pair ([R-COO(-)LH(+)]) and free species (L) and (LH(+)) were determined by the selective extraction of (L) with cyclohexane (CH) together with pH measurements, i.e., CH in a ratio CH/hydrogel 2:1 extracted 48% of the whole concentration of lidocaine [L(T)] of a (C-L)(100), [[L(T)] = ([R-COO(-)LH(+)]) + (L) + (LH(+))]. The remaining species in the aqueous phase were distributed as: (L) 3.82%, (LH(+)) 14.5%, and [R-COO(-) LH(+)] 81.7%. Rheology and pH as a function of (C-L) concentration are also reported. Delivery rates of free base L were measured in a Franz-type bicompartmental device using water and NaCl 0.9% solution as receptor media. (C-L) hydrogels behave as a reservoir that releases the drug at a slow rate. pH effects on rate suggest that, under the main conditions assayed, dissociation of [R-COO(-)LH(+)] is the slow step that controls releasing rates. Accordingly, release rate was increased upon addition of a second counterion (i.e., Na(+)), or through the diffusion of neutral salts such as NaCl, into the matrix of the gel.     

On the release of drug from hard gelatin capsules

The effect of particle size and packing on the in vitro release of a water-insoluble hydrophobic drug from hard gelatin capsules has been related to the liquid permeability of powder beds of similar porosities. Drug release and permeability decrease with a decrease in particle size and porosity of the powder bed. A simple moist granulation process transforms a non-permeable powder bed, which allows low drug release, into one with high permeability and high drug release.     

Controlled release of DSBP from genipin-crosslinked gelatin thin films

Controlled release of a marker drug, 4,4'-bis(2-sulfostyryl) biphenyl (DSBP) from genipin crosslinked gelatin thin films, with application to drug delivery by transdermal patches is studied in this paper. A simple method for fabrication of nano-thin films, using basic lab equipment is introduced. This method consists of two steps: dipping of the substrate in a deposition solution, followed by centrifugation of the substrate. Also, swelling and drug release from thin films is modeled, using the Fick's second law of diffusion. The effect of genipin concentration on release of DSBP molecules from thin films is investigated, experimentally and numerically. The results show that controlled release of DSBP from the genipin-crosslinked gelatin thin films is achieved, using various concentrations of genipin in gelatin.     

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.     

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.     

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.     

The influence on some physicochemical parameters on drug release from PMMA salt hydrogels

In vitro drug liberation results from PMMA (Eudispert)-salt hydrogels are explained from the aspect of polymer concentration, polymer molecular mass, viscosity as well of neutralisation grade and cation (Na+, K+, NH+4, ethanolamine, triethanolamine) of the polymer molecule and solubility properties of the drugs. Drug diffusion through hydrogel is regulated with the polymer network, in dependence of polymer nature and further with die mobility of water. The considered influences predominantly cover each other.     

Effect of corticosteroids,cyclosporin A,and methotrexate on cytokine release from monocytes and T-cell subsets

Corticosteroids are the most effective drugs in the management of asthma. However, because of their known side effects and the existence of corticosteroid-resistant patients, there is a need for substitute medications in asthma therapy. Using cell lines, in the present study, the two corticosteroids dexamethasone (Dex), and beclomethasone (Bec), as well as the immunosuppressant cyclosporin A (CsA), and the antimetabolic drug methotrexate (Mtx) were examined in their effect on release of immunoreactive IL-1β, IL-2, IL-4, IL-5, and IL-8. THP-1 cells served as a test model for monocytes secreting IL-1β and IL-8 upon stimulation by lipopolysaccharide. Jurkat cells were used as a test model for T_H 1-type T-cells and were stimulated for IL-2 release with a combination of phytohemagglutinin and phorbol myristate acetate. Representing T_H2-type T-cells, D10.G4.1 cells challenged by anti-CD3-mAb produced IL-4, and IL-5. Considerable qualitative and quantitative differences in the relative efficacy of the test compounds were found. Following IC50 values (nmol/1) of the test compounds were estimated (IL-1β/IL-8/IL-2/IL-4/IL-5): Dex (10.8/35.7/>10,000.0/5.1/4.1), Bec (30.9/102.2/8591.4/0.6/0.4), CsA (318.7/6211.2/2.3/68.2/237.9). Mtx in concentrations up to 10,000.0 nmol/1 was completely inactive. It can be concluded that corticosteroids show another inhibition pattern than CsA: corticosteroids affect mainly T_h2-type T-cells, while CsA primarily inhibits the T_h1-type T-cell response.)