Ca-alginate microspheres encapsulated in chitosan beads

Chitosan beads (CBs) incorporating Ca-alginate microspheres (CAMs), containing a drug, were prepared as an oral sustained delivery system. Stable and monodisperse Ca-alginate microspheres loaded with drug were obtained by a membrane emulsification method. The Ca-alginate microspheres were encapsulated in chitosan beads by the ionotropic gelation method with a polyelectrolyte complex reaction between two oppositely charged polyions. The surface and internal characteristics of the beads were improved by ionic cross-linking in tripolyphosphate (TPP) solution adjusted to pH 5.0. The release experiments were performed using lidocaine.HCl (cationic drug) and sodium salicylate (anionic drug) as model drugs. Initial release of drugs depended on the degree of swelling. Ca-alginate microspheres encapsulated in chitosan beads were superior to both drug-loaded CBs and CAMs beads for sustained release because they had a three-layer composition; a calcium alginate core bounded by an inter-phasic chitosan-alginate membrane, which itself was surrounded by a layer of chitosan-TPP.     

Ca-alginate microspheres encapsulated in chitosan beads

Chitosan beads (CBs) incorporating Ca-alginate microspheres (CAMs), containing a drug, were prepared as an oral sustained delivery system. Stable and monodisperse Ca-alginate microspheres loaded with drug were obtained by a membrane emulsification method. The Ca-alginate microspheres were encapsulated in chitosan beads by the ionotropic gelation method with a polyelectrolyte complex reaction between two oppositely charged polyions. The surface and internal characteristics of the beads were improved by ionic cross-linking in tripolyphosphate (TPP) solution adjusted to pH 5.0. The release experiments were performed using lidocaine·HCl (cationic drug) and sodium salicylate (anionic drug) as model drugs. Initial release of drugs depended on the degree of swelling. Ca-alginate microspheres encapsulated in chitosan beads were superior to both drug-loaded CBs and CAMs beads for sustained release because they had a three-layer composition; a calcium alginate core bounded by an inter-phasic chitosan-alginate membrane, which itself was surrounded by a layer of chitosan-TPP.     

Pharmaceutical suspensions: micro electrophoretic properties

The microelectrophoretic properties of the drugs griseofulvin, betamethasone, nalidixic acid and thiabendazole in aqueous dispersion have been examined and the zeta potentials calculated from the measured mobilities. Variation in magnitude of particle charge with pH of dispersion is reported and related to the chemical structure and surface characteristics. The effect of adding anionic (sodium dodecyl sulphate) cationic (dodecyl trimethyl bromide) and non-ionic (polyoxyethylene glycol monoethers of hexadecanol) surface-active agents, and mixtures of these ionic and non-ionic species, on the electrophoretic properties of the drug dispersions has been measured. The results reported agree with those found previously for a model polystyrene latex suspension system under the same conditions.     

Pharmaceutical suspensions: micro electrophoretic properties.

The microelectrophoretic properties of the drugs griseofulvin, betamethasone, nalidixic acid and thiabendazole in aqueous dispersion have been examined and the zeta potentials calculated from the measured mobilities. Variation in magnitude of particle charge with pH of dispersion is reported and related to the chemical structure and the surface characteristics. The effect of adding anionic (sodium dodecyl sulphate) cationic (dodecyl trimethyl bromide) and non-ionic (polyoxyethylene glycol monoethers of hexadecanol) surface-active agents, and mixtures of these ionic and non-ionic species, on the electrophoretic properties of the drug dispersions has been measured. The results reported agree with those found previously for a model polystyrene latex suspension system under the same conditions.     

Sustained release of highly water-soluble drugs with micelle forming ability from polyionic matrix tablets

The aim of present study was to evaluate the application of a hydrophilic matrix tablet capable of polyion complex (PIC-tablet) to a controlled-release device for highly water-soluble drugs. The PIC-tablet was prepared from a mixture of dextran sulfate and [2-(diethylamino)ethyl] dextran chloride, and diltiazem hydrochloride was used as a model drug. Release tests revealed that the drug release was sustained even in 50% drug loading and was influenced by ionic strength but not by pH in medium. The drug release mechanism was thus investigated from the viewpoint of drug micelle forming property. The micelle forming ability of diltiazem was examined by the conductivity method, and was found to be influenced by ionic strength but not by pH value in accordance with the release tests. The results suggested that the drug's micelle interacted with the polyionic matrix. Further studies were conducted using metoprolol tartrate and thiamine hydrochloride as cationic drugs and sodium cloxacillin and sodium salicylic acid as anionic ones. The release profiles of the micelle-forming drugs metoprolol tartrate and sodium cloxacillin were also suppressed in spite of different solubility or opposite ionic charge from diltiazem hydrochloride. These findings demonstrated that the PIC-tablet is a promising device for oral controlled release delivery of water-soluble drugs with good micelle-forming ability.     

The effect of various surfactants on the release rate of propranolol hydrochloride from hydroxypropylmethylcellulose (HPMC)-Eudragit matrices.

Hydrophilic and lipophilic polymers are widely used excipients to control the release rate of drugs from matrices. Researchers found that surfactants are able to control the release rate of drugs. The aim of the present investigation is to determine the effects of surfactant type, its concentration and the different ratios of surfactants on the release rate of highly soluble drug (propranolol HCl). In this study, sodium lauryl sulphate (SLS) as an anionic surfactant, cetyl trimethyl ammonium bromide (CTAB) as a cationic surfactant, Tween 65 and Arlacel 60 as non-ionic surfactants were selected. The different concentrations of surfactants were incorporated into hydroxypropylmethylcellulose-Eudragit matrices and then dissolution rate of the drug from the matrices were evaluated at pH 1.2 or 6.8. The results showed that the release rate of propranolol decreased as the concentration of SLS increased. This is due to that SLS is able to form complex with propranolol. In contrast Tween 65 caused an increase in the release rate of the drug. Cationic surfactant (CTAB) had little effect on the release rate of the drug. It was shown that as the ratio of CTAB:SLS increased the release rate of propranolol increased from matrices. This indicated that as CTAB is able to interact with SLS molecules, therefore number of the interacting anionic molecules with the cationic drug was decreased. It can be concluded that, the type and ionization of surfactant, hydrophilicity and lipophilicity of surface active agent and various ratios of surfactants are important factors in controlling the release rate of propranolol.     

Preparation and release characteristics of polymer-coated and blended alginate microspheres

To prevent a rapid drug release from alginate microspheres in simulated intestinal media, alginate microspheres were coated or blended with polymers. Three polymers were selected and evaluated such as HPMC, Eudragit RS 30D and chitosan, as both coating materials and additive polymers for controlling the drug release. This study focused on the release characteristics of polymer-coated and blended alginate microspheres, varying the type of polymer and its concentration. The alginate microspheres were prepared by dropping the mixture of drug and sodium alginate into CaCl(2) solution using a spray-gun. Polymer-coated microspheres were prepared by adding alginate microspheres into polymer solution with mild stirring. Polymer-blended microspheres were prepared by dropping the mixture of drug, sodium alginate and additive polymer with plasticizer into CaCl(2) solution. In vitro release test was carried out to investigate the release profiles in 500 ml of phosphate buffered saline (PBS, pH 7.4). As the amount of polymer in sodium alginate or coating solution increase, the drug release generally decreased. HPMC-blended microspheres swelled but withstood the disintegration, showing an ideal linear release profiles. Chitosan-coated microspheres showed smooth and round surface and extended the release of drug. In comparison with chitosan-coated microspheres, HPMC-blended alginate microspheres can be easily made and used for controlled drug delivery systems due to convenient process and controlled drug release.     

Sodium alginate microspheres of metformin HCl: formulation and in vitro evaluation

Metformin microspheres with sodium alginate alone and in combination with gellan were prepared using an emulsion-cross linking method. The prepared microspheres were evaluated for their physico-chemical characteristics like particle size, morphology using SEM, incorporation efficiency, equilibrium water content (swelling) and in vitro drug release. The effect of various formulation variables like polymer concentration (sodium alginate; and proportion of gellan in microspheres prepared by a combination of sodium alginate and gellan), drug loading, crosslinking agent concentration and cross-linking time on the in vitro dissolution of the prepared microspheres were evaluated. The results showed that both the particle size and the incorporation efficiency were proportional to the polymer concentration. In case of microspheres containing both sodium alginate and gellan, the mean diameter and the incorporation efficiency were higher than the corresponding microspheres containing only alginate, both increasing with an increase in proportion of gellan. The prepared microspheres were found to be discrete and spherical in shape and were successful in sustaining the drug release for 8 hours. Incorporation of gellan caused a significant decrease in drug release. The release followed a biphasic profile, in all cases, characterized by an initial phase of moderate drug release followed by a phase of higher release. Further, the kinetic treatment of the dissolution data revealed the prevalence of matrix diffusion kinetics.     

Serum albumin-alginate coated microspheres: role of the inner gel in binding and release of the KRFK peptide

In continuation with our previous study using fluorescein-isothiocyanate (FITC)-Lys-Arg-Phe-Lys (KRFK) peptide, the aim of this work was to study the interaction of the unlabelled KRFK with calcium alginate gel microspheres coated with a serum albumin (HSA)-alginate membrane prepared using a transacylation method. Coated microspheres were prepared with two main sizes and two gel strengths. Control microspheres made of cross-linked alginate-HSA without calcium alginate gel were also prepared. A series of loading and release assays conducted with methylene blue showed the requirement of inner gel for binding the cationic molecule. Release experiments were performed in different media using unlabelled KRFK and coated microspheres. A plateau was reached within 1h, in contrast with the slow release of the FITC-peptide observed in our previous work. This discrepancy was attributed to modified properties of the labelled peptide. Adsorption assays of KRFK on coated microspheres were performed in the presence of growing concentrations of NaCl or imidazole. The ions were able to displace the peptide from the particles, which demonstrated ionic interactions, probably involving carboxylate groups of alginate. Adsorption isotherms showed that gel strength influenced affinity (4x10(5) L/mol or 8x10(5) L/mol for gelation with 5% or 20% CaCl(2), respectively). Binding site number doubled (from 2.6x10(-7) mol/mg to more than 5x10(-7) mol/mg) when microsphere size decreased from 450 microm to 100 microm. Binding sites were assumed to be located in the gel underneath the membrane.     

正辛胺改性海藻酸钠凝胶微球的制备及其性质研究

目的:制备正辛胺改性海藻酸钠凝胶微球,并研究其性质。方法:以超声波辅助氧化法制备多醛基海藻酸钠,通过希夫碱反应制备正辛胺改性海藻酸钠,并表征其结构;以乳化-内部凝胶化技术制备负载小分子抗肿瘤药物β-榄香烯的改性海藻酸钠凝胶微球,采用气相色谱法测定其8、15、24、48h时的累积释放率及海藻酸钠和正辛胺改性海藻酸钠凝胶微球中β-榄香烯的包封率。结果:表征并证实了多醛基海藻酸钠和正辛胺改性海藻酸钠的结构;制备得到的改性海藻酸钠凝胶微球中8、15、24、48h时β-榄香烯的累积释放率分别为16%、28%、40%、83%;海藻酸钠和正辛胺改性海藻酸钠凝胶微球中β-榄香烯的包封率分别为36%、73%。结论:制备的正辛胺改性海藻酸钠凝胶微球,具有优良的缓释性能,对β-榄香烯的包封率高。     

Adsorption of drugs onto a poly(acrylic acid) grafted cation-exchange membrane.

The influence of pH, ionic strength and the concentration of albumin in the adsorption medium as well as the charge and lipophilicity of a model drug on their adsorption onto poly(acrylic acid) grafted poly(vinylidene fluoride) (PAA-PVDF) membranes was evaluated. The PAA-PVDF membrane is a responsive porous polymer membrane that we have studied for controlled drug delivery. Sodium salicylate (anionic), flunitrazepam (neutral), primidone (neutral), desipramine (cationic) and thioridazine (cationic) were used as model drugs. The extent of drug adsorption was dependent on pH. Drug adsorption was enhanced by the dissociation of the grafted PAA chains and by a positive charge and a high lipophilicity of the drug. Increasing the ionic strength of the medium retarded the adsorption of the cationic drugs. Interestingly, the present results showing that drugs are adsorbed onto the membrane while albumin is not adsorbed onto the membrane suggest that the PAA-PVDF membrane may be suitable for separating drugs from proteinaceous substances for subsequent monitoring and evaluation.     

Polymer-surfactant nanoparticles for sustained release of water-soluble drugs

Poor drug encapsulation efficiency and rapid release of the encapsulated drug limit the use of nanoparticles in biomedical applications involving water-soluble drugs. We have developed a novel polymer-surfactant nanoparticle formulation, using the anionic surfactant Aerosol OT (AOT) and polysaccharide polymer alginate, for sustained release of water-soluble drugs. Particle size of nanoparticles, as determined by atomic force microscopy and transmission electron microscopy, was in the range of 40-70 nm. Weakly basic molecules like methylene blue, doxorubicin, rhodamine, verapamil, and clonidine could be encapsulated efficiently in AOT-alginate nanoparticles. In vitro release studies with basic drug molecules indicate that nanoparticles released 60-70% of the encapsulated drug over 4 weeks, with near zero-order release during the first 15 days. Studies with anionic drug molecules demonstrate poorer drug encapsulation efficiency and more rapid drug release than those observed with basic drugs. Further studies investigating the effect of sodium concentration in the release medium and the charge of the drug suggest that calcium-sodium exchange between nanoparticle matrix and release medium and electrostatic interaction between drug and nanoparticle matrix are important determinants of drug release. In conclusion, we have formulated a novel surfactant-polymer drug delivery carrier demonstrating sustained release of water-soluble drugs.     

Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr<alg<pectin<NaCMC<trgh<HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.     

Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH 7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr < alg < pectin < NaCMC < trgh < HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.     

Effects of nondenaturating zwitterionic detergent CHAPS, 3-[(3-cholamido propyl) dimethyl ammonio]-1-propanesulfonate, on rat liver mitochondrial and microsomal monoamine oxidase

It has been reported that monoamine oxidase (MAO) activity (EC1.4.3.4) and, in general, enzymes possessing cationic substrates, were activated and inhibited by anionic and cationic detergents, respectively. In order to examine this hypothesis, the effect of the zwitterionic detergent CHAPS 3-[(3-cholamido propyl) dimethyl ammonio]-1-propanesulphonate was studied in comparison with the effects of cationic, anionic, and non-ionic detergents. The non-denaturating zwitterionic detergent CHAPS was used to solubilise rat liver monoamine oxidase MAO (EC1.4.3.4) of mitochondrial and microsomal origin; the solubilisation conditions, purification, inhibition and kinetic studies were then determined. These results are compared with those previously obtained with the non-ionic detergent Triton X-100, which would also be expected to have no net charge, and are interpreted in terms of specific ionic effects.     

The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs

The effects of types of surfactants on the solubilization and dissolution of poorly soluble acidic drugs were compared to identify the most suitable surfactant for conducting an acidic drug dissolution test. Cetyltrimethylammonium bromide (CTAB) as a cationic surfactant, sodium lauryl sulfate (SLS) as an anionic surfactant, and polysorbate 80 as a non-ionic surfactant were used in the study. And, mefenamic acid, nimesulide, and ibuprofen were selected as model drugs. The dissolution rates of these acidic drugs were substantially enhanced in medium containing CTAB. Electrostatic interactions between acidic drugs and cationic surfactants were confirmed by measuring UV spectra of each drug. Solubility of drugs in various media and the partition coefficients of drugs into micelles were found to depend on drug characteristics. For acidic drugs, the ability of media containing a cationic surfactant to discriminate rates of dissolution of acidic drugs seemed to be greater than that of media containing other surfactant types.     

Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs

The objective of this study is to develop chitosan–anionic polymers based extended-release tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading. Here, the combination of sodium valproate (VPS) and valproic acid (VPA) were chosen as the model drugs. Anionic polymers studied include xanthan gum (XG), carrageenan (CG), sodium carboxymethyl cellulose (CMC-Na) and sodium alginate (SA). The tablets were prepared by wet granulation method. In vitro drug release was carried out under simulated gastrointestinal condition. Drug release mechanism was studied. Compared with single polymers, chitosan–anionic polymers based system caused a further slowdown of drug release rate. Among them, CS–xanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 h. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies demonstrated that polyelectrolyte complexes (PECs) were formed on the tablet surface, which played an important role on retarding erosion and swelling of the matrix in the later stage. In conclusion, this study demonstrated that it is possible to develop highly water-soluble drugs loaded extended-release tablets using chitosan–anionic polymers based system.     

Drug release from complexes with a series of poly(carboxyalkyl methacrylates), a new class of weak polyelectrolytes

Carboxyalkyl methacrylates, a new class of non-cross-linked, hydrophobic weak polyelectrolytes, were synthesized, and then bound to cationic drugs (propranolol.HCl, diltiazem.HCl and verapamil.HCl) to form water-insoluble complexes that release the bound drug only in ionic media (pH 7.4). Compressed tablets were prepared from these cation exchange polyelectrolytes. Release profiles followed zero order kinetics (n>0.90; n is the release exponent). As the hydrophobicity of the polyelectrolytes increased, the rate of release decreased and deviated from linearity (n=0.7). Both the ionic strength of the medium as well as the solubility of the drug affected the rate of release. In acidic media (pH 1.2) a burst of drug was released but the release was halted by a layer of non-ionized polymer precipitated on the surface of the tablets. The results indicate that it is possible to "tailor-make" the release kinetics by using a polyelectrolyte from the series with the suitable hydrophobicity.     

Preparation of sodium alginate microspheres containing hydrophilic β-lactam antibiotics

Alginate microspheres were prepared by the emulsification process as a drug delivery system of ampicillin sodium (AMP-Na). The preparation parameters such as the concentration of calcium chloride, the stirring time and the amount of AMP-Na were investigated. The alginate microspheres containing hydroxypropylmethylcellulose (HPMC) were found to be generally spherical, discrete and had smoother surfaces when compared to without HPMC. However, there was no significant difference in the release profile of AMP-Na from alginate microspheres prepared with or without HPMC. The concentration of calcium chloride solution and the stirring time in the preparation of alginate microspheres influenced the aggregation of alginate microspheres. The amount of AMP-Na in alginate microspheres influenced the surface morphology and the practical drug content in microspheres.     

The influence of Surelease and sodium alginate on the in-vitro release of tamsulosin hydrochloride in pellet dosage form

The objective of this study was to prepare controlled-release pellets containing 0.2 mg tamsulosin hydrochloride using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers with Surelease and sodium alginate. The release of tamsulosin HCl from pellets coated with the commercial aqueous ethylcellulose dispersion (Surelease) was investigated at different coating loads. In addition, the effect of sodium alginate on drug release was investigated by varying the ratio of sodium alginate to microcrystalline cellulose (MCC). Dissolution studies were first performed in 500 mL simulated gastric fluid (pH 1.2) containing 0.003% (w/w) polysorbate 80 and then in simulated intestinal fluids (pH 7.2). The morphology of pellet surfaces and cross sections were examined by scanning electron microscopy (SEM). Apparently, the spherical pellets were prepared using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers. The release profiles of tamsulosin HCl from Surelease-coated pellets were significantly affected by changing the content of Surelease, the pH of the dissolution medium and the ratio of sodium alginate to MCC. The drug release rates not only decreased with increase in the coating load, but also increased when the pH of the dissolution medium was increased from 1.2 to 7.2 regardless of the sodium alginate-to-MCC ratio. Moreover, the drug release rate at pH 7.2 was gradually increased by increasing the ratio of sodium alginate to MCC. SEM showed smooth surfaces of Surelease-coated pellets. These results suggest that Surelease and sodium alginate would be useful excipients in the preparation of controlled-release pellets with the desired release profiles.