Enhancement of the dissolution rates of poorly water-soluble drugs by water-soluble gelatin

The dissolution behavior of several acidic and basic drugs from kneaded mixtures with water-soluble gelatin have been studied in comparison with that of the drug alone. The results revealed a significant increase of dissolution rate of drugs from kneaded mixtures. The water-soluble gelatin showed little interaction with any of the drugs in solution or in the solid state. Interestingly, the contact angle of the kneaded mixture was remarkably decreased compared with that of the drug powder and was found to be almost the same as that of water-soluble gelatin powder. Thus, the enhanced dissolution rate of the drug caused by water-soluble gelatin was explained by the improvement of wettability of the drug by water.     

Study of tolbutamide-hydroxypropyl-gamma-cyclodextrin interaction in solution and solid state

Tolbutamide-hydroxypropyl-gamma-cyclodextrin (TBM-HPGCD) interaction has been investigated in an aqueous environment and in the solid state. The solubility of TBM was increased in accord with the amount of HPGCD added to the aqueous medium forming a soluble inclusion compound. The phase solubility diagram obtained was of A(L) type. Physical mixtures and kneaded systems of the drug and cyclodextrin derivative were prepared in 1:1 and 1:2 drug/cyclodextrin mol/mol ratio. All solid binary systems were characterised by hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetry (TG) and X-ray powder diffractometry (XRD). An inclusion complex was formed in both of the kneaded systems. In the 1:2 kneaded system, the entire drug was included in the cyclodextrin cavity, while, in the 1:1 kneaded system only a part of the drug formed an inclusion complex with the cyclodextrin. A significant improvement in the dissolution of the drug was obtained from the kneaded systems in comparison with that of the pure TBM and physical mixtures. However, there was no significant difference between the dissolution profiles of the two kneaded systems. The study suggests that an inclusion complex was obtained both in aqueous solution and in solid state.     

Preparation,Characterization and ex vivo Intestinal Permeability Studies of Ibuprofen Solid Dispersion

The aim of the present study was to improve the solubility and dissolution rate of ibuprofen and to evaluate, ex vivo, the intestinal permeation. Solid dispersions (SD) were prepared with Kollicoat IR^® by solvent evaporation technique in different drug:carrier ratios. The permeation intestinal of ibuprofen was evaluated by inverted intestinal sac method. The SD was characterized by solubility equilibrium, FT-IR, DSC, PXRD, SEM, and dissolution rate. The solubility, dissolution rate, and permeability were significantly greater for SD 1:2. The PXRD, SEM and DSC indicated a partial change in the crystalline state of ibuprofen. The solubility equilibrium of SD (1:2) was approximately 15 times greater than the solubility of ibuprofen. Dissolution rate enhancement was attributed to the decreased crystallinity of the ibuprofen, and increase of wettability and decrease of particle size. In conclusion, dissolution rate and intestinal permeability of ibuprofen were enhanced by the use of Kollicoat IR^® carrier in the SD formulation.     

Effect of the hydrophobic nature of triacetyl-beta-cyclodextrin on the complexation with nicardipine hydrochloride: physicochemical and dissolution properties of the kneaded and spray-dried complexes

The inclusion ability of triacetyl-beta-cyclodextrin (TAbetaCD), a hydrophobic cyclodextrin (CD) derivative was examined, using nicardipine hydrochloride (NC) as model drug. The binary compounds were prepared in a 1 : 1 molar ratio by the kneading and the spray-drying techniques. In order to confirm the complexation between NC and TAbetaCD in the solid state, differential scanning calorimetry, X-ray diffractometry, Fourier transformation-infrared spectroscopy and scanning electron microscopy were carried out and the results were compared with the corresponding physical mixture in the same molar ratio. The kneaded product presented only slight modifications on the drug physicochemical and morphological properties, which could mean that no complex formation occurred during this process. In contrast, spray-drying was found to produce inclusion complexes with amorphous nature. In vitro dissolution studies were carried out in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids, according to the United States Pharmacopoeia (USP) basket method. The NC in vitro release from the kneaded and spray-dried products was markedly retarded in both dissolution media. However, this retarding effect was significantly more evident for the spray-dried compound. It was concluded that the formation of real inclusion complexes could only be achieved by the spray-drying method.     

Rheological analysis and quantitative evaluation of wet kneaded wax matrix

The properties of the wet kneaded wax matrix were evaluated using a compression tester, whereby a newly proposed sigma index for the plastic deformation was assessed in the pressure transmission diagram. The sigma index was indicative of a characteristic of the plastic yield point in the rheological behavior, and presented an initial and abrupt deformation of wet kneaded mass when the wet kneaded mass was subjected to the pressure. The value of sigma index was confirmed to decrease along with an increase in the plasticity of wet kneaded mass. The wet mass of wax matrix was prepared under various kneading time, and then extruded. The properties of the extruded granules such as pore volume, strength and dissolution were investigated. As a result, it was found that the sigma index decreased with an increase in kneading time. The granules with small value of sigma index showed few porosities, large strength and slow dissolution. It was demonstrated that the sigma index linked the characteristics of wet kneaded mass to the dissolution and the other granule properties. Existence of this link was revealed by sigma index evaluation relevant to the plasticity. The sigma index could be a decisive criterion to permit an in-process evaluation of the kneading progress quantitatively, and also useful for anticipating the dissolution of the final granules roughly.     

The effect of β-cyclodextrin on the solubility and dissolution rate of meloxicam and investigation of the driving force for complexation using molecular modeling

The aim of this study was to investigate the effect of β-cyclodextrin (β-CD) on the solubility and dissolution rate of meloxicam. The methods that were employed to prepare meloxicam–β-cyclodextrin complexes were physical mixture, kneaded dispersion, and spray drying. Spray drying method was found to be the best to form a true inclusion complex. Complexes were characterized by thermal analysis, X-ray diffractometry (XRD), and Fourier transform infrared (FT-IR) spectroscopy. The apparent stability constant of the complex, K _c, calculated from the slope and intercept of the A_L solubility diagram was found to be 429.73, 259.96, 183.31, and 36.50 L mol^?1 at pH 2, 3, 6.5, and 10.3, respectively. The dissolution rate of meloxicam from the complexes was higher than from meloxicam alone. Molecular modeling was also used to investigate the interaction between meloxicam and β-CD. The dominant driving force for the complexation was evidently Van der Waals force with very little electrostatic contribution.     

Granulation of core particles suitable for film coating by agitation fluidized bed II. A proposal of a rapid dissolution test for evaluation of bitter taste of ibuprofen

To prepare powdered drugs that do not have a bitter taste, a film coating covering the surfaces of the core particles is required. The dissolution rate of ibuprofen from the coated particles changes according to the physical properties of the core particles. In this study, the effects of the physical properties of granules prepared by using several scales of agitation fluidized beds on the drug dissolution rate were investigated. The dissolution rate of ibuprofen decreased when the apparent density and shape factor of the granules increased. In contrast, the dissolution rate of the drug increased with the friablility of the granules increased. Thus, the structures of the granules appear to affect the dissolution rate of the drug to a large degree. A rapid dissolution test that can be used to investigate the early dissolution rate of ibuprofen in vitro was proposed to evaluate the taste-masking level of the coated particles. The bitter taste-masking level of the coated particles was successfully confirmed by using this novel test method.     

Design and optimization of a new self-nanoemulsifying drug delivery system

To improve the dissolution rate of ibuprofen, a model poorly water soluble drug, self-nanoemulsifying drug delivery systems (SNEDDS) were developed. Various surfactants and oils were screened as candidates for SNEDDS on the basis of droplet size of the resulting emulsions. The influence of the constituent structure, concentration and the composition of SNEDDS formulations, and the emulsifier HLB value, on the properties of the resulting emulsions was systematically investigated. Several SNEDDS formulations were employed to study the relationship between the emulsion droplet size and the dissolution rate of ibuprofen. The dissolution rate was accelerated by decreasing the nanoemulsion droplet size, and was significantly faster than that from a conventional tablet. The optimal SNEDDS formulation had a mean nanoemulsion droplet diameters of 58 nm in phosphate buffer, pH 6.8 (simulated intestinal fluid), and released ibuprofen more than 95% within 30 min. Therefore, these novel SNEDDS carriers appear to be useful for controlling the release rate of poorly water soluble drugs.     

Iron cross-linked carboxymethyl cellulose—gelatin complex coacervate beads for sustained drug delivery

The formation and smooth recovery of ibuprofen encapsulated in microcapsules using gelatin and carboxymethyl cellulose (CMC) complex coacervation without glutaraldehyde were the objectives of this investigation. The microcapsules were recovered as ionically cross-linked beads using aqueous ferric chloride in 50 vol.% of 2-propanol. A physical mixture of CMC/gelatin (FP1) and CMC alone (FP2) beads was also prepared for comparison. The drug-entrapment efficiency of complex coacervate beads (FP3-FP5) was dependent on the drug-to-polymer ratio and was in the range of 86–92 mass %. Beads prepared with the highest ratio of the drug (FP5) exhibited the lowest entrapment. FP1 and FP2 beads exhibited an entrapment efficiency of 98.5 mass % and 91.3 mass %, respectively. Infrared spectroscopy (FTIR) revealed different functional groups in complex coacervate, physical mixture and FP2 beads. Optical and scanning electron microscopy revealed the distinct appearance and surface morphology of the various beads. The stable and crystalline nature of ibuprofen in the beads was confirmed by FTIR and differential scanning calorimetry (DSC), respectively. Ibuprofen release from FP1 and FP2 beads was very slow and unsuitable for oral delivery. The bead prepared by complex coacervation (FP5) showed a better release profile over 48 h and could be developed as a sustained drug delivery system.     

Prediction of granule physical property by a novel compression energy of wet powder

Wet granulation is a very important process and a reliable evaluation method for formulation study; thus it requires appropriate process control. In this study, a novel and effective method that involves a compression test of wet powder is proposed. Here, the compression energy, which could predict the capability of the wet powder for extrusion granulation as well as the physical properties of the final products, is used as a novel characteristic of wet powder. The compression energy was defined as the energy consumption derived from the compression speed and the transmission loss during the compression test. Lactose monohydrate was mixed with various additives such as hydroxypropylcellulose in the mass ratio of 0-10%. Various amounts of water were fed into the mixtures, which were kneaded in a planetary motion mixer to prepare the kneaded wet powders. The characteristics of these powders were evaluated by the compression energy. The kneaded wet powders were then extruded through an extrusion granulator, the electrical loads of the granulator during the operation were analyzed as the extrusion energy, and the physical properties of extruded granules were investigated. As a result, the granule strength and granule size distribution showed a good correlation with the compression energy. A good correlation was also observed between the compression energy of the kneaded wet powder and the extrusion energy regardless of the different additives and water contents. It was concluded that the compression energy of the wet powder could be used for the formulation study and the process control of wet granulation.     

Control of prolonged drug release and compression properties of ibuprofen microspheres with acrylic polymer, eudragit RS, by changing their intraparticle porosity [corrected]

Prolonged-release spherical micro-matrices of ibuprofen with Eudragit RS were prepared using a novel emulsion-solvent diffusion method. Those particles were termed "microspheres" due to their characteristic sponge-like texture and unique dissolution and compression properties unlike conventional microcapsules or microspheres. The internal porosity of microspheres could be easily controlled by changing the concentration of the drug and the polymer in the emulsion droplet (ethanol). With lower concentration of ibuprofen in the ethanol, the resultant microspheres had a higher porosity, about 50%. The drug release rate from the microspheres was interpreted by the Higuchi model of spherical matrices, which depended only on their internal porosity of the microspheres when size distribution and drug content were the same. The tortuosities in the microspheres were found to be almost constant (3-4) irrespective of porosity, suggesting the same internal texture. Microsphere compressibility was much improved over the physical mixture of the drug and polymer owing to the plastic deformation of their sponge-like structure. The more porous microspheres produced stronger tablets [corrected].     

Thermal studies on mixtures of benzoic and salicylic acids with cyclodextrins

The thermal behaviour of benzoic and salicylic acids is compared with the behaviour of 1:1 molar ratio physical and kneaded mixtures of these acids with each of three different cyclodextrins (b-, hydroxypropyl-b-, and g-cyclodextrin). Differential scanning calorimetry and thermogravimetry coupled with evolved gas analysis by Fourier transform infrared spectroscopy were used for the thermal studies and X-ray powder diffraction and infrared spectroscopy provided complementary information. Thermal studies of benzoic acid with the cyclodextrins showed significant interactions in both physical and kneaded mixtures of benzoic acid/b-cyclodextrin and benzoic acid/hydroxypropyl-b-cyclodextrin. Interactions in the kneaded benzoic acid/g-cyclodextrin mixtures were the most extensive as might be expected for the cyclodextrin with the largest molecular cavity. The results for the salicylic acid/b-cyclodextrin and salicylic acid/hydroxypropyl-b-cyclodextrin mixtures were similar to those for benzoic acid/b-cyclodextrin and benzoic acid/hydroxypropyl-b-cyclodextrin. Again, the kneaded salicylic acid/g-cyclodextrin mixture showed the most interaction. This revised version was published online in July 2006 with corrections to the Cover Date.     

戊二醛蒸汽交联明胶材料的性能研究

利用戊二醛蒸汽对明胶材料进行交联改性。研究了交联反应时间对明胶材料力学性能、溶出性能和溶胀特性的影响。研究发现,随着交联时间的延长,交联反应从明胶瓣表面至内部逐步进行,由此可获得交联度呈梯度变化的明胶材料。研究结果表明,明胶材料的拉伸强度、模量和冲击强度随交联反应时间的延长而增加,而溶出速率和溶胀率随交联反应时间的延长而减小。蒸汽交联明胶材料的溶胀动力学不能用二次速率方程来描述。     

肽类药物口服剂型材料及控制释放性能研究──Ⅱ.含有添加剂的壳聚糖-海藻酸盐微囊对胰岛素的控释作用

应用壳聚糖－海藻酸盐微囊技术制备了一系列含有添加剂的胰岛素微囊,并研究了在添力。剂存在下,不同反应条件对微囊的胰岛素包封率及其释放性能的影响．结果表明,在添加剂存在下,海藻酸钠浓度越高,微囊在胃液中释放率越大,在模拟小肠液中释放速率越低,并且微球的韧性很强,不易破裂;海藻酸钠与添加剂的质量比越大,微囊的包封率越大,胃液中释放率减小;胰岛素含量越高,包封率越小,胃液中释放率越大;明胶和牛血清白蛋白的加入使微囊在胃液中释放率显著增大,微球的强度和韧性大大增强,尤其明胶的加入使微囊在模拟小肠液中释放率显著降低,释放达到最大值的时间延长．     

某些助剂对明胶的凝胶强度的影响的研究

众所周知,物理力学性能是照相明胶的一种很重要的属性。在各种彩色及黑白胶片都面向高温快速加工发展的今天,这种属性就显得更为重要。提高胶片的物理力学性能,一方面要从提高明胶本身的胶冻强度着手,例如减少明胶中溶胶组份(分子量小、冷水中溶解度高),提高明胶中的α和β组份的相对含量,减少分子量过大的组份等等。     

Laser diffraction estimation of particle size distribution of slightly water-soluble drugs coexisting with additives: application to solid dosage forms.

A simple and quantitative evaluation method for particle size distribution (fx(r)) of slightly water-soluble drugs dispersed in an aqueous medium together with other water-insoluble additives was developed using a laser diffraction method. The particle size distribution function of the powder mixture, (f(r)), was assumed as f(r) = phi x.fx(r) + phi a.fa(r), where phi is the volume fraction of each component dispersed in a measurement medium and fa(r) is the distribution function of another water-insoluble additive "a". In order to calculate fx(r) from f(r), it is necessary to know the density of drug and additive in the measurement medium, d(x) and d(a), but this is difficult to determine since particles usually swell in the medium. Thus, a method was developed to use their relative value, delta a (= da/dx). As a practical application, oxolinic acids (OA) of three sizes (OA-S (about 2 microns), OA-M (about 7 microns) and OA-L (about 24 microns)) were used as model drugs. delta a values were determined for various additives using the mixture of OA-S and each additive. Then, using delta as, fx(r) of OA-M or OA-L in the mixture containing OA-M or OA-L and additives was calculated from the f(r) experimentally determined for the mixture. They agreed well with their original distributions. The method was applied to some dosage forms, and the results obtained had good correlation with those from turbidity, wet sieving or dissolution test.     

Enhancement of solubility, dissolution and bioavailability of ibuprofen in solid dispersion systems

To improve its solubility, dissolution, and bioavailability; Ibuprofen-polyethylene glycol 8000 (PEG 8000) solid dispersions (SDs) with different drug loadings were prepared, characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC), and evaluated for solubility, in-vitro release, and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Preliminary results of this study suggested that the preparation of ibuprofen SDs using PEG 8000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution and bioavailability of ibuprofen.     

Improvement of dissolution and bioavailability for mebendazole, an agent for human echinococcosis, by preparing solid dispersion with polyethylene glycol.

The solid dispersion of mebendazole was prepared with polyethylene glycol (PEG) to enhance the dissolution rate of mebendazole, an agent for the chemotherapy of human echinococcosis. The dissolution rate of the solid dispersion increased compared with the physical mixture, and also increased with the incorporation of an increasing amount of PEG-6000. An extensive improvement of the dissolution rate was observed when the ratio of the solid dispersion of mebendazole to PEG-6000 was more than 1: 2. Furthermore, greater bioavailability in rabbits was obtained after oral administration of the solid dispersion compared with the physical mixture.     

Physical chemical characterization of binary systems of prilocaine hydrochloride with triacetyl-β-cyclodextrin

Interaction products of prilocaine hydrochloride (PRL), a local anesthetic agent highly soluble in water, with triacetyl-β-cyclodextrin (TAβCD), a hydrophobic CD derivative practically insoluble in water, were prepared to estimate their suitability for the development of a prolonged-release dosage form of the drug. Equimolar PRL-TAβCD solid systems were prepared by different methods (physical mixing, kneading, co-grinding, sealed-heating, coevaporation, spray-drying), in order to investigate their effectiveness and influence on the physical chemical properties of the end products. Differential scanning calorimetry, X-ray powder diffractometry, FTIR spectroscopy and environmental scanning electron microscopy (ESEM) were used for the solid-state characterization of the different PRL-TAβCD systems, whereas their in vitro dissolution properties were determined according to the dispersed amount method. On the basis of the overall solid-state studies results, the ability of the different methods to bring about effective drug-TAβCD interactions varied in the order: spray-drying > co-grinding ≈ coevaporation > sealed-heating > kneading > physical mixing. This rank order was not observed in dissolution studies, where coevaporated, kneaded and sealed-heated products exhibited very similar profiles, practically superimposable to that of pure drug and physical mixture, all reaching 100% dissolution in less than 10 min. Evidently, all these techniques gave rise only to weak surface interactions, rapidly destroyed in solution. Some decrease in dissolution rate was observed for co-ground system (100% dissolved drug after 40 min), probably due to electrostatic and aggregation phenomena associated with the high-energy mechanical treatment. A very different behaviour was shown by the spray-dried system, which give rise to an almost linear slow-dissolving profile, reaching 100% of dissolved drug after 420 min, suggesting in this case the formation of an actual inclusion compound. Thus, the drug-TAβCD product obtained by spray-drying was selected as the best candidate for the future development of a suitable prolonged-release oral dosage form of PRL.     

Rheology and stability of oil-in-water nanoemulsions stabilised by anionic surfactant and gelatin 2) addition of homologous series of sugar-based co-surfactants

The oil-in-water emulsions used in silver-halide photographic coatings are stabilised with anionic surfactants and made in the presence of excess gelatin, which acts as an electrosteric stabilising agent and continuous phase viscosifier. The oil droplet sizes are close to 100 nm but the adsorbed gelatin increases the effective volume of the droplets significantly. These nanoemulsions are manufactured and coated at temperatures in excess of 40 degrees C, where gelatin adopts a random coil structure. At oil concentrations above 15% by volume, the emulsions are viscoelastic liquids with a high low-shear viscosity and strong shear-thinning. The viscosity and shear-thinning can be decreased by reducing the adsorption of gelatin, which can be achieved by addition of nonionic surfactants. This is a rheological study of the effects of adding novel, nonionic sugar-based surfactants on the rheology of photographic nanoemulsions, with additional measurements of static and dynamic surface tension. These surfactants have two sugar (gluconamide) heads and either one or two alkyl tails. Homologous series of each type of sugar surfactant were investigated over a wide range of alkyl tail length. The optimum surfactant choice for commercial applications depends not only on rheological effects but also on ease of synthesis, purification and dissolution, and of course, cost. The dynamic surface tension of the emulsion containing the anionic-nonionic surfactant mixture must also be compatible with the multilayer coating process.