Bimodal drug release achieved with multi-layer matrix tablets: transport mechanisms and device design.

The aim of this study was to develop new multi-layer matrix tablets to achieve bimodal drug release profiles (fast release/slow release/fast release). Hydroxypropyl methylcellulose acetate succinate (HPMCAS, type MF) was chosen as a matrix former, because it is water-insoluble at low, and water-soluble at high pH values. Studies focused on the elucidation of the drug release mechanisms from HPMCAS-MF:drug tablets. In 0.1 N HCl the resulting release kinetics can be described using Fick's second law of diffusion, taking into account axial and radial mass transfer in cylindrical geometry. As the diffusion coefficients are found to be constant and the boundary conditions to be stationary, these systems are purely drug diffusion-controlled. In contrast, the dominating mass transport phenomena in phosphate buffer pH 7.4 are more complex. Due to polymer dissolution the resulting matrix structure is time-variant, leading to increasing drug diffusion coefficients and decreasing tablet dimensions, and thus moving boundary conditions. Drug release is affected by water imbibition, drug diffusion and polymer dissolution and is faster compared to 0.1 N HCl. With knowledge of these underlying release mechanisms, multi-layer matrix tablets were developed to achieve bimodal drug release. HPMCAS-MF:drug mixtures were used as tablet cores. As expected, changing the release medium from 0.1 N HCl to phosphate buffer pH 7. 4 after 2 h, lead to a significant increase in drug release. The abruptness of this rate change could be enhanced by adding two drug-free HPMCAS-MF barrier layers (one on each side) to the system. The addition of a fourth, drug-containing and fast disintegrating initial dose layer yielded the desired bimodal drug release patterns. The process and formulation parameters affecting the resulting release rates were investigated using theophylline and acetaminophen as model drugs.     

Blends of enteric and GIT-insoluble polymers used for film coating: physicochemical characterization and drug release patterns.

THE OBJECTIVES OF THIS STUDY WERE: (i). to use blends of gastrointestinal tract (GIT)-insoluble and enteric polymers (ethyl cellulose and Eudragit L) as coating materials for multiparticulate controlled release dosage forms; (ii). to investigate the effects of the polymer blend ratio and coating level on the resulting drug release patterns; and (iii). to explain the observed phenomena based on the physicochemical properties of the systems. Propranolol HCl-loaded pellets were coated in a fluidized bed coater with organic polymer solutions; thin, drug-containing and drug-free, polymeric films were prepared using a casting knife. In vitro drug release, water uptake and dry weight loss studies were performed in 0.1 M HCl and phosphate buffer pH 7.4, respectively. The apparent drug diffusion coefficients within the polymeric systems were determined using different experimental and theoretical techniques (side-by-side diffusion cells, in vitro drug release from thin films; exact and approximate solutions of Fick's second law of diffusion). A broad range of drug release patterns from coated pellets could be achieved by varying the GIT-insoluble:enteric polymer blend ratio. With increasing relative amounts of Eudragit L, the release rates in both media significantly increased. The increase at low pH could be attributed to an increase in water uptake, as observed with thin films. Interestingly, only partial Eudragit L leaching occurred in phosphate buffer pH 7.4 even at high enteric polymer contents, indicating that the GIT-insoluble polymer effectively hindered the dissolution of the entrapped Eudragit L. At high pH, both polymer leaching and polymer swelling contributed to the control of drug release. The determined apparent drug diffusion coefficients take the two effects adequately into account.     

In vitro release test system of ( -lactic-glycolic) acid copolymer microcapsules for sustained release of LHRH agonist (leuprorelin)

Release of leuprorelin, an LHRH agonist, from injectable microcapsules and degradation of its biodegradable polymer [( -lactic-glycolic) acid copolymer: PLGA] matrix were investigated to optimize an in vitro release test system and to clarify the difference between the in vivo release and in vitro release test system. Many factors such as pH, salt concentration and osmolarity of dispersion medium changed drug release. Weight loss along with the decrease of the molecular weight of PLGA was delayed in the in vitro release test system that successfully predicted in vivo drug release. Most remarkable difference in the change of the molecular weight of PLGA was shown by accumulation of degraded products of PLGA in in vivo, although the ratio of lactic acid to glycolic acid in the polymer as another indicator of the degradation increased similarly as a function of the PLGA weight loss in both systems. Judging from the fact that resembling drug release was acquired despite the different degradation rate of matrix, distinctive mechanism governs the drug release in the in vitro release test system.     

Blends of aqueous polymer dispersions used for pellet coating: importance of the particle size.

Blends of aqueous dispersions of a water-insoluble and an enteric polymer, namely ethyl cellulose:hydroxypropyl methylcellulose acetate succinate (EC:HPMCAS) and ethyl cellulose:methacrylic acid ethyl acrylate copolymer (EC:Eudragit L), were used as coating materials to control theophylline release from matrix pellets. Varying the polymer blend ratio, broad ranges of drug release patterns were obtained at low as well as at high pH. Interestingly, the resulting release profiles were rather similar for both types of blends in 0.1 M HCl, whereas significant differences were observed in phosphate buffer pH 7.4. Surprisingly, drug release at high pH was much slower for EC:HPMCAS blends compared to EC:Eudragit L blends, although HPMCAS leached out more rapidly (and to a higher extent) from the film coatings than Eudragit L. To explain these phenomena and to better understand the underlying drug release mechanisms, thin polymeric films of identical composition as the pellet coatings were prepared and physicochemically characterized before and upon exposure to the release media. Importantly, the polymer particle size was identified to be a very crucial formulation parameter, determining the resulting film coating structure and properties. The Eudragit L particles are much smaller than the HPMCAS particles (nano- vs. micrometer size range) and, thus, more effectively hinder the formation of a continuous and mechanically stable EC network. Consequently, the EC structures remaining after enteric polymer leaching at high pH are mechanically much weaker in the case of Eudragit L. Upon exposure to phosphate buffer, water-filled cracks are formed, through which the drug rapidly diffuses out. In contrast, the EC structures remaining upon HPMCAS leaching are mechanically stronger and drug release is controlled by diffusion through the polymeric remnants.     

Controlled release of a local anesthetic from fatty acid dimer based polyanhydride

Prolonged reversible nerve blockade has broad applications in a number of clinical areas involving acute or chronic pain. The desired periods of reversible nerve blockade could vary from as little as one day to as long as one week. Implantation of a biodegradable controlled release local anesthetic device adjacent to nerves could potentially be a valuable dosage form. Therefore, controlled release devices based on polyanhydride polymers were prepared which would release the local anesthetic bupivacaine hydrochloride with varying rates. The parameters affecting the release of drug were studied in order to optimize the formulation. The studies were conducted with rectangular devices consisting of bupivacaine HCl dispersed homogeneously in the polymer at a loading of 10% w/w. Devices fabricated from three different copolymers, synthesized from fatty acid dimer and sebacic acid, were studied to determine the effect of comonomer on the release kinetics of the drug. Release studies were conducted at pH 7.4, 37°C, and the release profiles were analysed to determine the mechanism of release. The release of bupivacaine HCl could be best described by first order release kinetics from all the three copolymers and the release rate constant, k_r, was directly proportional to the hydrophilicity of the polymer. The first order release rate constants were linearly proportional to both, the erosion rate and drug release rate (r² = 0.999). Release profiles from all the three copolymers could also be described by an equation derived for a surface eroding cylindrical device. The erosion rate, B in cm/day, was obtained by fitting the release profile to the equation using a nonlinear regression method. The results showed that the drug release is controlled by erosion for the three copolymers, P(FAD-SA) 30:70, 20:80, and 10:90 and the release rates were 0.0004, 0.00066 and 0.0012 g/cm²/day, respectively. In addition, release profiles expressed as m_t/m_∞ (fractional agent release profile) versus t/t_∞ fitted the theoretical equation for all the three copolymers. These results suggest that polyanhydrides undergo pure surface erosion at pH 7.4 and therefore the device geometry and erosion rate determine the release kinetics. Thus, knowing the erosion rate of the fatty acid dimer based polyanhydride, would help in achieving the appropriate drug release kinetics by manipulating the geometry of the device.     

Model prodrugs for the intestinal oligopeptide transporter: model drug release in aqueous solution and in various biological media.

The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a target for increasing intestinal transport of low permeability compounds by creating prodrugs designed for the transporter. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for benzyl alcohol have been shown to have affinity for hPepT1. Furthermore, in aqueous solution at pH 5.5 to 10, the release of the model drug seems to be controlled by a specific base-catalyzed hydrolysis, indicating that the compounds may remain relatively stable in the upper small intestinal lumen with a pH of approximately 6.0, but still release the model drug at the intercellular and blood pH of approximately 7.4. Even though benzyl alcohol is not a low molecular weight drug molecule, these results indicate that the dipeptide prodrug principle is a promising drug delivery concept. However, the physico-chemical properties such as electronegativity, solubility, and log P of the drug molecule may also have an influence on the potential of these kinds of prodrugs. The purpose of the present study is to investigate whether the model drug electronegativity, estimated as Taft substitution parameter (sigma*) may influence the acid, water or base catalyzed model drug release rates, when released from series of D-Glu-Ala and D-Asp-Ala pro-moieties. Release rates were investigated in both aqueous solutions with varying pH, ionic strength, and buffer concentrations as well as in in vitro biological media. The release rates of all the investigated model drug molecules followed first-order kinetics and were dependent on buffer concentration, pH, ionic strength, and model drug electronegativity. The electronegativity of the model drug influenced acid, water and base catalyzed release from D-Asp-Ala and D-Glu-Ala pro-moieties. The model drug was generally released faster from D-Asp-Ala- than from the D-Glu-Ala pro-moieties. In biological media the release rate was also dependent on the electronegativity of the model drug. These results demonstrate that the model drug electronegativity, estimated as Taft (sigma*) values, has a significant influence on the release rate of the model drug.     

Evaluation of matrices containing molecularly imprinted polymers in the enantioselective-controlled delivery of beta-blockers.

Granules and beads of methacrylic acid (MAA) and granules of N-acryloyl-alanine polymer (NAA) were produced using ethylene glycol dimethacrylate as cross-linking monomer either by bulk (in the case of granules) or suspension (in the case of beads) polymerization. Either R- or S-propranolol, were used as an imprint molecule, acting as a template, with a view to conferring enantioselectivity of release upon the polymer. The molecularly imprinted polymers (MIPs) or nonMIPs (control) were formulated with racemic propranolol and other excipients and compressed to form matrix tablets. Enantioselective release of propranolol in vitro was monitored using a stereoselective HPLC assay. The influence of the method of polymer synthesis, drug: polymer ratio, pH and temperature on the release of the two enantiomers was determined. Stereoselectivity of release was identified in tablets containing either MAA or NAA granules or MAA beads, with the latter showing the greatest differences between enantiomers. Release of the enantiomer used as the print was always faster than the release of the nonprint enantiomer. In the case of S-propranolol-MIP bead matrices composed of MAA, greater differences in the release of enantiomers could be promoted by increasing the polymer: drug ratio of the tablet. Differences in the release rate of the two propranolol enantiomers was still apparent as the pH was varied between 3 and 7.4 and when the temperature was decreased from 37 to 25 degrees C. S-Propranolol-MIP bead matrices demonstrated cross-reactivities of stereoselective dissolution for enantiomers of pindolol and oxprenolol, both of which have structural similarities to the imprint molecule. It is concluded that polymers of this type may have great potential in controlling, via means of formulation, the release of drug eutomer whilst enhancing retention of distomer in the dosage form.     

Matrices for site-specific controlled-delivery of 5-fluorouracil to descending colon.

Colon-specific controlled-delivery 5-fluorouracil (5-FU) matrices for the treatment of colorectal carcinoma were prepared and evaluated. Matrices are destined to be introduced into enteric-coated capsules and thereby carried to and liberated in the ileum. There, drug release should be prevented until matrices reach descending colon where release should occur. Matrices (50 mg, diameter 0.6 mm) were prepared by compression of powders or of granules prepared by melt granulation. The ingredients comprised 30-70% w/w 5-FU, glyceryl palmitostearate as rate-controlling material and 5% w/w Aerosil as glidant. Drug release was measured by the rotating basket method. The matrix containing 60% w/w drug, prepared by compression of powders, was appropriate to make the planned system, in virtue of its fairly high drug load and its nearly constant and reasonable release rate. This matrix was spray-coated with Eudragit S100 (EUD). Subsequently, an external layer of chitosan hydrochloride (CH-HCl) was applied by a dipping-drying technique. When transit of coated matrix through ileum (phosphate buffer (PB) pH 7.4), ascending colon (PB pH 6 containing rat cecal contents) and descending colon (PB pH 7.4) was simulated in vitro, the pH 4.7 of the CH-HCl gel layer and the pH 6 of the ascending colon prevented dissolution of the protective EUD film until descending colon was reached, then controlled release started. The present small matrices can enter size no. 00 capsules. Considering that each capsule contains 10 matrices, the maximal dose is 300 mg.     

Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles.

Block copolymer micelles, containing dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt), the oxaliplatin parent complex, were prepared through polymer-metal complex formation of DACHPt with poly(ethylene glycol)-poly(glutamic acid) block copolymer [PEG-P(Glu)] in distilled water. By dynamic light scattering (DLS) measurement, the micelle size was determined to be 40 nm with narrow distribution. The release of platinum complexes from the micelle core was measured in phosphate buffer saline (pH 7.4) at 37 degrees C. DACHPt-loaded micelle showed a sustained release rate of platinum after an induction period of 12 h. In the same conditions, the kinetic stability of DACHPt-loaded micelle was measured. The micelle was found to be very stable, keeping the initial size, for 240 h. Against murine colon adenocarcinoma 26 (C-26) cells, DACHPt-loaded micelle exhibited considerable in vitro cytotoxicity, lower than oxaliplatin but increasing with exposure time as a result of the release of platinum complexes from the micelle. In vivo biodistribution assay performed on tumor-bearing mice demonstrated that the micelle showed prolonged blood circulation due to its high stability and high tumor accumulation for a prolonged time.     

pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets.

Weakly basic drugs or salts thereof demonstrate pH-dependent solubility. The resulting release from conventional matrix tablets decreases with increasing pH-milieu of the gastrointestinal tract. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Two different polymers were used as matrix formers, the water-insoluble and almost unswellable ethylcellulose (EC), and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). Two different approaches to solve the problem of pH-dependent release of weakly basic drugs are demonstrated in this paper. The first one is based on the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS, an enteric polymer), the second one on the addition of organic acids such as fumaric, succinic or adipic acid to the drug-polymer system. The first approach failed to achieve pH-independent drug release, whereas the addition of organic acids to both matrix formers was found to maintain low pH values within the tablets during drug release in phosphate buffer (pH 6.8 or 7.4). Thus, the micro-environmental conditions for the dissolution and diffusion of the weakly basic drug were almost kept constant. The release of verapamil hydrochloride from tablets composed of ethylcellulose or HPMC and organic acids was found to be pH-independent.     

Inhibition of in vitro calcium phosphate precipitation in presence of polyurethane via surface modification and drug delivery.

Biomaterial associated calcification is the principal cause of the clinical failure of bioprosthetic implants. The present investigation describes the mineralization of polymeric substrate in an extracirculatory environment and the possible methods of prevention. Calcification was examined on various polyurethane films (and bioprosthetic tissue) incubated in metastable solutions of calcium phosphate and the role of polymer casting and precipitation was evaluated. The formulation and the in vitro efficacy of prolonged controlled-release chitosan matrices, containing the novel anticalcification agents, such as Fe +++ or protamine sulfate (PS), were also attempted. The in vitro release profiles of PS from chitosan beads was performed in a rotating shaker (100 rpm) in 0.1 M phosphate buffer (pH 7.4) and was monitored spectrophotometrically. The amount and percentage of drug release were much higher initially, which was controlled with the incorporation of egg phosphatidyl choline (EPC). The PS loaded chitosan beads (coincubated in calcium phosphate solution with the calcifiable polyurethane films) significantly inhibited biomaterial calcification (about 40-50% inhibition). Surface modification of polyurethanes with Fe +++ or PS also inhibited the calcification profile of the material. These findings suggest the possibility of a combination therapy for prevention of biomaterial associated calcification via surface modifications in conjunction with long-term controlled release of the anticalcifying drugs.     

海藻酸钙凝胶微球的制备和pH敏感释放

背景:大多数蛋白质和多肽药物存在稳定性差、生物利用度低等缺点,为提高其生物利用度,目前常用将蛋白类药物包裹在高分子材料中,制成缓释控释体系.由于蛋白质外层的载体材料能起到一定保护作用,因此可增加此类药物的稳定性.目的:以含水率为指标,通过正交实验设计,找出制备海藻酸钙微球的最佳条件.并以牛血清白蛋白为模型药物,考察微球载药性能及DH环境下的释放规律.设计、时间及地点:对比观察实验,于2007-10/2009-05在四川大学高分子科学与工程实验楼完成.材料:海藻酸钠、无水氯化钙由成都科龙试剂公司提供,牛血清白蛋白由上海伯奥生物科技有限公司提供.方法:采用滴制法制备了海藻酸钙微球,考察了海藻酸钠质量分数、氯化钙质量分数、交联时间对微球含水率的影响.采用牛血清白蛋白作为模型药物,对优化条件下海藻酸钠凝胶微球进行载药量和释放行为的考察.主要观察指标:微球中牛血清白蛋白包封率及在不同pH介质中白蛋白的释放行为.结果:当海藻酸钠质量分数、氯化钙质量分数均为2.0%,交联时间为6 h,所得微球含水率最高能达到70%.pH溶胀实验显示,微球在盐酸溶液,氯化钠溶液中不溶胀,而在磷酸盐缓冲液中溶胀体现一定的pH敏感性.微球载药量约为5%,包封率为70%左右.对药物释放曲线几种模型方程进行拟合,发现释放曲线不符合Higuchi释放模型.结论:滴制法制备海藻酸钠微球条件温和,不接触有机溶剂.微球含水率高具有pH敏感性且能有效载药,适合作为蛋白质和多肽药物包裹材料.     

Dependence of copolymer composition, swelling history, and drug concentration on the loading of diltiazem hydrochloride (DIL.HCl) into poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels and its release behaviour from hydrogel slabs.

The loading of an antihypertensive cationic drug, diltiazem hydrochloride (DIL.HCl), into poly(N-isopropylacrylamide) [P(N-iPAAm)], poly(methacrylic acid) [P(MAA)], and their poly[(N-isopropylacrylamide)-co-(methacrylic acid)] P[(N-iPAAm)-co-(MAA)] hydrogels as well as their release behaviour have been investigated. For this purpose, two series of hydrogels have been tested, one previously soaked under acidic pH (treated hydrogels) and the other from the synthesis and washed in deionized water (untreated hydrogels). For the drug loading, these two series of hydrogels have been soaked in drug solutions with different concentrations. DIL.HCl amounts loaded by the gels as well as swelling degrees as a function of both hydrogel composition and DL.HCl concentration in the loading solution have been analyzed. Due to the interactions among DIL.HCl and the MAA group, "untreated" enriched MAA copolymer hydrogels present the highest drug load and loading efficiency. A DIL.HCl concentration of 320 microm/mL has been employed to load copolymers for release experiments, because for this concentration, hydrogels reach relative high drug load with a still high efficiency of loading. Release has been tested in three media, namely, fresh water (Milli-Q grade, pH 7.0), 0.1 N hydrogen chloride (pH 1.2), and a phosphate buffer (pH 7.0). In general, release is lower in fresh water and acidic media than in phosphate buffer. To explain these results, the effect of temperature, medium, and composition on the pH and thermo sensitivity of the hydrogels as well as the diltiazem-polymer interactions have been taken into account.     

In vitro release test system of (d,l-lactic-glycolic) acid copolymer microcapsules for sustained release of LHRH agonist (leuprorelin)

Release of leuprorelin, an LHRH agonist, from injectable microcapsules and degradation of its biodegradable polymer [(d,l-lactic-glycolic) acid copolymer: PLGA] matrix were investigated to optimize an in vitro release test system and to clarify the difference between the in vivo release and in vitro release test system. Many factors such as pH, salt concentration and osmolarity of dispersion medium changed drug release. Weight loss along with the decrease of the molecular weight of PLGA was delayed in the in vitro release test system that successfully predicted in vivo drug release. Most remarkable difference in the change of the molecular weight of PLGA was shown by accumulation of degraded products of PLGA in in vivo, although the ratio of lactic acid to glycolic acid in the polymer as another indicator of the degradation increased similarly as a function of the PLGA weight loss in both systems. Judging from the fact that resembling drug release was acquired despite the different degradation rate of matrix, distinctive mechanism governs the drug release in the in vitro release test system.     

In vitro-in vivo characterization of gentamicin bone implants.

A gentamicin carrier system composed of calcium phosphates, poly(DL-lactide) (PLA) and gentamicin was developed and characterized in vitro and in vivo for use in the prevention and treatment of bone infection. Four formulations were prepared according to an experimental design based on the Hadamard matrix. The technological variables included in the design were: gentamicin loading with respect to the implant weight, weight average molecular weight (M(w)) of the PLA as a compound of the matrix and the presence or absence of a PLA coating of 200 kDa. The variable to be optimized in vitro was the gentamicin release level during the first week. According to this goal, the selected formulation was F-D which was composed of 80% phosphates (25% hydroxyapatite, HAP and 75% tricalcium phosphate, TCP), 20% PLA (M(w), 30 kDa) and 3.5% gentamicin sulfate (GS) and was coated with PLA (M(w), 200 kDa). To elucidate the in vitro release mechanism of this implant, another implant lot (F-X) uncoated, but with identical matrix composition, was prepared. Results showed that the PLA coating delay the gentamicin release, indicating that part of the antibiotic released from the matrix diffuses through the polymer coating film. The selected formulation was tested in the femur of rabbits and showed a faster release rate in vivo than in vitro. This is due to a greater degree of PLA degradation, changes in the phosphate blend, and bone tissue invading the implant. Gentamicin concentration in the areas of the bone closest to the implant was higher than the minimum inhibitory concentration (MIC) against Staphylococcus aureus.     

Cross-linked alginate-gelatine beads: a new matrix for controlled release of pindolol.

This work is focused on the development of a new particulate drug delivery system using a sodium alginate matrix containing pindolol as a model drug molecule for intestinal drug prolonged release. Calcium alginate beads are known to be unable to control the release of most insoluble drugs. Pindolol-loaded alginate-gelatine beads have been developed using a solvent-free technique that involves a cross-linking reaction. Modifications in matrix structure and physicochemical behaviour caused by the cross-linking reaction were assessed during particle formation and drug release. Several parameters, such as matrix gelling rate, encapsulation efficiency, drug release profile and matrix erosion rate, were investigated. Physicochemical characterisation indicates the formation of a new alginate-gelatine matrix and shows that pindolol does not interfere with the matrix formation process. Matrix swelling of calcium alginate beads induced by phosphate buffer ends up in erosion and destruction. However, for cross-linked beads swelling does not lead to complete erosion, which may be the main cause of pindolol retention within the matrix. The modifications introduced in the initial calcium alginate formulation by means of an appropriate method such as the use of a cross-linking agent successfully changed the matrix performance, allowing the controlled release of pindolol.     

Spectroscopic and chromatographic investigation of chiral interactions between tiaprofenic acid and alginate–metal-complexes

Alginate–metal-complexes of Ca, Ba, Zn, Fe and Al were prepared in the form of beads. The preparation was based on the ionotropic method to obtain blank beads (unloaded) and beads loaded with tiaprofenic acid. IR spectra of blank beads, drug loaded beads and physical mixtures of the drug with the blank beads were recorded. The comparison of these spectra, especially in the region of hydroxyl group, implied chiral interactions between the drug and the complexes. Additionally, the drug was released from the loaded beads in aqueous phosphate buffer solutions (PBS) at pH = 7.4. Chiral HPLC was used to determine the enantiomeric excess, % ee, of the released drug. The determined % ee values indicated chiral interactions between tiaprofenic acid and alginate–metal-complexes. However, various mathematical models were used to simulate the release kinetics for each enantiomer. The metal content of Na, Ca, Ba, Zn, Fe and Al in the studied materials was measured using atomic absorption spectroscopy.

Five alginate–metal-complexes were prepared in the form of beads. ESR and ee% were reported in some cases indicating chiral interactions between Tia and alginate–metal-complexes. IR investigation was carried out to give proof for these interactions.     

Characterization of chitosan acetate as a binder for sustained release tablets.

A chitosan derivative as an acetate salt was successfully prepared by using a spray drying technique. Physicochemical characteristics and micromeritic properties of spray-dried chitosan acetate (SD-CSA) were studied as well as drug-polymer and excipient-polymer interaction. SD-CSA was spherical agglomerates with rough surface and less than 75 microm in diameter. The salt was an amorphous solid with slight to moderate hygroscopicity. The results of Fourier transform infrared (FTIR) and solid-state (13)C NMR spectroscopy demonstrated the functional groups of an acetate salt in its molecular structure. DSC and TGA thermograms of SD-CSA as well as FTIR and NMR spectrum of the salt, heated at 120 degrees C for 12 h, revealed the evidence of the conversion of chitosan acetate molecular structure to N-acetylglucosamine at higher temperature. No interaction of SD-CSA with either drugs (salicylic acid and theophylline) or selected pharmaceutical excipients were observed in the study using DSC method. As a wet granulation binder, SD-CSA gave theophylline granules with good flowability (according to the value of angle of repose, Carr's index, and Hausner ratio) and an excellent compressibility profile comparable to a pharmaceutical binder, PVP K30. In vitro release study of theophylline from the tablets containing 3% w/w SD-CSA as a binder demonstrated sustained drug release in all media. Cumulative drug released in 0.1 N HCl, pH 6.8 phosphate buffer and distilled water was nearly 100% within 6, 16 and 24 h, respectively. It was suggested that the simple incorporation of spray-dried chitosan acetate as a tablet binder could give rise to controlled drug delivery systems exhibiting sustained drug release.     

Antitumor characteristics of methoxypolyethylene glycol-poly(DL-lactic acid) nanoparticles containing camptothecin.

The novel nanoparticles (CPT-NP) were prepared by the solvent evaporation method using methoxypolyethylene glycol-poly(DL-lactic acid) block copolymer as a matrix and camptothecin (CPT) as an antitumor agent, and the antitumor characteristics were examined in vitro and in vivo. The mean diameter of CPT-NP was approximately 250 nm. The drug release from CPT-NP in phosphate-buffered saline, pH 7.4, depended on the particle concentration; in the diluted condition, the initial rapid release was greater and subsequent gradual release was faster. After i.v. administration (0.5 mg CPT eq./kg) in rats, CPT-NP showed a longer plasma retention than CPT solution. In both single (2.5 mg CPT eq./kg) and double (2.5 mg CPT eq./kg x 2) administration to mice bearing sarcoma 180 solid tumor, CPT-NP were much more effective than CPT solution; especially, the tumor disappeared completely in three of the four mice in twice administration of CPT-NP, when the body weight did not decrease markedly. After i.v. administration to the tumor-bearing mice, CPT-NP showed better plasma retention, and high and long tumor localization. CPT-NP are suggested to greatly improve the efficacy of CPT due to their pharmacokinetic features.     

Modulating insulin-release profile from pH/thermosensitive polymeric beads through polymer molecular weight.

Stimuli-sensitive statistical terpolymers of N-isopropylacrylamide (NIPAAm) (temperature-sensitive), butyl methacrylate (BMA) and acrylic acid (AA) (pH-sensitive) of various molecular weight (MW) with NIPAAm/BMA/AA feed mol ratio of 85/5/10 were used to modulate release of insulin, a model protein drug, from pH/thermosensitive polymeric beads. Protein drug loading from an aqueous medium into the beads was achieved by preparing a 7 or 10% (w/v) polymer solution with 0.2% (w/v) insulin at low pH and below the lower critical solution temperature (LCST) of the polymer (pH 2.0 and 4 degrees C), and then dropping the solution into an oil bath above the LCST of the solution (35 degrees C). This loading procedure maintained protein stability while achieving high loading efficiency, between 90 and 95% in the beads. Insulin-release studies from beads prepared from terpolymers of the same composition but increasing MW were performed at pH 2.0 and 7.4, at 37 degrees C. It was observed that there was negligible loss of insulin at pH 2.0 from the beads, indicating no burst effect. At pH 7.4, insulin release was seen from all the beads and the release rate was a function of the MW of the polymer. The low MW polymeric beads eroded, dissolved and released most of the insulin within 2 h at pH 7.4 and 37 degrees C, the intermediate MW polymeric beads swelled slightly, dissolved and released most of the insulin within 4 h, whereas the high MW polymeric beads swelled slowly and gradually released the loaded insulin over a period of 8 h. Thus, the release of protein from the low MW polymeric beads is controlled by the rate of dissolution of the polymer, whereas the release from the high MW polymeric beads is controlled by swelling of the beads and drug diffusion. Studies using fluorescein-labeled insulin revealed that insulin was uniformly distributed in the beads regardless of polymer MW. The loaded and released insulin were fully bioactive. Based on the described results, the low MW polymeric beads may be used for immediate delivery of protein drugs in the duodenum, the intermediate MW polymeric beads may be used for lower small intestine targeting, while the high MW polymeric beads may be used to target protein drugs predominantly to the colon.