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 effect of hydrophilic and lipophilic polymers and fillers on the release rate of atenolol from HPMC matrices

The objective of this study is to investigate the effect of various polymers, and fillers, and their concentrations on the release rate of atenolol from polymeric matrices. Four polymers namely hydroxypropylmethylcellulose (HPMC), Eudragit RSPO, ethylcellulose (EC) and sodium carboxymethylcellulose (NaCMC) were used. The dissolution profiles showed that an increase in the concentration of HPMC and EC resulted in a reduction in the release rate of atenolol. The results indicate that it is difficult to obtain a zero-order release from the matrices containing either HPMC or EC. It is also observed that the amount of HPMC played a dominant role, affecting the drug release in binary mixtures of Eudragit-HPMC. Generally, the presence of NaCMC caused an increase in the release rate of atenolol from HPMC matrices. To determine the effect of fillers on the release rate of atenolol from HPMC matrices, lactose (a soluble filler) and dicalcium phosphate (an insoluble filler) were used. The results showed that an increase in the concentration of fillers resulted in an increase in the release rate of the drug from matrices and hydrophilicity or hydrophobicity of fillers had no significant effect on the release profile. In order to determine the mode of release, the data were analysed based on the equation Q = K (t - l)(m). Values of m were in the range of 0.32-0.99 indicating that release was controlled by both diffusion and erosion, depending on the type of polymer and concentration.     

Release behaviour of diclofenac sodium dispersed in Gelucire® and encapsulated with alginate beads

Sustained release polymeric particles containing diclofenac sodium dispersed in Gelucire® matrix and encapsulated in calcium alginate shell were prepared with different drug-to-polymer ratios and also with different concentrations of sodium alginate for a fixed drug-to-polymer ratio in an aqueous environment. Spherical particles were formed by dropping an emulsion of diclofenac sodium in Gelucire® matrix, emulsified with sodium alginate, into calcium chloride solution. The gelled beads formed by ionotropic gelation of alginate with calcium ions showed sustained release of the water soluble drug in in-vitro release study. Drug release was a function of square-root of time, suggesting a matrix diffusion release pattern. The rate of release was significantly suppressed with increasing proportions of Gelucire® in the mixture. Sustained and complete release was achieved with Gelucire® of low melting point and low HLB value. No significant drug release occurred in a dissolution medium of pH 1.5, whereas complete release was observed at pH 6.8, consistent with considerable swelling of the alginate gel at this pH.     

Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropylmethylcellulose matrix tablets

The dissolution of 7 drugs from hydroxypropylmethylcellulose (HPMC) matrices have been examined to determine the time exponent (tⁿ) required to produce linear dissolution profiles. A value of n = ˜ 0.67 was obtained for time-dependent release for soluble drugs, the precise values being 0.71, 0.65, 0.67 and 0.64 for promethazine hydrochloride, aminophylline, propranolol hydrochloride and theophylline, respectively. The insoluble drugs, indomethacin and diazepam, displayed values of n = 0.90 and 0.82 indicating a near zero-order release. Matrices containing tetracycline hydrochloride, however, showed a value of n = 0.45 and displayed complex release patterns and lower release rates than anticipated on the basis of solubility. Replacement of HPMC by calcium phosphate or lactose increased the dissolution rates of promethazine hydrochloride although the values of n were unchanged. Differences in release rates between lactose and calcium phosphate replacement occurred only when matrices contained high levels of the diluents. A straight line relationship existed between release rates and tablet surface area for HPMC tablets containing promethazine hydrochloride.     

Effect of various surfactants and their concentration on controlled release of captopril from polymeric matrices

Various methods are available to formulate water soluble drugs into sustained release dosage forms by retarding the dissolution rate. One of the methods used to control drug release and thereby prolong therapeutic activity is to use hydrophilic and lipophilic polymers. In this study, the effects of various polymers such as hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC) and sodium carboxymethylcellulose (CMC) and surfactants (sodium lauryl sulphate, cetyltrimethylammonium bromide and Arlacel 60) on the release rate of captopril were investigated. The results showed that an increase in the amount of HPMC K15M resulted in reduction of the release rate of captopril from these matrices. When HPMC was partly replaced by NaCMC (the ratio of HPMC/NaCMC was 5:1), the release rate of the drug significantly decreased. However, there was no significant difference in release rate of captopril from matrices produced with ratios of 5:1 and 2:1 of HPMC/NaCMC. The presence of lactose in matrices containing HPMC and NaCMC increased the release rate of captopril. It was interesting to note that although partial replacement of HPMC by EC reduced the release rate of the drug (ratio of HPMC/EC 2:1), the release rate was increased when the ratio of HPMC/EC was reduced to 1:1. The effects of various surfactants on the release rate of captopril from HPMC/EC (1:1) matrices were also investigated. The results showed that the surfactants did not significantly change the release rate of the drug. Release data were examined kinetically and the ideal kinetic models were estimated for the drug release. The kinetic analysis of drug release data from various formulations showed that incorporation of surfactants in HPMC/EC matrices did not produce a zero-order release pattern.     

Characterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethylcellulose used in the preparation of controlled release tablets

Cross-linked amylose starch (CLA), hydroxypropylmethylcellulose (HPMC), and HPMC/CLA matrices were prepared by direct compression. HPMC was used to slow down the enzymatic degradation of CLA matrices. CLA was either granulated alone and mixed with HPMC or cogranulated with the latter. Compaction characteristics of the powder, hydration and mechanical properties of the resulting matrices, as well as the release profiles of three model drugs were investigated. The results showed that wet granulation of CLA in the presence of 10% HPMC improved significantly the flow properties of the powder without compromising its compactibility. Both CLA and HPMC deformed mainly by plastic flow (yield pressures are 75 and 124 MPa, respectively), but CLA exhibited a stronger elastic component (elastic recoveries are 18.4 and 11.5%, respectively). The values of yield pressure increased linearly with the concentration of HPMC. The addition of HPMC to CLA slightly decreased the resistance to consolidation but the crushing force of the final compacts was found to be proportional to the HPMC concentration. Mechanical studies on swollen matrices revealed that CLA formed a stronger gel than HPMC or CLA/HPMC mixture, and swelling and erosion of the tablets increased with HPMC content and incubation time. The in vitro release kinetics of three model drugs (pseudeoephedrine sulfate, sodium diclofenac, and prednisone) showed a clear effect of drug solubility and presence of alpha-amylase in the dissolution medium on the release rate. The addition of HPMC to CLA protected the tablets against alpha-amylase hydrolysis and reduced the release rate of prednisone and sodium diclofenac. The release of pseudoephedrine sulfate was fast and independent of HPMC and occurred mainly by diffusion.     

Characterization of Binary Mixtures Consisting of Cross‐Linked High Amylose Starch and Hydroxypropylmethylcellulose Used in the Preparation of Controlled Release Tablets

Cross‐linked amylose starch (CLA), hydroxypropylmethylcellulose (HPMC), and HPMC/CLA matrices were prepared by direct compression. HPMC was used to slow down the enzymatic degradation of CLA matrices. CLA was either granulated alone and mixed with HPMC or cogranulated with the latter. Compaction characteristics of the powder, hydration and mechanical properties of the resulting matrices, as well as the release profiles of three model drugs were investigated. The results showed that wet granulation of CLA in the presence of 10% HPMC improved significantly the flow properties of the powder without compromising its compactibility. Both CLA and HPMC deformed mainly by plastic flow (yield pressures are 75 and 124 MPa, respectively), but CLA exhibited a stronger elastic component (elastic recoveries are 18.4 and 11.5%, respectively). The values of yield pressure increased linearly with the concentration of HPMC. The addition of HPMC to CLA slightly decreased the resistance to consolidation but the crushing force of the final compacts was found to be proportional to the HPMC concentration. Mechanical studies on swollen matrices revealed that CLA formed a stronger gel than HPMC or CLA/HPMC mixture, and swelling and erosion of the tablets increased with HPMC content and incubation time. The in vitro release kinetics of three model drugs (pseudeoephedrine sulfate, sodium diclofenac, and prednisone) showed a clear effect of drug solubility and presence of α‐amylase in the dissolution medium on the release rate. The addition of HPMC to CLA protected the tablets against α‐amylase hydrolysis and reduced the release rate of prednisone and sodium diclofenac. The release of pseudoephedrine sulfate was fast and independent of HPMC and occurred mainly by diffusion.     

Influence of sodium dodecyl sulfate on swelling,erosion and release behavior of HPMC matrix tablets containing a poorly water-soluble drug

The effect of sodium dodecyl sulfate (SDS) on the swelling, erosion and release behavior of HPMC matrix tablets was examined. Swelling and erosion of HPMC matrix tablets were determined by measuring the wet and subsequent dry weights of matrices. The rate of uptake of the dissolution medium by the matrix was quantified using a square root relationship whilst the erosion of the polymer was described using the cube root law. The extent of swelling decreased with increasing SDS concentrations in the dissolution medium but the rate of erosion was found to follow a reverse trend. Such phenomena might have been caused by the attractive hydrophobic interaction between HPMC and SDS as demonstrated by the cloud points of the solutions containing both the surfactant and polymer. Release profiles of nimodipine from HPMC tablets in aqueous media containing different concentrations of SDS were finally studied. Increasing SDS concentrations in the medium was shown to accelerate the release of nimodipine from the tablets, possibly due to increasing nimodipine solubility and increasing rate of erosion by increasing SDS concentrations in the dissolution medium.     

The effects of casein on diclofenac release from hydroxypropylmethylcellulose (HPMC) compacts

The inclusion of casein, either as the acid or sodium salt form, was found to significantly modify the release of the acidic drug diclofenac from hydroxypropylmethycellulose (HPMC, Methocel grades K100LV and K15M)-based matrices. The presence of casein in diclofenac-K100LV matrices increased the drug release rate and rendered the release profile more linear. Furthermore, sodium caseinate appeared to retard the disintegrating tendency of the higher molecular weight HPMC-drug systems, apparently by enhancing the initial gel forming ability of these systems. Surprisingly, dissolution profiles of the salt and acid forms of the drug were similar when co-compressed with sodium caseinate, and addition of HPMC retarded release of both forms of drug to the same extent. Swelling and erosion experiments indicated that the presence of casein decreased the extent of medium uptake (swelling) of the matrices and accelerated the rate of erosion, while not altering the dissolution medium infiltration rate. Phase solubility analysis indicated that the solubility of the drug was also enhanced by sodium caseinate, consistent with complex formation between the drug and casein.     

Dual cross-linked pulsatile beads for chronotherapy of asthma: Development and evaluation

In the present investigation, pulsatile release beads were prepared by ionic gelation technique. Theophylline dual-cross-linked beads were prepared by dropping dispersed phase of theophylline, Delonix regia gum (DRG), and sodium alginate into the dispersion phase of different concentration of calcium chloride solution followed by aluminium chloride solution. The formulated beads were further coated by Eudragit L & S 100 in the ratio 1:2 w/w in order to achieve desired lag time. In vitro release study showed lag time of 5–7?h before release of theophylline from the formulated beads, which were found to be intact for 6?h. Thus, formulated dual cross-linked beads when administered at bed time may release theophylline when needed most for chronotherapeutics of early morning asthmatic attacks in chronic patients. In vivo radio imaging study carried out in New Zealand white strain rabbit confirms the findings of in vitro results.     

Alginate-based pellets prepared by extrusion/spheronization: a preliminary study on the effect of additive in granulating liquid.

The aim of this study was to investigate the possibility of producing alginate-based pellets by extrusion/spheronization and also to improve the formation of spherical alginate-based pellets by investigating the effect of additive in granulating liquid on characteristics and drug release from resulting pellets. Two types of sodium alginate (30%) were evaluated in combination with theophylline (20%), microcrystalline cellulose (50%) and different granulation liquids. The pellets were then prepared in a basket extruder, then spheronized and dried. The final products were characterized by morphological examination and drug release study. Different additives in the granulating liquid influenced the ability of the extruded mass to form pellets (the processability) with this technique. However, different sodium alginate types responded to shape modifications to a different extent. Long, dumbbell-shaped pellets were obtained with viscous granulating liquids. However, short, nearly spherical pellets were obtained with watery granulation liquid with calcium chloride that reduced the swelling ability of sodium alginate. Improvements in the pellet characteristics were also dependent on the sodium alginate type employed. Most of pellet formulations released about 75-85% drug within 60min and showed a good fit into both Higuchi and Korsmeyer-Peppas equations. Higher amount of 3% calcium chloride, as a granulating liquid, in the formulation showed higher mean dissolution time resulting from the cross-linking properties of calcium ions to the negative charges of alginate molecules.     

Impact of cross-linker on alginate matrix integrity and drug release

Sodium alginate, a biopolymer, was employed in the formulation of matrix tablets. They cracked or laminated at acidic pH, compromising their dissolution performance. Improved mechanical strength and reduced barrier permeability of calcium alginate gel provided the rationale for cross-linking the alginate matrix to sustain drug release. Studies had suggested that the incorporation of soluble calcium salts in alginate matrix tablets could sustain drug release at near-neutral pH due to in situ cross-linking. However, results from the present study showed otherwise when gastrointestinal pH conditions were simulated. Significant reduction in drug release rate was only observed when an external calcium source was utilized at low concentration. High calcium ion concentrations caused matrix disintegration. In contrast, matrices pre-coated by calcium alginate could sustain drug release at pH 1.2 followed by pH 6.8 for over 12h. The presence of cross-linked barrier impeded matrix lamination and preserved matrix structure, contributing to at least three-fold reduction in drug release at pH 1.2. Zero order release as well as delayed burst release could be achieved by employing appropriate grade of alginate and cross-linking conditions.     

Release of propranolol hydrochloride from matrix tablets containing sodium carboxymethylcellulose and hydroxypropylmethylcellulose.

Hydroxypropylmethylcellulose (HPMC) and three viscosity grades of sodium carboxymethylcellulose (NaCMC), namely NaCMC (Blanose 7H 4XF), NaCMC (Courlose P 800), and NaCMC (Courlose P 350), were investigated for their ability to provide a sustained release of propranolol hydrochloride from matrices. The rank order of release rate, in the absence of HPMC, was NaCMC (Blanose) < NaCMC P 800 < NaCMC P 350 for matrices containing 95-285 mg NaCMC, and was dependent on their viscosity grades. The effects of changing the ratio of HPMC to NaCMC (Blanose) and the drug/total polymer ratio were examined. The release rates decreased as the proportion of NaCMC in the matrices increased. Zero-order release of propranolol hydrochloride was obtained from matrices containing 285 mg 3:1 NaCMC (Blanose)/HPMC. Differential scanning calorimetry was used to quantify the moisture uptake by the polymers at 37 degrees C. Wafers containing NaCMC (Blanose) or 1:1 HPMC/NaCMC (Blanose) absorbed water similarly. A study of the erosion rates of matrices containing polymer only indicated that NaCMC (Blanose) eroded more quickly than HPMC. When propranolol hydrochloride was included in matrices containing NaCMC (Blanose), the erosion was reduced as a result of the insolubility of a complex formed between NaCMC and propranolol hydrochloride. The interaction between propranolol hydrochloride and NaCMC (Blanose) was confirmed by both dialysis and by monitoring the release of sodium ions from the matrices.     

Preparation of pH-sensitive beads for NSAID using three-component gel systems

The aim of this study is to prepare novel pH-sensitive beads to obtain a gastric mucosa protective formulation and to ensure drug delivery into the intestine. Diclofenac sodium was used as a model drug. Bead formation was achieved by ionotropic gelation method using three-component gel system containing sodium alginate (Na-Alg), hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC). Factors influencing the characteristics of beads (exposure time, cross-linking agent concentration, polymer ratio) were investigated by swelling and erosion tests based on gravimetric method. Drug release was tested in distilled water and/or artificial digestive fluids and evaluated with Korsmeyer–Peppas equation and Baker–Lonsdale model. The encapsulation behaviour was qualitatively indicated by differential scanning calorimetry (DSC) method. In vivo experiments were conducted to test ulcerogenicity and intestinal absorption in rats. HPMC increased the encapsulation efficiency (EE) and HEC improved the drug release in the intestinal fluids. The equilibrium water uptake (EWU) was correlated with exposure time, calcium chloride concentration and HEC amounts. Bead erosion increased proportionately to exposure time, while it reduced when calcium chloride concentrations were increased. Higher amounts of HEC increased, while higher pH values reduced the encapsulation efficacy. The in vivo experiments demonstrated that the studied encapsulation technology markedly reduced the ulcerogenic effect of diclofenac. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4285–4295, 2009     

Preparation and release characteristics of polymer-reinforced and coated alginate beads

Polymeric reinforcement and coatings of alginate beads were carried out to control the release rate of drug from alginate beads. A poorly water-soluble ibuprofen (IPF) was selected as a model drug. A commercially available Eudragit^® RS100 was also used as a polymer. Effects of polymeric contents, the presence of plasticizers and amount of drug loading on the release rate of drug were investigated. The release rate of drug from alginate beads in the simulated gastric fluid did not occur within 2 h but released immediately when dissolution media were switched to the simulated intestinal fluid. No significant difference of release rate from polymer-reinforced alginate bead without plasticizers was observed when compared to plain (simple) beads. However, the release rate of drug from polymer-reinforced alginate beads was further sustained and retarded when aluminium tristearate (AT) as a plasticizer was added to polymer. However, polyethylene glycol 400 (PEG400) did not change the release rate of drug from alginate beads although PEG400 was used to improve dispersion of polymer and sodium alginate, and plasticize Eudragit^® RS100 polymer. The presence of plasticizer was crucial to reinforce alginate gel matrices using a polymer. As the amount of drug loading increased, the release rate of drug increased as a result of decreasing effects of polymer contents in matrices. The significantly sustained release of drug from polymer-coated alginate beads occurred as the amount of polymer increased because the thickness of coated membrane increased so that cracks and pores of the outer surface of alginate beads could be reduced. The sustained and retarded action of polymer-reinforced and coated beads may result from the disturbance of swelling and erosion (disintegration) of alginate beads. From these findings, polymeric-rein-forcement and coatings of alginate gel beads can provide an advanced delivery system by retarding the release rate of various drugs.     

海藻酸钙作为缓释片的骨架材料的研究

海藻酸钠(NaAl)与可溶性钙盐同时存在干片剂中服后遇胃液即生成酸不溶性海藻酸钙(CaAl)的凝胶骨架,其中所含药物因缓释而具长效作用。用扫描电镜研究了这种骨架并发现NaAl粉末的细度、钙盐的形式及用量、制片工艺、颗粒大小等因素对释药速度均有明显影响。硝酸异山梨醇(ISDN)、普鲁卡因酰胺(P)、苯妥因(DPH)、茶碱(Th)、氯丙嗪(Ch)均可藉CaAl而获得不同程度的缓释作用。着重研究了ISDN长效片,结合到该药的消除速度常数,从工艺方面研究了释药速度t₃₀=50分钟的处方。     

Physicochemical characterization and mechanisms of release of theophylline from melt-extruded dosage forms based on a methacrylic acid copolymer

The purpose of the current study was to investigate the physicochemical properties of melt-extruded dosage forms based on Acryl-EZE and to determine the influence of gelling agents on the mechanisms and kinetics of drug release from thermally processed matrices. Acryl-EZE is a pre-mixed excipient blend based on a methacrylic acid copolymer that is optimized for film-coating applications. Powder blends containing theophylline, Acryl-EZE, triethyl citrate and an optional gelling agent, Methocel K4M Premium (hydroxypropyl methylcellulose, HPMC, hypromellose 2208) or Carbopol 974P (carbomer), were thermally processed using a Randcastle single-screw extruder. The physical and chemical stability of materials during processing was determined using thermal gravimetric analysis and HPLC. The mechanism of drug release was determined using the Korsmeyer-Peppas model and the hydration and erosion of tablets during the dissolution studies were investigated. The excipient blends were physically and chemically stable during processing, and the resulting dosage forms exhibited pH-dependent dissolution properties. Extrusion of blends containing HPMC or carbomer changed the mechanism and kinetics of drug release from the thermally processed dosage forms. At concentrations of 5% or below, carbomer was more effective than HPMC at extending the duration of theophylline release from matrix tablets. Furthermore, carbomer containing tablets were stable upon storage for 3 months at 40 degrees C/75% RH. Thus, hot-melt extrusion was an effective process for the preparation of controlled release matrix systems based on Acryl-EZE.     

The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix

Previous work has shown how high concentrations of sugars can accelerate drug release from hydroxypropyl methylcellulose (HPMC) matrices by suppressing polymer hydration. This study investigates the effects of combining sugar and salts, using sucrose, sodium chloride and trisodium citrate, soluble ingredients commonly found in foods. A factorial study showed that each solute suppressed HPMC solution sol–gel transition temperature (a sensitive measure of molecular hydration) independently, and their effects reflected their rank order in the Hofmeister series. In mixtures, the effects were purely additive, with no evidence of antagonism or synergy. In dissolution tests, both salts significantly reduced the threshold sugar concentration required to elicit an acceleration of drug release, and when used in combination, 0.15 M sodium chloride with 0.015 M trisodium citrate reduced the threshold sucrose concentration from 0.7 M to 0.35–0.4 M, a reduction of almost 50%. The results show that food salts can significantly reduce the concentration required for sugar effects on HPMC matrices, and this may be a factor to consider when interpreting their in vivo behaviour in the fed state.     

The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix

Previous work has shown how high concentrations of sugars can accelerate drug release from hydroxypropyl methylcellulose (HPMC) matrices by suppressing polymer hydration. This study investigates the effects of combining sugar and salts, using sucrose, sodium chloride and trisodium citrate, soluble ingredients commonly found in foods. A factorial study showed that each solute suppressed HPMC solution sol–gel transition temperature (a sensitive measure of molecular hydration) independently, and their effects reflected their rank order in the Hofmeister series. In mixtures, the effects were purely additive, with no evidence of antagonism or synergy. In dissolution tests, both salts significantly reduced the threshold sugar concentration required to elicit an acceleration of drug release, and when used in combination, 0.15 M sodium chloride with 0.015 M trisodium citrate reduced the threshold sucrose concentration from 0.7 M to 0.35–0.4 M, a reduction of almost 50%. The results show that food salts can significantly reduce the concentration required for sugar effects on HPMC matrices, and this may be a factor to consider when interpreting their in vivo behaviour in the fed state.     

Prolonged delivery of ciprofloxacin hydrochloride from hydrophilic ocular inserts

Ocular inserts were developed with prolonged release of drug and minimum swelling within cul-de-sac using ciprofloxacin (CPF) hydrochloride as a model drug. The ocular inserts were fahricated with sodium alginate films loaded with drug and then treated with calcium chloride. A 4% w/v solution of calcium chloride and an exposure of 15 s to this solution was found to be the optimum treatment combination of inserts. Four types of inserts were produced: type-I contained CPF hydrochloride and alginate, type-II contained CPF crystals and alginate, type-III contained CPF hydrochloride inalginate and hydroxypropylmethylcellulose (HPMC) matrix and type-IV contained CPF crystals entrapped inalginate and HPMC matrix. In vitro release profile of drug from the inserts followed Higuchi and first-order kinetic models. Longer duration for 90% drug release were obtained from types-II and IV inserts than from types I and III, although type III had a longer duration than type-I inserts. In vivo studies were carried out in rabbit eyes by measuring the tear concentrations against time. From the pharmacokinctic parameters obtained types II and IV were found to prolong the duration of action more than 2 days while types I and II inserts the duration of action lasted for about 1.5 days.