A Diffusion Controlled Drug Delivery System for Theophylline

Abstract

The goal of achieving ideal attributes of a drug delivery system including reliability and predictability has led investigators to design controlled release (CR) systems based on the principles of microporous coatings, diffusion controlled coatings and various hydrogel type systems.

In this study, the critical role of “water content fraction” of a polymer in deciding its diffusion characteristics has been ascertained and the correlation between molecular size/shape, membrane thickness, pore radii and drug diffusion has also been demonstrated. The theoretical considerations, designing and engineering of a “barrier coated-reservoir” type of a delivery system for theophylline using poly (vinyl alcohol) [PVA] as the coating material are discussed. After realizing the desired theoretical in-vitro release profile, in-vivo studies were carried out on a dog model. The potential of poly (vinyl alcohol) as a barrier coating material in developing a CR system is interestingly observed.     

Comparison of Diffusion Studies of Hydrocortisone Between the Franz Cell and the Enhancer Cell

The Franz diffusion cell remains a popular method to study diffusion of transdermal drug delivery systems through membranes. Recently, VanKel Industries, Inc., (Edison, NJ) developed the “Enhancer Cell,” a new device for in vitro transdermal drug diffusion testing. The purpose of this study was to evaluate the enhancer cell for in vitro transdermal diffusion of hydrocortisone from an ointment using a synthetic membrane and a biological membrane and compare it to the traditionally employed Franz cell. The Enhancer cell utilizes existing USP dissolution equipment (USP Apparatus II). Results show a higher cumulative release from the Enhancer cell as compared to the Franz cell. The Enhancer cell demonstrated more durability and was easier to use during experimentation and after completion of the experiment no apparent change was observed in the condition of the ointment or the skin when compared to the Franz cell.     

High-throughput evaluation of non-swellable controlled release matrix tablets

Drug release from controlled-release (CR) matrix tablets involves the permeation and diffusion of water through the system. In this study, a new methodology is proposed for the measurement of water permeation and simultaneous drug release from the inert, non-swellable CR matrix tablet of diltiazem (DLT) and a correlation is made between these two processes. Cylindrical matrices were readily prepared by direct compression of pellets obtained by extrusion-spheronization. Water transport was studied using tritiated water (HTO) as a permeant in a Franz-diffusion cell and simultaneously drug release was measured. Further, dissolution was performed on USP XXI/XXII dissolution apparatus I using demineralized water. Matrices showed a steady water-uptake up to 6 h and the steady state for HTO permeation lasting from 6-h to 24-h Flux of water permeated and flux of drug released correlated well. Thus, HTO permeation through the matrix tablet and the proposed methodology can be used as a tool and/or surrogate marker for evaluation of controlled release matrix tablets. This methodology can be coined as “high-throughput” in terms of amount of labor and resources required in comparison to that of dissolution.     

Development of a Formulation of Sustained Release Potassium Chloride

The purpose of this work has been the designing and “in vitro” evaluation of a potassium chloride tablet using a wax matrix.

Camauba wax, stearyl alcohol and stearic acid ware employed to prepare granulates at different drug/wax ratios. Fran dissolution kinetic studies and technological performances a 75/25 - KCl/camauba wax granulates was selected. The rheolqgical properties of granulates were characterized and tablets were manufactured employing ccrrmun tablets excipients. Also a coating procedure was developed. The coated tablet formulation selected release the potassium chloride according to the USP requirements.

The dissolution kinetics of the potassium chloride from both coated and uncoated tablets fit the Higuchi diffusion model, giving a straight line when the amount dissolved is plotted against the square root of time.     

Relationship between the swelling process and the release of a water-soluble drug from a compressed swellable-soluble matrix of poly(vinyl alcohol)

An attempt was made in this study to relate the release of a highly water-soluble model drug from tablet matrices of poly(vinyl alcohol) (PVAL) with the factors that may affect the release behavior. Swelling was evaluated using a simple projection method. The swollen layer was photographed to monitor its thickness. The polymer and drug dissolution were determined simultaneously by spectrophotometric methods. The resulting change of tablet area showed that the process of swelling occurred in three different stages that were intimately related to polymer dissolution: (a) a rapid initial swelling, resulting in an increased area; (b) a period with an approximately constant area; and (c) a decrease of the tablet area. In spite of the significant dissolution of PVAL during the release process, the thickness of the gel layer gradually increased. Thus, the delivery was governed by the drug concentration gradient along the diffusional path length. The drug release appeared to be controlled by a diffusion process according to Higuchi-type kinetics. The data analysis of drug and polymer profiles confirmed the diffusional mechanism.     

Addition of “Living” Polymers onto C60.

Various “living” polymers were grafted onto C₆₀ The number of arms of the so obtained “star” molecules can be controlled by stoechiometry and/or by varying the reactivity of the carbanion on the “living” chain against a double bond on the C₆₀. Even the oxanion of “living” polyethylenoxide is able to add onto the reactive double bonds on C₆₀. In some conditions, the carbanions present on these alkaline salts of grafted fullerenes becomes able to initiate anionic polymerization of vinyl monomers. Using “living” poly(phenylvinylsulfoxide) as a precursor polymer for PA, polyacetylene chains could be attached to the fullerene.     

Evaluation of intratympanic formulations for inner ear delivery: methodology and sustained release formulation testing

A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid)–poly(ethylene glycol)–poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions.     

Relationship Between the Swelling Process and the Release of a Water-Soluble Drug from a Compressed Swellable-Soluble Matrix of Poly(Vinyl Alcohol)

An attempt was made in this study to relate the release of a highly water-soluble model drug from tablet matrices of poly(vinyl alcohol) (PVAL) with the factors that may affect the release behavior. Swelling was evaluated using a simple projection method. The swollen layer was photographed to monitor its thickness. The polymer and drug dissolution were determined simultaneously by spectrophotometric methods. The resulting change of tablet area showed that the process of swelling occurred in three different stages that were intimately related to polymer dissolution: (a) a rapid initial swelling, resulting in an increased area; (b) a period with an approximately constant area; and (c) a decrease of the tablet area. In spite of the significant dissolution of PVAL during the release process, the thickness of the gel layer gradually increased. Thus, the delivery was governed by the drug concentration gradient along the diffusional path length. The drug release appeared to be controlled by a diffusion process according to Higuchi-type kinetics. The data analysis of drug and polymer profiles confirmed the diffusional mechanism.     

Poly (vinyl alcohol) hydrogels for pH dependent colon targeted drug delivery

Oral drug administration is convenient with pH dependent drug delivery system since the drug has to pass through different pH environments in gastro intestinal (GI) tract. The pH dependent swelling/shrinking behavior of hydrogel drug carrier controls the drug release without affecting the function of drug. pH dependent hydrogels of poly (vinyl alcohol) (PVA) were prepared by cross linking with maleic acid (MA). The hydrogels were characterized by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, DSC, porosimetry, SEM, TEM, biocompatibility study and by measuring their swelling behavior in water, simulated gastric fluid (SGF) and intestinal fluid (SIF). Swelling of the hydrogels was found to be highest in SIF (pH: 7.5) and lowest in SGF (pH: 1.2) resembling that required in colon targeted drug delivery systems. Since the swelling behavior of the gel is pH dependent, these hydrogels were studied for colon targeted drug delivery in an in-vitro set-up resembling the condition of GI tract. The ratio of PVA and MA in the hydrogel was varied to study the effect on the drug diffusion rate. For drug delivery study, vitamin B₁₂ and salicylic acid were used as model drugs. The hydrogel, loaded with model drugs vitamin B₁₂ and salicylic acid also demonstrated colon specific drug release with a relatively higher drug release in SIF (pH: 7.5) than that in SGF (pH: 1.2).     

Effect of chitosan and dextran on the properties of poly(vinyl alcohol) hydrogels

Hydrogels are three-dimensional polymeric networks very similar to biological tissues and potentially useful as drug delivery systems. Poly(vinyl alcohol)-based hydrogels containing different amounts of dextran or chitosan were prepared using the freezing–thawing method. Repeated freezing–thawing cycles of a poly(vinyl alcohol) (PVA) aqueous solution lead to the formation of crystallites which act as cross-linking sites, and a hydrogel with a high capacity to swell is obtained. The effects of the two different polysaccharides on the properties of the obtained materials were investigated by differential scanning calorimetry, dynamic mechanical analysis and scanning electron microscopy. In addition the release with time of poly(vinyl alcohol) in aqueous medium, was monitored and evaluated. On the basis of the obtained results it seems that the presence of dextran favors the crystallization process of PVA, allowing the formation of a more ordered and homogeneous structure. Instead, chitosan seems to perturb the formation of PVA crystallites leading to a material with a less regular structure. © 1999 Kluwer Academic Publishers     

Mechanistical Analysis of Release Kinetics for Lipophilic Drug from Matrix-Type Drug Delivery Devices

The release kinetics of lipophilic drug from hydrophobic polymer-based matrix-type drug delivery system was studied. Using the “intrinsic formula”, several experimental problems can be analyzed and solved. The results reveal that intrinsic release, calculated from the model, shows the true properties of the drug delivery system, which might have been disguised by the boundary layer effect. The results also demonstrated the needs of maintaining sink condition and uniform distribution of dispersed phase in studying the matrix diffusion-controlled drug release.     

The changes of structure upon thermal treatment of gold coatings electrodeposited on vacuum-sputtered Ti and electrodeposited Ni---B or Ni---Fe layers

The changes in structure and chemical composition of gold coatings after thermal treatment in dependence on the composition of metallic layers has been studied by transmission electron microscopy, scanning electron microscopy and X-ray diffraction (XRD). An electrodeposited gold coating on Ti as well as on Fe---Ni/Cu and Ni---B/Cu systems had no observable changes in phase composition and structure after thermal treatment of 200 h at 150–200 °C. Spontaneous growth of gold crystal whiskers were observed on the gold coating on a Ti substratum (50–100 h, 350 °C). There were changed friable structures in some places. XRD data testify a presence of Au₂Ti and AuTi₃. A changed structure containing big grains developed in some places on the gold coating of the system Au/Fe---Ni/Cu after thermal treatment (50 h, 350 °C). Nickel diffusion and the presence of intermetallic AuCu in the gold coating was also observed. The gold coating of the system Au/Ni---B/Cu remains stable with respect to structure and chemical purity. The electrodeposited Ni---B layer (B, 4–8 wt.%; C, 3–7 and 10⁻² wt.% in dependence of the technique of electrodeposition) is amorphous. The gold coating on a Ni---B substratum had no observable changes in structure after a thermal treatment of 200 h, 350 °C.     

Influence of Drug Loading and Gel Structure on in-Vitro Release Kinetics from Photopolymerized Gels

Precious work has shown that stabls and homogenous poly HEMA gels can be prepared using a visible light sensitive initiator system. Gels were prepared from solutions of water and poly-2-hydroxyethyl methacrylate monomer. At concentrations of water greater than 10% v/v, translucent gel resulted. However, polymerization solvents such as glycerol and tertiary butyl alcohol (T.B.T.A) gave transparent, flexible gels over a wider range of concentrations. Subsequent work showed that changes in polymerization solvent and monomer concentration brought about changes in the mechanical and structural properties of the gels.

In this work, the effects of drug loading and polymerization solvents on in vitro drug release rate from the photopolymerized polyHEMA gels were studied. Polymerization solvents used included glycerol and tertiary butyl alcohol. Results indicated that the release rate in vitro was a diffusion-controlled process except at high drug concentrations in poly HEMA - T.B.T.A. gels when a departure from root-time kinetics occurred. Poly HEMA T.B.T.A. gels presented greater hindeirance to the mobility of the drug than polyHEMA - glycerol gels. Higuch's model for release from incoluble homogenous matrices containing dispersed solute was found to be inappropriate for the analysis of the release of the drug from the gels. A simple equation based on the modelling of desorption in diffusion was found more appropriate. Estimates of drug release rates in vitro may be made from measurements of the physical crosslinking density of the polymer (if matrix-diffusion controlled release is operative). Quantitative drug loading was achieved in the gels as evidenced from variation in crosslinking density and in vitro release rate with drug loading.     

Poly (vinyl alcohol) hydrogels for pH dependent colon targeted drug delivery

Oral drug administration is convenient with pH dependent drug delivery system since the drug has to pass through different pH environments in gastro intestinal (GI) tract. The pH dependent swelling/shrinking behavior of hydrogel drug carrier controls the drug release without affecting the function of drug. pH dependent hydrogels of poly (vinyl alcohol) (PVA) were prepared by cross linking with maleic acid (MA). The hydrogels were characterized by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, DSC, porosimetry, SEM, TEM, biocompatibility study and by measuring their swelling behavior in water, simulated gastric fluid (SGF) and intestinal fluid (SIF). Swelling of the hydrogels was found to be highest in SIF (pH: 7.5) and lowest in SGF (pH: 1.2) resembling that required in colon targeted drug delivery systems. Since the swelling behavior of the gel is pH dependent, these hydrogels were studied for colon targeted drug delivery in an in-vitro set-up resembling the condition of GI tract. The ratio of PVA and MA in the hydrogel was varied to study the effect on the drug diffusion rate. For drug delivery study, vitamin B12 and salicylic acid were used as model drugs. The hydrogel, loaded with model drugs vitamin B12 and salicylic acid also demonstrated colon specific drug release with a relatively higher drug release in SIF (pH: 7.5) than that in SGF (pH: 1.2).     

Evaluation of starch based cryogels as potential biomaterials for controlled release of antibiotic drugs

In the present study starch has been blended with poly(vinyl alcohol) to design macroporous architectures following a repeated freeze-thaw method. These macroporous cryogels were loaded with an antibiotic drug, ciprofloxacin hydrochloride (Cfx), and evaluated for its in vitro delivery in a completely controlled manner thus exploring possibilities to use it as a biomaterial in burn or wound healing applications. The key advantage of the present system is that cryogels formed do not contain any chemical crosslinking agent which is often harmful to organic compounds. These Cfx loaded cryogels were characterized by infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) techniques. The controlled release of Cfx drug from cryogels was investigated under varying experimental conditions such as percent loading of the antibiotic drug, chemical architecture of the cryogels and pH, temperature, and nature of the release media. The prepared cryogels show promise to provide a possible pathway for controlling delivery of antibiotic drug thus minimizing the known side effects and improving efficacy also.     

The release of 5-fluorouracil from microspheres of poly(epsilon-caprolactone-co-ethylene oxide)

The purpose of this study was to evaluate the in vitro release of 5-fluorouracil from microspheres prepared using a novel triblock copolymer of ε-caprolactone and ethylene oxide as the encapsulating material. Microspheres of poly(ε-caprolactone-co-ethylene oxide) were prepared by employing the “hot-melt” method of microencapsulation. Microspheres were sized using sieve analysis and scanning electron microscopy (SEM). Release studies were performed using a custom-made rotating paddle dissolution apparatus. Copolymer microspheres, fabricated by the hot melt method were shown by electron microscopy to have smooth, nonporous surfaces. Drug-loaded microspheres were found to have a broad distribution of sizes, which was thought to be a consequence of the wide range of crystal sizes of the encapsulated unmilled drug. Nonlinear release kinetics were observed from microspheres in the size fraction 75-250 μm, with a pronounced “burst release” associated with the presence of drug at the surface of the microspheres. A specific delineation of the drug release mechanism was not possible due to rapid gelation, swelling, and subsequent dissolution of the microspheres that occurred on hydration. This work describes the preparation of microspheres that swell rapidly and coalesce together on hydration, accompanied by rapid drug release and copolymer dissolution over a 2-hr period.     

A Flow-Through Dissolution Approach to In Vivo/In Vitro Correlation of Adinazolam Release from Sustained Release Formulations

A Copley^TM fraction collector and a Disotest^TM flow-through system were coupled to provide an automatic discrete sampling flow-through dissolution system for use both in the “open-loop” and “closed-loop” mode. The system was used to investigate the release characteristics of adinazolam in sustained release formulations using a pH 1.2 simulated gastric fluid (without enzymes) dissolution medium (USP XXI). These experimental formulations are designed to provide relatively slow to rapid drug release. The dissolution effluent was analysed off-line by reverse phase HPLC to determine the adinazolam concentration at programmed timed intervals. The differential dissolution profiles produced when the system is used in the “open-loop” configuration are more discriminating in describing the release characteristics of the formulations according to the relative release rates than the “closed-loop” cumulative profiles. Using the characteristic dissolution time parameter from the Weibull function, a better correlation with in vivo bioavailability data was achieved for the data from the system in the “open-loop” mode than when it was used in the “closed-loop” mode. In the “open-loop” mode the Weibull function characteristic dissolution time parameter yielded the best quantitative correlation with a correlation coefficient of 0.92 compared to a value of 0.85 for the “closed-loop” configuration     

On the combined influences of Young''s modulus and stress ratio on the LEFM fatigue crack growth process: A new mechanistic approach

A new mechanistic approach (NMA) was used recently to examine the physical aspects of LEFM (long) fatigue crack growth (FCG) process in crack-ductile materials in stages I and II. In this paper, NMA is extended to examine both the physical and analytical aspects of the combined effects of Young's modulus, E and stress ratio, R, in the same stages of the same materials. It is shown that, (i) with submicroscopic cleavage or reversed shear mechanism operating in the pure form, E is the most influential intrinsic “material” property controlling FCG, (ii) E-dependence of da/dN is a natural consequence of near-crack-tip displacement control proposed previously, and (iii) the demonstrated similarity of FCG curves and the existence of characteristic “pivot points” on these curves for a “class of materials” results from E-influence which continues even at a higher R. A simple analytical model based on “strain intensity factor,” K₀, which contains E-influence implicitly and controls da/dN in all materials irrespective of class, is proposed. Model-predicted K₀-based theoretical values of threshold, “Idealised Master Growth Curves (IMGCs)” and mechanism transition point, all agreed excellently with experimental data for at least three classes of materials, i.e. steels, Al-alloys and Ti-alloys at extreme R-values of 0 and ≥ 0.6. The K₀-parameter concept is used here to raise the status of the analysis of the E-effect from a simple “normalisation” to that of direct data “representation”. Using NMA existing empirical relations are given some sound theoretical base. In addition to aiding in a clearer physical understanding of the FCG process, the unique IMGCs developed for different R-values are considered useful in quick, accurate and conservative life estimations, and performing failure analyses usually required in selection and design of materials.     

Application of Poly(oxyethylene) Homopolymers in Sustained Release Solid Formulations

Water soluble poly(oxyethylene) homopolymers, with molecular mass ranging from four hundred thousand to four million, were used as carriers to generate, by direct compression techniques, sustained release matrix tablets of both water-soluble and insoluble bioactive agents. Dissolution studies showed that the release kinetics of the tablets depends upon the solubility and molecular mass of polymer, solubility of drug, and the ratio of the drug to polymer in the tablets. Following drug release, the tablet components dissolved leaving behind no residue, or “ghost”, as is commonly observed with wax-based systems.     

Investigation of the effect of various shellac coating compositions containing different water-soluble polymers on in vitro drug release

In this study drug pellets were coated with aqueous shellac coating formulations containing different amounts of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and carbomer 940. The coating level needed for enteric coating was determined. The influence of different amounts of PVA, HPMC, and carbomer on drug release and mechanism; the porosity, and the stability of shellac coatings was investigated. The results show that the incorporation of different concentrations of HPMC into shellac coatings, due to the increasing of pores, could considerably increase the drug release from the pellets in purified water. Moreover, the swelling effect of carbomer 940 leads to much more diffusivity through shellac coatings in water. In addition, PVA results in small cracking in the films and much more diffusion of drug in water. Furthermore, all coating systems containing different hydrophilic polymers that were used in the present work could prevent the dissolution of drug in simulated gastric juice for 2 hours. On the other hand, a rapid and complete release of drug within 45 minutes was observed in simulated intestinal fluid. Drug release from shellac coated pellets and ones containing different amounts of carbomer was affected between 3-6 months, whereas shellac coatings containing different amounts of PVA or HPMC show the same dissolution profiles with small deviation after 12 months.