Dynamic Release of Propranolol HCl from Cationic Ion–Exchanger–Loaded Calcium Alginate Beads

The dynamic release of drug propranolol HCl from the propranolol HCl–resin complex (PRC) loaded calcium alginate beads has been studied in the buffer media of pH 1.2 at the physiological temperature 37°C. The PRC encapsulated beads demonstrated nearly 58.04% release while naked PRC particles released 98.00% drug in 24 h in the gastric fluid. The amount of drug released was found to increase with and decrease in the amount of sodium alginate in the beads. Similarly, with the increase in the amount of entrapped PRC particles within the beads, the quantity of drug released was also observed to increase. The degree of crosslinking of beads also affected the release kinetics. Interestingly, the release from naked PRC particles followed ‘first‐order’ kinetics while PRC particles, entrapped in calcium–alginate beads, exhibited ‘diffusion controlled’ release behavior as indicated by liner nature of fractional release vs. √t plot.     

Flow Through Diffusion Cell Method: A Better Approach to Study Drug Release Behavior as Compared to Traditional Dissolution Test Method

Co‐polymeric hydrogels consisting of N‐vinyl‐2‐pyrrolidone (NVP) and acrylic acid (AAc) were synthesized and evaluated for release of a model drug, i.e., vitamin B₁₂. Release studies in simulated gastric fluid (pH 1.2) and intestinal fluid (pH 7.4), at 37°C, showed the hydrogels to be pH sensitive. An in vitro release study by ‘traditional dissolution test’ (TDT) showed that percent drug released from the hydrogel was nearly 8.6±2.1 and 83.2±4.8 in the media of pH 1.2 and 6.8, respectively. However, in order to incorporate in vivo GI conditions such as acidic pH and high water content in the stomach, low water content and the presence of a semi–solid mass in the large intestine, a new test model, called flow through diffusion cell (FTDC) was also used. The two approaches yielded almost different release profiles. The gels were characterized by thermogravimetric analysis and FTIR spectroscopy.     

Thermoresponsive N-vinyl caprolactam grafted sodium alginate hydrogel beads for the controlled release of an anticancer drug

A series of thermoresponsive sodium alginate-g-poly(vinyl caprolactam) (NaAlg-g-PNVCL) beads were prepared as drug delivery matrices of 5-flurouracil (5-FU) crosslinked by glutaraldehyde (GA) in the hydrochloric acid catalyst. Graft copolymers of sodium alginate with vinyl caprolactam were synthesized using azobisisobutyronitrile as an initiator, and characterized by Fourier infrared spectroscopy, differential scanning calrimetry and X-ray diffraction for analysis of the amorphous nature drug in the beads, and by scanning electron microscopy for the spherical nature of the beads. Preparation condition of the beads was optimized by considering the percentage of encapsulation efficiency, swelling behavior of beads and their release data. Effects of variables such as GA concentration, drug/polymer ratio and catalyst concentration on the release of 5-FU were carried out at two different temperatures (25 and 37 °C) in simulated intestinal fluid for 12 h. It was observed that, drug release from the beads decreased with increasing drug/polymer (d/p) ratio, extent of crosslinking agent and catalyst concentration. The swelling degree of graft copolymer beads was found to be increased with decreasing of environmental temperature. In vitro release studies were performed at 25 and 37 °C for 12 h, and showed that thermoresponsive graft copolymer beads had higher drug release behavior at 25 °C than that at 37 °C, following Fickian diffusion transport mechanism with slight deviation.     

Studies in the development of nateglinide loaded calcium alginate and chitosan coated calcium alginate beads

Nateglinide loaded alginate-chitosan beads were prepared by ionic gelation method for controlling the drug release by using various combinations of chitosan and Ca2+ as cation and alginate as anion. IR spectrometry, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffractometry were used to investigate the physicochemical characteristics of the drug in the bead formulations. The calcium content in beads was determined by atomic absorption spectroscopy. The swelling ability of the beads in different media (pH 1.2, 4.5, 6.8) has been found to be dependent on the presence of polyelectrolyte complex of the beads and the pH of the media. The ability to release the Nateglinide was examined as a function of chitosan and calcium chloride content in the gelation medium. It is evident that the rate of drug release and its kinetics could be controlled by changing the chitosan and the calcium chloride concentrations. Calcium alginate beads released more than 95% of drug with in 8 h; whereas coated beads sustained the drug release and released only 75-80% of drug. The drug release mechanism analyzed indicates that the release follows either "anomalous transport" or "case-II transport".     

Extended release of Gliclazide from highly stabilized calcium alginate/poly(acrylamide) beads for diabetes management

In the present work, stability of calcium alginate beads has been remarkably improved by a novel strategy which consists of in situ formation of poly (acrylamide) within the calcium ions cross-linked sodium alginate beads. The resulting beads have been found to be stable for more than 48 h, in the physiological fluid (PF) of pH 7.4, while the plain alginate beads disintegrated within a couple of hours. The release of the anti-diabetic drug Gliclazide (Glz) from the beads was investigated under physiological conditions. The enhanced stability and prolonged release was also confirmed by an in vivo study on Albino Wistar rats.     

Properties of calcium-induced gel beads prepared with alginate and hydrolysates

Calcium-induced alginate gel beads (Alg-Ca) containing alginate hydrolysate, such as the guluronic acid block (GB), was prepared and the drug release profiles were investigated under simulated gastrointestinal conditions. The addition of GB to Alg-Ca altered its rheological properties. A model drug (hydrocortisone) was incorporated at 78% of its theoretical yield within the dried Alg-Ca containing 5% GB and it was gradually released from the beads in JP XIV 1st medium for disintegration test (pH 1.2), while it was rapidly released with disintegration of the gel matrix in JP XIV 2nd medium (pH 6.8). In contrast, for Alg-Ca containing GB and chitosan, disintegration was not observed in these media and the drug release rate was markedly different. These results demonstrate that the release profiles of drugs incorporated into Alg-Ca can be controlled by adding these polysaccharides.     

Examination of the Higuchi Model for the Release of Vitamin B2 from Multilayered Calcium Alginate/Chitosan Beads in Varying pH Medium

The release of model drug vitamin B₂ from calcium alginate/chitosan multi‐layered beads has been studied in the media of varying pH (3 h in the medium of pH 1.0 and for the remaining time in pH 7.4) at 37°C. The quantitative deviation of experimental data from the Higuchi model has been interpretated by using a newly developed ‘curve area measurement’ (CAM) approach. The higher deviation in the initial phase has been explained on the basis of porous structure of beads due to the use of low molecular weight polymers in the preparation of beads.     

Novel alginate-poly(L-histidine) microcapsules as drug carriers: in vitro protein release and short term stability

Spherical, smooth-surfaced and mechanically stable alginate-poly(L-histidine) (PLHis) microcapsules with narrow particle size distributions were prepared by incubating calcium alginate beads in aqueous solutions of PLHis. The in vitro release characteristics, drug loading and encapsulation efficiency of the microcapsules were investigated using bovine erythrocytes hemoglobin (Hb) as a model drug. The results showed that the concentration of Ca(2+) ions had a considerable effect on the drug loading, encapsulation efficiency and in vitro release behavior of the microcapsules. When the concentration of CaCl(2) in the PLHis solution was increased from 0 to 3.0% (w/v), the drug loading and encapsulation efficiency decreased significantly from 38.0 to 4.3% and from 92.9 to 8.0%, respectively, while the total cumulative release of Hb from microcapsules in phosphate buffered saline solution (PBS, pH 6.8) decreased from 96.2 to 72.8% in 24 h. No significant protein release was observed during 70 h of incubation in hydrochloric acid solution (pH 1.2). However, under neutral conditions (PBS, pH 6.8), the Hb was completely and stably released within 24-70 h. An explosion test showed that the stability of alginate-PLHis microcapsules depended strongly on the concentration of PLHis and the calcium ions in solution. [Diagram: see text] Microscopy photo of Hb-loaded alginate-PLHis microcapsules.     

Synthesis of pH-responsive mesoporous silica nanotubes for controlled release

A novel mesoporous silica tubes (MMT) which possessed pH-sensitive controlled release ability had been fabricated and synthesized by using carbon nanotubes (CNTs) as template. The sample replicated the morphologies of the CNTs successfully. The Brunauer–Emmett–Teller surface area of the materials can reach 1,017 m² g^?1 with the pore size of 3.8 nm. As a model drug, metformin HCl was applied to study the drug loading and control release ability of the materials. MMT possesses higher drug loading ratio (36 %) than that of MCM-41 (27.5 %). The release kinetics were studied in simulated gastric fluid (pH = 1.2) and in simulated proximal intestine fluid (pH = 7. 4), respectively. The result shows that the delivery systems exhibit well pH-sensitive control release ability and the as-synthesized materials have potential application in biomedical field.     

Dual crosslinked pH‐ and temperature‐sensitive hydrogel beads for intestine‐targeted controlled release

Novel drug‐loaded hydrogel beads for intestine‐targeted controlled release were developed by using pH‐ and temperature‐sensitive carboxymethyl chitosan‐graft‐poly(N,N‐diethylacrylamide) (CMCTS‐g‐PDEA) hydrogel as carriers and vitamin B₂ (VB₂) as a model drug. The hydrogel beads were prepared based on Ca²⁺ ionic crosslinking in acidic solution and formed dual crosslinked network structure. The structure of hydrogel and morphology of drug‐loaded beads were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The study about swelling characteristics of hydrogel beads indicated that the beads had obvious pH‐ and temperature‐sensitivity. In vitro release studies of drug‐loaded beads were carried out in pH 1.2 HCl buffer solution and pH 7.4 phosphate buffer solution at 37°C, respectively. The results indicated that the dual crosslinked method could effectively control the drug release rate under gastrointestinal tract (GIT) conditions, which was superior to traditional single crosslinked beads. In addition, the effects of grafting percentage, pH value, and temperature on the release behavior of the VB₂ were investigated. The drug release mechanism of CMCTS‐g‐PDEA drug‐loaded beads was analyzed by Peppa's potential equation. According to this study, the dual crosslinked hydrogel beads based on CMCTS‐g‐PDEA could serve as suitable candidate for drug site‐specific carrier in intestine. Copyright © 2009 John Wiley & Sons, Ltd.     

大豆蛋白基茶碱控释片的制备及稳定性研究

以茶碱为模型药物,大豆蛋白和海藻酸钠作为骨架材料,采用混合压片法制备了不同比例的药物片剂。采用紫外比色法测定释放效果,考察了大豆蛋白与海藻酸钠不同比例以及不同pH释放介质和高湿度对茶碱片稳定性的影响。结果表明:大豆蛋白和海藻酸钠作为骨架材料的片剂释药时间都达到了8h以上,在pH6.8PBS中的释药率相对pH1.2盐酸溶液要快,具有良好的定向控释特性。随着湿度的增加,茶碱释放率略有下降,具有较好的湿度稳定性。通过适度调节大豆蛋白和海藻酸钠的比例可实现不同控释效果。实验结果表明大豆蛋白和海藻酸钠共混物是一种良好的天然药物缓控释骨架材料,其释放过程符合一级动力学特征,是药物扩散和骨架溶蚀二者共同作用的结果。     

pH-responsive interpenetrating network hydrogel beads of poly(acrylamide)-g-carrageenan and sodium alginate for intestinal targeted drug delivery: synthesis, in vitro and in vivo evaluation

In the present work, we synthesized pH-responsive interpenetrating network (IPN) hydrogel beads of polyacrylamide grafted κ-carrageenan (PAAm-g-CG) and sodium alginate (SA) for targeting ketoprofen to the intestine. The PAAm-g-CG was synthesized by free radical polymerization followed by alkaline hydrolysis under nitrogen gas. The PAAm-g-CG was characterized by elemental analysis, FTIR spectroscopy and thermogravimetric analysis (TGA). The drug-loaded IPN hydrogel beads were prepared by simple ionotropic gelation/covalent crosslinking method. The amorphous nature of drug in the beads was confirmed by differential scanning calorimetry and X-ray diffraction studies. The spherical shape of the beads was confirmed by scanning electron microscopic analysis. The beads exhibited ample pH-responsive behavior in the pulsatile swelling study. The ketoprofen release was significantly increased when pH of the medium was changed from acidic to alkaline. The beads showed maximum of 10% drug release in acidic medium of pH 1.2, and about 90% drug release was recorded in alkaline medium of pH 7.4. Stomach histopathology of albino rats indicated that the prepared beads were able to retard the drug release in stomach leading to the reduced ulceration, hemorrhage and erosion of gastric mucosa.     

pH-sensitive polyelectrolyte complex gel microspheres composed of chitosan/sodium tripolyphosphate/dextran sulfate: swelling kinetics and drug delivery properties

Porous chitosan (CS) polyelectrolyte complex (PEC) hydrogel microspheres were prepared via either wet phase-inversion or ionotropic crosslinking with sodium tripolyphosphate (Na+ - TPP) and dextran sulfate (DS). The resulting microspheres were characterized using scanning electron microscopy (SEM) and elemental analysis (EA). The controlled release behavior of ibuprofen (IBU) from these microspheres was investigated. The PEC microspheres were about 700-950 microm in diameter with large pores and open porous structure. The CS/TPP/DS microspheres resisted hydrolysis in strong acid and biodegradation in enzymatic surroundings. The swelling kinetics for CS microspheres was close to Fickian diffusion, whereas those for CS/TPP and CS/TPP/DS were non-Fickian. Furthermore, the equilibrium water content (EWC) and water diffusion coefficient (D) increased with the pH of the media. The release profiles of IBU from CS/TPP/DS microspheres were slow in simulated gastric fluid (SGF, pH 1.4) over 3 h, but nearly all of the initial drug content was released in simulated intestinal fluid (SIF, pH 6.8) within 6 h after changing media. Overall the results demonstrated that CS/TPP/DS microspheres could successfully deliver a hydrophobic drug to the intestine without losing the drug in the stomach, and hence could be potential candidates as an orally administered drug delivery system.     

Inorganic–organic hybrid alginate beads with LCST near human body temperature for sustained dual‐sensitive drug delivery

In order to obtain dual‐stimuli‐responsive (temperature/pH) alginate beads that exhibit LCST close to human body temperature for sustained drug release applications, poly (NIPAAm‐co‐AAm) hydrogel (with LCST 37.5°C) were selected and associated with calcium alginate to prepare inorganic–organic hybrid biomineralized polysaccharide alginate beads via a one‐step method in this paper. Scanning electron microscopy (SEM) and energy dispersive X‐ray spectrometer (EDS) results demonstrated that calcium phosphate could not only be found in the surface but also in the cross‐section of biomineralized polysaccharide beads. Both equilibrium swelling and indomethacin release behavior were found to be pH‐ and thermo‐responsive. In addition, indomethacin release profile could be sustained with a inorganic–organic hybrid membrane: the release amount reached 96% within 4 hr for the unmineralized beads, while a drug release of only 64% obtained after subjecting the biomineralized polysaccharide beads to the same treatment. These results indicate that the biomineralized polysaccharide membrane could prevent the permeability of the encapsulated drug and reduce the drug release rate effectively. The studied system has the potential to be used as an effective smart sustainable delivery system for biomedical applications. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthèse de copolymères supports de sulfanilamide. Hydrolyses dans un milieu gastrique de pH=1.2

Hydrolyses of two copolymers with amide functions, and of monomer carrier of sulfanilamide have been carried out mostly in heterogeneous acid medium (pH=1.2). A suitable percentage of sulfanilamide has been released after some hours. The drug release depends on the ammonium cation formed during the hydrolyses and the release of the drug being not described by a classical kinetics equation (0, 1, 2 and n). These kinetics are probably partially controlled by diffusion, and they can also be explained by the diffusion of the liquid (pH=1.2) through the copolymers.     

基于HPMCP包覆介孔SBA-15的pH敏感药物缓释系统

以肠溶性包衣材料羟丙甲纤维素邻苯二甲酸酯(HPMCP)为原料,在负载法莫替丁(Famo)的SBA-15药片表面包覆聚合物膜,成功制备了一种新型的pH敏感药物缓释系统, 并考察了此缓释系统在不同pH释放环境中的释放行为. 结果表明: 在模拟胃液中(SGF, pH=1.2),HPMCP能致密包覆在药片表面,从而明显延缓Famo的释放速度;而在模拟肠液中(SIF, pH=7.5),HPMCP能够迅速溶于缓释溶液中,因而对Famo释放速度的影响甚微. 因此,可以将这种新型智能药物缓释系统应用于肠道靶向给药.     

Formulation characterization and in vitro evaluation of acacia gum–calcium alginate beads for oral drug delivery systems

In the present work, new matrix bead formulations based on linear and branched polysaccharides have been developed using an ionic gelation technique, and their potential use as oral drug carriers has been evaluated. Using calcium chloride as a cross‐linking agent and sodium diclofenac (SD), as a model drug, acacia gum–calcium alginate matrix beads were formulated. The response surface methodology based on 3² factorial design was used as a statistical method to evaluate and optimize the effects of the biopolymers‐blend ratio and the concentration of calcium chloride on the particle size (mm), density (g/cm³), drug encapsulation efficiency (%), and the cumulative drug release after 8 hours (R_8h,%). The optimized beads with the highest drug encapsulation efficiency were examined for a drug‐excipients compatibility by powder X‐ray diffraction, differential scanning calorimetry, thermo‐gravimetric analysis, and Fourier transform‐infrared spectroscopy analyses. The swelling and degradation of the matrix beads were found to be influenced by the pH of medium. Higher degrees of swelling were observed in intestinal pH than in stomach pH. Accordingly, the drug release study showed that the amount of SD released from the acacia gum–calcium alginate beads was higher in intestinal pH than in stomach pH. Therefore, the in vitro drug release from the SD‐loaded beads appears to follow the controlled‐release (Hixson‐Crowell) pattern involving a case‐2 transport mechanism operated by swelling and relaxation of the polymeric blend matrix.     

Synthesis, characterization and sustaining controlled release effect of mesoporous SBA-15/ramipril composite drug

A loading of ramipril in SBA-15 (Santa Barbara Amorphous) mesoporous material was studied. (SBA-15)-ramipril composite material was characterized by chemical analysis, infrared spectroscopy, powder X-ray diffraction, low temperature N₂ adsorption–desorption at 77 K characterization techniques. Ramipril drug release processes from SBA-15 host to simulated body fluid (SBF), simulated gastric juice (SGJ), simulated intestinal fluid (SIF) were monitored in a simulated way and actions of the sustained release of (SBA-15)-ramipril was studied. The results showed that the loading amount of ramipril drug in SBA-15 was 90.30 mg/g. The cumulative sustained release rate of ramipril composite drug in SBF achieved 99.7 % after 27 h. When the sustained release of composite drug in SGJ was 8 h, the maximum cumulative sustained release ratio achieved 54.9 %. When the sustained release of composite drug was 9 h in SIF, the maximum cumulative sustained release ratio achieved 34.9 %. The method described in this study is suitable for carrying ramipril drug on SBA-15, and a new carrier to load ramipril drug was found. Meanwhile, the efficacy of ramipril drug and time efficacy could be improved.     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

Starch cellulose acetate co-acrylate (SCAA) polymer as a drug carrier

The present study aims to create a controlled-release system through the preparation and characterization of starch cellulose acetate co-acrylate (SCAA) polymer for application as a carrier for cancer drugs. SCA was prepared from maize starch and different ratios of cellulose acetate. The obtained product SCA was reacted with acrylic acid monomer to give cellulose acetate co-acrylate. The best ratio of starch to cellulose acetate was found to be 90:10, giving a stable product with acrylic acid. The cancer drug 8-(2-methoxyphenyl)-3,4-dioxo-6-thioxo-3,4,6,7-tetrahydro-2h-pyrimido[6,1-c]-[1,2,4]triazine-9-carbonitrile was dissolved in dimethylformamide then added gradually at the end of the previous reaction under stirring for 15 min. The prepared polymers with and without the drug were characterized by Fourier-transform infrared spectroscopy. Cuboids discs of the prepared polymer/drug were subjected to drug release in aqueous media at different pH values. The release was measured spectrophotometrically. It was found that the release rate depends on the pH of the aqueous medium as well as on the concentration of the drug loaded onto the polymer carrier. Above pH 12, the polymer containing the drug degraded completely within 1 h after being subjected to alkaline media. Sustained release of drug extended to about 20 days. The amount released depended on the pH of the media in the following order: basic media > acidic media > neutral. According to Higuch’s equation, the diffusion coefficient was found to be 4.2 × 10^?8 and 5.5 × 10^?8 cm s^?1 for the two evaluated concentrations (1.5 and 2 %) of active organic compound (drug).