Release Of Water-soluble Drugs Research Articles

A mesoporous core-shell structure for pH-controlled storage and release of water-soluble drug

A novel pH-controlled delivery system has been developed based on hollow mesoporous silica spheres using pH-sensitive polyelectrolyte multilayer coated on the spheres as a switch to store and release gentamicin molecules (a model drug). The polyelectrolyte layers with an average thickness of 12 nm was coated on hollow mesoporous silica spheres through a layer-by-layer technique. Gentamicin molecules were successfully stored in these spheres by means of adjusting the gentamicin solution from pH 2 to pH 8. The storage capacity can reach 614.8 mg/g (34.11%) at an initial gentamicin concentration of 60 mg/ml. The controlled release of gentamicin molecules from this system has been achieved by simply changing the pH value in the release media. Therefore, this type of material is of potentials for the controlled drug release applications.

Analysis of surface properties of cellulose ethers and drug release from their matrix tablets

Detailed knowledge based on new developments, especially in analytical techniques, is needed for characterizing polymer excipients. Inverse gas chromatography (IGC) is a useful method for investigating polymer surfaces in terms of thermodynamic parameters. The aim of our work was to study the correlation between polymer surface properties determined with IGC and the mechanisms of release of water-soluble pentoxifylline and vancomycin hydrochloride from cellulose ether matrices. Tablets were made of hydroxypropyl (HPC), hydroxyethyl (HEC) or hydroxypropylmethyl (HPMC) cellulose and contained 25% of drug. Differences in dispersive component of the surface free energy for these polymers were relatively small and ranged from 26 to 33 mN/m. However, polar properties, expressed as specific component of the enthalpy of adsorption and as acid–base properties show larger differences between the polymers and demonstrate their relative polarity in the order HEC > HPMC > HPC, which correlates well with water sorption on bulky polymers and with the swelling degree of polymer matrices. The release of pentoxifylline and vancomycin from HPC is governed mainly by Fickian diffusion, whereas from HEC the relaxation of polymer chains is important too. The analysis of the release profiles in the light of Peppas–Sahlin model lead to the conclusion that the surface properties of the cellulose ethers influence the interactions with water and the release mechanisms of the drug. It was found out, that data obtained by IGC enable rapid inference about the behaviour of polymers in water and the release of water-soluble drugs.

Potential use of 2-hydroxypropyl-β-cyclodextrin as a release modifier of a water-soluble drug, metoprolol tartrate, from ethylcellulose tablets

Drug release behavior was investigated for tablets of a ternary system in which metoprolol tartrate (Met)/2-hydroxypropyl-β-cyclodextrin (HP-β-CD) complexes with different molar ratios were dispersed in an ethylcellulose (EC) matrix. The release rate of Met from the tablets decreased due to the formation of the binary solid dispersion with EC and was further slowed down by dispersal of the Met/HP-β-CD complex in the EC matrix. The release rate of Met decreased with the increase in contents of HP-β-CyD in EC matrix up to (30/10)/60%w/w (Met/HP-β-CD)/EC but further increases in HP-β-CD content led to faster release rates. The analysis of the release rates by Korsmeyer's and Higuchi's equations and their temperature dependence suggested that Met is released according to a diffusion-controlled mechanism. Water penetration studies and microscopic observation suggested that the retarding effect of HP-β-CD is attributable to a gel formation in small pores of the EC matrix. Moreover, the release rate of Met from the ternary (Met/HP-β-CD)/EC ((30/10)/60%w/w) tablet was negligibly influenced by the pH of the dissolution medium, paddle rotation rate, viscosity of the solution and storage conditions of the tablet. The results suggested that HP-β-CD can work as a release rate-decelerating agent for Met when it is formulated in appropriate amounts in a hydrophobic EC matrix. Therefore, a combination of HP-β-CD and EC may be useful for the controlled release of water-soluble drugs, and the release control can be tuned by adjusting the composition of components.

Sustained release of water-soluble drug from directly compressed alginate tablets.

The release of acetyl salicylic acid from directly compressed alginate tablets was investigated. The effect of the amount and type of alginate on the drug release rate was evaluated in different formulations. Four different grades of alginate were used. The in vitro release studies were carried out using the apparatus II (paddle) equipment as described in the USP 23/NF dissolution monograph. Dissolution medium was 0.1 M HCl for 2 h followed by phosphate buffer pH 6.8; both at 37 degrees C. Sustained drug release up to 16 h was achieved using sodium alginate in combination with dibasic calcium phosphate.

Targeted cytosolic delivery of hydrogel nanoparticles into HepG2 cells through engineered Sendai viral envelopes

Hydrogel nanoparticles of cross-linked polyvinylpyrrolidone (PVP-NP) (35–50 nm in diameter) containing fluoresceinated dextran (FITC-Dx) were encapsulated in reconstituted Sendai viral envelopes containing only the fusion (F) protein (F-virosomes 1 1 Process for Producing a Targeted Gene (1997) US Patent 5, 683, 866). ). Incubation of these loaded F-virosomes with human hepatoblastoma cells (HepG2) in culture resulted in membrane-fusion-mediated delivery of NPs to the cell cytoplasm, as inferred from the ability of cells to internalize FITC-Dx loaded PVP-NP (PVP f-NP) in the presence of azide (an inhibitor of the endocytotic process). Introduction of PVP f-NP into the HepG2 cells was assured by selective accumulation of FITC fluorescence in the cytosolic compartment. The structural integrity of the internalized PVP f-NP was also confirmed by fluorescence microscopy and ultracentrifugation analysis. The potential usefulness of PVP-NP-mediated cytosolic release of water soluble drugs both in vitro and in vivo has been established for the first time.

Influência do comonômero e do método de polimerização na cinética de liberação de fenobarbitona a partir de hidrogéis

A liberação de drogas solúveis em água a partir de matrizes de hidrogéis hidratados, geralmente envolve simultaneamente a absorção de água e a liberação da droga via mecanismo de difusão controlada. Foi analisado o comportamento difusional da fenobarbitona no hidrogel do copolímero 2-hidroxietil metacrilato (HEMA) e monoitaconato de metila (MMI). A liberação da droga no meio aquoso foi acompanhada por cromatografia líquida de alta pressão e os resultados mostraram que a liberação da fenobarbitona a partir dos hidrogéis estudados, considerando-se os valores dos coeficientes de difusão, não variou com a temperatura e com o método de polimerização. Os valores de energia de ativação sugerem um favorecimento na liberação da fenobarbitona a partir dos hidrogéis de p(HEMA-co-MMI) polimerizados em massa e em solução.

トリバレリル化β‐シクロデキストリン膜を用いた水溶性薬物の放出制御

Among various acylated β-cyclodextrins where all hydroxyl groups are substituted with different acyl groups, trivaIeryl β-cyclodextrin (TV-β-CyD) preferentially formed a transparent, adhesive thin-film. For example, when ethanol solution of TV-β-CyD was spread on the backing membranes such as polyethylene terephthalate film, polyethylene film and aluminium foil, a transparent film was formed, the film being tightly stuck on the membranes. The detaching force of TV-β-CyD film was higher and the decrease in the force by the addition of oleic acid was smaller than those of a commercial silicone pressure-sensitive adhesive which is used in transdermal drug delivery system. A vasodilator, isosorbide dinitrate (ISDN), was incorporated in TV-β-CyD film in molar ratios of 1 : 1 and 2 : 1 (ISDN : TV-β-CyD). The release rate of ISDN from TV-β-CyD film increased with increase in the film area, and slightly increased by the addition of oleic acid in the film. The plasma levels of ISDN after topical application of TV-β-CyD film containing ISDN to abdominal skin of rats were maintained 100 ng/ml for about 10 hours. The results suggests that TV-β-CyD film can serve as a drug reservoir for prolonged release of water-soluble drugs in transdermal preparations.

Influence of lipophilic surfactant on the release kinetics of water-soluble molecules entrapped in a W/O/W multiple emulsion

The aim of this work was to study the release kinetics of a water-soluble drug from two different W/O/W multiple emulsions prepared with two lipophilic surfactants at different concentrations. The study of the kinetics under both iso-osmotic and hypo-osmotic conditions allowed us to distinguish between two possible release mechanisms: swelling-breakdown or facilitated diffusion. The results obtained indicate that water-soluble drug release occurs by a mechanism of swelling followed by a breakdown of the oil globules, in which the lipophilic surfactant is a decisive factor. It appears that the globule's swelling capacity is considerably increased when the lipophilic surfactant concentration increases, and the more the oil globule swells, the less the water-soluble drug releases. It seems that the stability could be improved by increasing the lipophilic surfactant concentration which could strengthen the interfacial film. In contrast, an excess of hydrophilic surfactant destabilized the emulsion.

Pharmacokinetics of Vancomycin after Intravenous Administration of a W/O/W Emulsion to Rats

A stable water-in-oil-in-water multiple emulsion (w/o/w emulsion) was prepared, and its potential for drug delivery was evaluated. W/o/w emulsions were prepared using a Lipiodol Ultra-Fluid(r) and isopropyl myristate oil mixture for the oily phase and vancomycin (VCM) for the entrapped drug. The surfactants, HCO-40 (5% [w/v]) and Pluronic F-88 were dissolved in the oily phase and the external aqueous phase, respectively. Resultant w/o/w emulsions were evaluated for entrapment efficiency, particle size, viscosity, drug release in vitro, and disposition kinetics of the drug and the w/o/w emulsion in vivo. The particle size of the w/o/w emulsion decreased with an increase in the concentration of F-88 in the external aqueous phase and stirring speed at the second emulsification stage (the smallest being 2.9 ± 1.5 μm). Entrapment efficiency of VCM in the w/o/w emulsion decreased with an increase in the concentration of F-88 (the maximum being 65.3 ± 5.4%). VCM release from the w/o/w emulsion was prolonged and tended to be slower with an increase in the particle size of the emulsion. After intravenous administration, significant differences in pharmacokinetic parameters, such as k21, kelβ, AUC0-±, MRT0-6, and MRT0-±, were observed between the VCM solution and the w/o/w emulsion-entrapped drug. When the w/o/w emulsion with Sudan II in the oily phase was administered intravenously, the emulsion accumulated in the lung at first (the highest value was observed just after administration) and then in the liver (the highest value was observed at 60 min). The w/o/w emulsion prepared in this study is expected to be a possible carrier for the prolonged release of water-soluble drugs after intravenous administration.

Study of diabietic acid as matrix forming material

Abietic acid was extracted from rosin N grade and further standardized. Diabietic acid, a derivative of abietic acid was prepared by dimerization with sulfuric acid and evaluated for different physicochemical properties. A yellowish brown colour product with an acid value of 98 mg KOH, a softening point of 142—145°C and an acid/alkali resistant property was obtained. Moisture absorption study indicated its hydrophobic nature. Water vapour transmission and scanning electron micrography showed that the free films of diabietic acid are smooth, flexible, nonporous with 0.024 g h −1 mmHg of water vapour transmission rate at 82.5°C relative humidity (RH). Matrix tablets of Diclofenac sodium were formulated using diabietic acid as a matrix-forming material and evaluated for hardness, friability, release characteristics and material balance study. The results showed that diabietic acid having good film forming, acid/alkali resistant properties could be successfully used to prolong release of water-soluble drug for up to 24 h.

An Examination of Assumptions Underlying the First-Order Kinetic Model for Release of Water-Soluble Drugs from Dicalcium Phosphate Dihydrate Matrices

It has been shown that the release of highly water-soluble drugs from compressed dicalcium phosphate dihydrate matrices follows first-order kinetics (1). Good correlation between the rate constant and tablet geometry (2) was also reported. However, the rate constants for different geometry could not be predicted accurately by using the constants obtained for cylindrical tablets. In this work the assumptions regarding the surface area, porosity, and inertness of the drug toward the matrix have been tested using simple experimental designs and techniques such as porosimetry, electron microscopy, and differential scanning calorimetry. No interactions between the drug and the matrix were observed. The assumptions regarding porosity/void volume seemed to hold. Using water as a penetrant gave better estimate of porosities than those obtained using mercury. The assumption regarding surface area needs correction; however, a better alternative has not been proposed.

A linear drug release from erosion‐controlled drug/resin complex systems

The linear release of water-soluble drugs (diphenhydramine and propanolol) from erodible, drug/resin complex, gel matrices using poly(methyl methacrylate-co-sodium acrylate) was investigated

Injectable Polyanhydride Granules Provide Controlled Release of Water-Soluble Drugs with a Reduced Initial Burst

A method for preparing polyanhydride granules of an injectable size was developed. The resulting granules permitted a nearly constant release of low-molecular-weight, water-soluble drugs without an initial burst. The polyanhydrides used were poly(fatty acid dimer), poly(sebacic acid), and their copolymers. The dyes acid orange 63 and p-nitroaniline were used as model compounds for drugs. Polymer degradation and drug release for disks and variously sized granules of copolymers containing drugs, prepared by a water-in-oil (W/O) emulsion method, were compared with those for devices prepared by the usual compression method. In the W/O emulsion method, a mixture of aqueous drug solution and polymer-chloroform solution was emulsified by probe sonication to prepare a very fine W/O emulsion. The powder obtained by freeze-drying of the W/O emulsion was pressed into circular disks. In the compression method, the drug was mechanically mixed with the polymer, and the mixture was compressed into circular disks. The resulting disks were ground to prepare granules of different sizes. The granules encapsulated more than 95% of the drug, irrespective of the preparation method. Both methods were effective in preparing polymer disks capable of controlled drug release without any initial burst. However, as the granule size decreased to an injectable size (diameter, < 150 microns), a large difference in the drug release profile was observed between the two preparation methods. The injectable granules obtained by the W/O emulsion method showed nearly constant drug release without any large initial burst, in contrast to those prepared by the compression method, irrespective of the drug type.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of drug release from hydrogel matrices

The release of water soluble drugs from initially dehydrated hydrogel matrices generally involves the simultaneous absorption of water and desorption of drug via a swelling-controlled diffusion mechanism. Thus, as water penetrates a glassy hydrogel matrix containing dispersed drug, the polymer swells and its glass transition temperature is lowered. At the same time, the dissolved drug diffuses through this swollen rubbery region into the external releasing medium. Such diffusion and swelling generally do not follow a Fickian diffusion mechanism. The existence of some molecular relaxation process in addition to diffusion is believed to be responsible for the observed non-Fickian behavior. In this article, the kinetics of drug release from hydrogel matrices will be examined both experimentally and theoretically. Special emphasis will be placed on the effect of local drug concentration on the swelling behavior of hydrogel drug carriers. A novel approach to constant-rate drug delivery from glassy hydrogel matrices via an immobilized non-uniform drug concentration distribution will also be described.

3] Incorporation of water-soluble drugs in albumin microspheres

This chapter presents the nature and extent of incorporation of water-soluble compounds into albumin microspheres. Physical characteristics with incorporated drug are discussed. It includes appearance, swelling, surface charge and microsphere size. Use of a water-in-oil technique for producing drug-bearing albumin microspheres leads to constrictions on the maximal amount of drug which may be incorporated. The chapter examines the relationship between drug physicochemical structure and its incorporation into albumin microspheres. It is shown that incorporation of water-soluble compounds can have an effect on the size of microspheres formed, their eventual swelling in water, their physical appearance, and their microelectrophoretic mobility. It is also shown that drug associated with the microspheres is probably entrapped within the matrix of the sphere, and that nonspecific protein binding has little effect on the incorporation of water-soluble compounds. The release of water-soluble drugs from albumin microspheres is briefly discussed.

Modelling of sustained release of water-soluble drugs from porous, hydrophobic polymers

The release behaviour of water-soluble drugs from hydrophobic, porous polymeric matrices is complicated by the dissolution of the drug in the water-filled pores under quiescent conditions. Mathematical models are presented for drug release above and below the solubility limit of the drug in the dissolution medium, for constant void fraction (porosity). Experimental studies of KCI release from porous ethyl cellulose tablets in water at 37°C are explained in terms of dissolution-controlled and diffusion-controlled steps of the release mechanism.

Effect of the morphology of hydrophilic polymeric matrices on the diffusion and release of water soluble drugs

Drug release mechanisms from, and diffusion processes in, hydrophilic crosslinked polymeric systems were investigated in two macromolecular states: in the glassy and rubbery states during the early part of countercurrent water diffusion, and in the rubbery state after thermodynamic equilibrium between the network and the surrounding dissolution medium (water) was attained. Dilute, aqueous poly(vinyl alcohol) (PVA) solutions containing theophylline were crosslinked with glutaraldehyde. The crosslinking ratio, X, varied between 0.01 and 0.20 moles glutaraldehyde per mole of PVA repeating unit. Theophylline release from these rubbery matrices was followed as a function of time. It was determined that, within the range of crosslinking ratios studied, the crosslinked macromolecular structure affected the solute diffusion process. Theophylline release from crosslinked PVA slabs, which were originally dehydrated at 30°C, was also measured. The drug release process was significantly impeded in these systems, especially for samples with crosslinking ratio X ≥ 0.10. This behavior was explained in terms of relaxation of the macromolecular chains and possible existence of ordered chain structures. Glass-to-rubber transitions, a result of the countercurrent diffusion of water into the originally dried (glassy) polymer, shifted the fractional release of theophylline from a f( t 1/2) to a f( t n) time dependence, with n taking values between 0.50 and 0.76. This type of release behavior indicates anomalous diffusion mechanisms. These results may be helpful in the development of swelling controlled drug delivery systems.