磷脂固体分散体对槲皮素溶出促进作用的研究

目的研究磷脂固体分散体对槲皮素溶出的促进作用。方法用溶剂法制备了不同比例的槲皮素的磷脂固体分散体 ,与其相应的物理混合物及槲皮素的PVP或PEG4 0 0 0 (1∶1)固体分散体并进行了溶出的对比研究。结果所制得固体分散体均可改善槲皮素的溶出 ,而质量比为 1∶1的槲皮素 磷脂固体分散体的溶出促进作用最为显著。DSC和X射线粉末衍射的研究表明 ,在质量比为1∶1的槲皮素 磷脂固体分散体中 ,槲皮素以无定形的状态分散于载体磷脂中 ,其熔点吸热峰消失。结论槲皮素溶出度的增大与其无定形的存在状态、磷脂对其的润湿作用以及磷脂在水中可形成脂质体有关     

Enhancement of dissolution rate of rofecoxib using solid dispersions with urea

The aim of this study was to enhance the dissolution rate of rofecoxib using solid dispersions (SDs) with urea. In preliminary studies, the solubility behavior of rofecoxib in the presence of polyethylene glycol (PEG)‐4000, polyvinylpyrrolidone (PVP) K30, mannitol, and urea in water was obtained at 37°C to choose an effective carrier for preparing its SDs. A systematic increase in the solubility behavior of rofecoxib was observed with increasing concentrations of these carriers in water except mannitol. The Gibbs free energy (ΔG) values were negative indicating the spontaneous nature of rofecoxib solubilization, and it decreased with increases in concentration, demonstrating that the reaction became more favorable as the concentration of these carriers increased. Since, urea exhibited higher solubilizing power than the other carriers, SDs of rofecoxib with urea were prepared at 1:1, 1:2, 1:5, and 1:10 (rofecoxib:urea) ratios by the fusion method. Evaluation of the properties of the SDs was performed using dissolution studies, fourier‐transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X‐Ray diffraction (XRD), and scanning electron microscopy (SEM). The dissolution rate of rofecoxib was enhanced rapid by its SDs with urea and increased with increasing concentrations of urea in SDs. The mean dissolution time (MDT) of rofecoxib decreased after preparation of SDs and physical mixtures with urea. FTIR spectroscopic studies showed the stability of rofecoxib and the absence of a well‐defined rofecoxib‐urea interaction. DSC and XRD studies confirmed the amorphous state of rofecoxib in SDs of rofecoxib with urea. SEM pictures showed the formation of effective SDs of rofecoxib with urea since well‐defined changes in the surface nature of rofecoxib, SDs, and physical mixture were observed. Drug Dev Res 63:181–189, (2004). © 2004 Wiley‐Liss, Inc.     

Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent.

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug-Gelucire 50/13-Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40 degrees C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.     

杨梅素固体分散体的制备以及体外溶出试验

目的运用固体分散技术制备杨梅素固体分散体并提高其体外溶出速率。方法选用PEG6000和PVPK30为载体,采用溶剂法和溶剂-熔融法制备杨梅素固体分散体,采用紫外分光光度法进行含量测定,并进行溶解度、体外溶出试验。结果两种载体的固体分散体均能增加药物的溶解度和溶出速率,杨梅素在载体中以高度分散状态存在。结论以PVPK30为载体的杨梅素固体分散体体外溶解度和溶出速率明显提高。杨梅素固体分散体能显著提高杨梅素的溶出速率。     

Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine

Amorphous solid dispersions are used as a strategy to improve the bioavailability of poorly water-soluble compounds. When formulating with a polymer, it is important not only for the polymer to stabilize against crystallization in the solid state, but also to improve the dissolution profile through inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. In this study, the dissolution profiles of solid dispersions of felodipine formulated with poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) were compared. In addition, concentration versus time profiles were evaluated for the supersaturated solutions of felodipine in the presence and absence of the polymers. HPMCAS was found to maintain the highest level of supersaturation for the greatest length of time for both the dissolution and solution crystallization experiments, whereas PVP was found to be the least effective crystallization inhibitor. All polymers appeared to reduce the crystal growth rates of felodipine at an equivalent supersaturation and this mechanism most likely contributes to the enhanced solution concentration values observed during dissolution of the amorphous solid dispersions.     

Influence of rapeseed phospholipids on ibuprofen dissolution from solid dispersions

The dissolution profiles of ibuprofen (IB) from solid dispersions prepared by the solvent evaporation method, containing the rapeseed lecithin ethanol soluble fraction (LESF) or rapeseed phosphatidylcholine (RPC) have been determined. The effect of incorporation of PEG 4,000 or PEG 8,000 in the solid dispersions on the controlled-release of IB was also investigated. Dissolution studies conducted in double-distilled water using the paddle dissolution apparatus showed that the initial dissolution rate (IDR) within the first 5 min and the maximum percent of dissolved IB of IB/LESF were double of those of IB/RPC (both in ratio 4:1 w/w). The low amounts of LESF markedly increased dissolution of IB. Increasing of LESF concentration from 0 to 10 and 20% in solid dispersions produced 60 and 100% improvement of IB maximum dissolution level respectively, to compare with that of IB alone. PEG 4,000 caused the slightly decreasing in IB dissolution rate, while PEG 8,000 markedly improved the dissolution of IB in examined conditions.     

Effect of chitosan crosslinking on bitterness of artemether using response surface methodology

This work examines the influence of various process parameters on artemether entrapped in crosslinked chitosan microparticles for masking bitterness. A central composite design was used to optimize the experimental conditions for bitterness masking. Critical parameters such as the amounts of artemether, chitosan and crosslinking agent have been studied to evaluate how they affect responses such as incorporation efficiency, particle size and drug release at pH 6.8. The desirability function approach has been used to find the best compromise between the experimental results. The optimized microparticles were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the crosslinking of chitosan significantly affects incorporation efficiency, particle size and drug release at pH 6.8. The bitterness score of microparticles was decreased to 0, compared with 3+ for pure artemether. The proposed method completed masked the bitter taste of artemether.     

Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions

Solid dispersions of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] in an amphiphilic vehicle [Gelucire 44/14; 2] and in polyethylene glycol (PEG) 1000, PEG 1450, and PEG 8000 were prepared. The vehicle 2 was a mixture of hydrogenated fatty acid esters with a mp of 44 degrees C, and had a HLB value of 14. Compound 1 was dissolved or dispersed in molten vehicles at elevated temperatures. The pulverization and compression of solid dispersions were avoided by encapsulating the hot solutions directly into hard gelatin capsules. At room temperature, the dispersions solidified forming plugs inside the capsules. On storage, greater than 180 mg of 1 remained dissolved per gram of vehicle, while the excess drug formed fine crystals (less than 20 micron). When mixed with water, the dissolved drug separated as a metastable liquid. Due to the surfactant property of 2, the oily form of 1 that separated from this vehicle formed an emulsified system with a globular size of less than 1 micron, while greater than 80% of 1 that separated from the other three formulations coalesced to form large oily masses. As a result of the large difference in surface area, the dissolution rate of 1 in simulated gastric fluid from capsules containing 2 was much higher than that of a PEG-based formulation. The bioavailability (AUC) of 1 in dogs from capsules containing 2 was also higher than that from PEG 1000-based capsules.     

Design,formulation and evaluation of Azithromycin binary solid dispersions using Kolliphor series for the solubility and in vitro dissolution rate enhancement

The main purpose of this investigation is increasing of the solubility and dissolution rate of Azithromycin by solid dispersion technique using Kolliphor P 237, Kolliphor P 338 and Kolliphor P 407. Kolliphor (P 237, P 338 and P 407) in various properties by weight {(1:0.5), (1:1), (1:1.5) and (1:2)}, utilizing solvent evaporation method. Dissolution studies carried out in phosphate buffer with pH 6.0 according to US pharmacopoeia method. The drug release profiles were studied, so we found that the dissolution rate of the drug (by calculating the dissolution parameters) was significantly increase compared to pure drug, also solubility of physical mixtures as well as solid dispersions increased compared to the intact drug. For example solubility of the drug increased from 85–753 μg mL^?1 (for Kolliphor P 237; 8 times more). The best results were as follows: Kolliphor P 237 > Kolliphor P 338 > Kolliphor P 407. IR spectra revealed no chemical incompatibility between drug and polymer. Drug-polymer interactions were investigated using differential scanning calorimetry, powder X-ray diffraction and scanning election microscopy. The dissolution rate and solubility of Azithromycin solid dispersions was improved significantly using Kolliphor. In addition, the simplicity of this method is very effective and have been met the project objectives.     

Effect of physical state and particle size distribution on dissolution enhancement of nimodipine/PEG solid dispersions prepared by melt mixing and solvent evaporation

The physical structure and polymorphism of nimodipine were studied by means of micro-Raman, WAXD, DSC, and SEM for cases of the pure drug and its solid dispersions in PEG 4000, prepared by both the hot-melt and solvent evaporation methods. The dissolution rates of nimodipine/PEG 4000 solid dispersions were also measured and discussed in terms of their physicochemical characteristics. Micro-Raman and WAXD revealed a significant amorphous portion of the drug in the samples prepared by the hot-melt method, and that saturation resulted in local crystallization of nimodipine forming, almost exclusively, modification I crystals (racemic compound). On the other hand, mainly modification II crystals (conglomerate) were observed in the solid dispersions prepared by the solvent evaporation method. However, in general, both drug forms may appear in the solid dispersions. SEM and HSM microscopy studies indicated that the drug particle size increased with drug content. The dissolution rates were substantially improved for nimodipine from its solid dispersions compared with the pure drug or physical mixtures. Among solid dispersions, those resulting from solvent coevaporation exhibited a little faster drug release at drug concentrations lower than 20 wt%. Drug amorphization is the main reason for this behavior. At higher drug content the dissolution rates became lower compared with the samples from melt, due to the drug crystallization in modification II, which results in higher crystallinity and increased particle size. Overall, the best results were found for low drug content, for which lower drug crystallinity and smaller particle size were observed.     

Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers

This study aimed to improve the dissolution rate and oral bioavailability of valsartan (VAL), a poorly soluble drug using solid dispersions (SDs). The SDs were prepared by a freeze-drying technique with polyethylene glycol 6000 (PEG6000) and hydroxypropylmethylcellulose (HPMC 100KV) as hydrophilic polymers, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 as a surfactant without using any organic solvents. In vitro dissolution rate and physicochemical properties of the SDs were characterized using the USP paddle method, differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform-infrared (FT-IR) spectroscopy, respectively. In addition, the oral bioavailability of SDs in rats was evaluated by using VAL (pure drug) as a reference. The dissolution rates of the SDs were significantly improved at pH 1.2 and pH 6.8 compared to those of the pure drug. The results from DSC, XRD showed that VAL was molecularly dispersed in the SDs as an amorphous form. The FT-IR results suggested that intermolecular hydrogen bonding had formed between VAL and its carriers. The SDs exhibited significantly higher values of AUC_0–24?h and C_max in comparison with the pure drug. In conclusion, hydrophilic polymer-based SDs prepared by a freeze-drying technique can be a promising method to enhance dissolution rate and oral bioavailability of VAL.     

Enhancement of dissolution of cyclosporine A using solid dispersions with polyoxyethylene (40) stearate

A solid dispersion containing cyclosporine A (CyA) and polyoxyethylene (40) stearate (PS) was prepared by the solvent-melt method and characterized by powder X-ray diffraction (PXRD), hot-stage microscopy (HSM), scanning electron microscopy (SEM) and dissolution studies. The crystalline peaks of CyA disappeared in the PXRD spectra of solid dispersions but were seen in those of physical mixtures, demonstrating the amorphous state of the drug in solid dispersions. The solubility of CyA in aqueous solutions of PS was increased linearly with increasing amount of PS in water. Dissolution of the drug from solid dispersions and physical mixtures was dramatically enhanced compared to the drug powder alone in water at 37 degrees C.     

Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine

In this study solid dispersions of carbamazepine in the hydrophilic Kollidon® VA64 polymer, adsorbed onto Neusilin® UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon® VA64 and Neusilin® UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin® UFL2. Proportion of Kollidon® VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30?min, whereby these parameters increase upon increasing in Kollidon® VA64 concentrations up to the middle values in the studied range of Kollidon® VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon® VA64 hydrophilic polymer and Neusilin® UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability.     

Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersion on enhanced dissolution and bioavailability of ketoconazole

Polyethylene glycol (PEG) 6000-based solid dispersions (SDs), by incorporating various pharmaceutical excipients or microemulsion systems, were prepared using a fusion method, to compare the dissolution rates and bioavailabilities in rats. The amorphous structure of the drug in SDs was also characterized by powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The ketoconazole (KT), as an antifungal agent, was selected as a model drug. The dissolution rate of KT increased when solubilizing excipients were incorporated into the PEG-based SDs. When hydrophilic and lipophilic excipients were combined and incorporated into PEG-based SDs, a remarkable enhancement of the dissolution rate was observed. The PEG-based SDs, incorporating a self microemulsifying drug delivery system (SMEDDS) or microemulsion (ME), were also useful at improving the dissolution rate by forming a microemulsion or dispersible particles within the aqueous medium. However, due to the limited solubilization capacity, these PEG-based SDs showed dissolution rates, below 50% in this study, under sink conditions. The PEG-based SD, with no pharmaceutical excipients incorporated, increased the maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC(0-6h)) two-fold compared to the drug only. The bioavailability was more pronounced in the cases of solubilizing and microemulsifying PEG-based SDs. The thermograms of the PEG-based SDs showed the characteristic peak of the carrier matrix around 60 degrees C, without a drug peak, indicating that the drug had changed into an amorphous structure. The diffraction pattern of the pure drug showed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of the numerous distinctive peaks of the drug in the PEG-based SDs demonstrated that a high concentration of the drug molecules was dissolved in the solid-state carrier matrix of the amorphous structure. The utilization of oils, fatty acid and surfactant, or their mixtures, in PEG-based SD could be a useful tool to enhance the dissolution and bioavailability of poorly water-soluble drugs by forming solubilizing and microemulsifying systems when exposed to gastrointestinal fluid.     

乙基纤维素固体分散体中5F释放度影响因素研究

目的制备不同乙基纤维素与5F固体分散体,并研究不同因素对5F溶出度的影响。方法溶剂法制备乙基纤维素固体分散体颗粒,测定其溶出度,考察各主要因素对5F释放的影响。结果乙基纤维素的黏度、含量、固体分散体的粒度、溶出介质的pH对药物释放均有影响。结论乙基纤维素可用来制备5F缓释固体分散体。     

响应面分析法优化阿霉素隐形脂质体的处方工艺

目的 利用响应面分析法优化阿霉素隐形脂质体的处方工艺.方法 根据Box-Benhnken的中心组合实验设计原理,采用3因素3水平的响应面分析法,以脂质体包封率为响应值作响应面,进行回归分析,并利用快速层析系统-葡聚糖凝胶柱法测定阿霉素的包封率.结果 最佳处方工艺条件为药脂比1:12,超声强度32%,孵育60 min;验证实验表明优选的工艺条件较理想.结论 在最佳处方工艺条件下,阿霉素隐形脂质体的实际包封率可达96.22%.     

无定形态药物结晶行为的研究进展

将药物的固体形态由晶态转变成分子无序排列的无定形态,可用于提高难溶性药物溶解度和溶出速率。无定形药物制剂已经成为提高难溶性药物生物利用度的最常用策略之一。目前,已有多种技术方法可将药物从晶态转变为无定形态,其中应用最成熟的技术包括喷雾干燥、热熔挤出技术等,在药物制剂工业中得到广泛的运用。此外,一些新型的技术方法例如3D打印技术和电纺丝技术等近年来也被报道用于无定形态药物的制备。这些不同的制备方法将会对无定形态药物的理化性质产生重要的影响。对无定形态药物制备方法的最新研究进行总结和分析,为无定形态药物的开发提供借鉴。

     

Effect of a melt agglomeration process on agglomerates containing solid dispersions

The purpose was to produce solid dispersions of a poorly water-soluble drug, Lu-X, by melt agglomeration in a laboratory scale rotary processor. The effect of binder type and method of manufacturing on the dissolution profile of Lu-X was investigated. Lactose monohydrate and Lu-X were melt agglomerated with Rylo MG12, Gelucire 50/13, PEG 3000, or poloxamer 188. Either a mixture of binder, drug, and excipient was heated to a temperature above the melting point of the binder (melt-in procedure) or a dispersion of drug in molten binder was sprayed on the heated excipient (spray-on procedure). The agglomerates were characterized by DSC, XRPD, SEM, and EDX-SEM. The study showed that the agglomerates containing solid dispersions had improved dissolution rates compared to physical mixtures and pure drug. The melt-in procedure gave a higher dissolution rate than the spray-on procedure with PEG 3000, poloxamer 188, and Gelucire 50/13, whereas the opposite was found with Rylo MG12. This was explained by differences in mechanisms of agglomerate formation and growth, which were dominated by immersion with PEG 3000, poloxamer 188, and Gelucire 50/13, and by distribution and coalescence with Rylo MG12. The spray-on procedure resulted in a higher content of Lu-X in the core of the agglomerates when immersion was the dominating mechanism, and in a higher content in the agglomerate surface when distribution was dominating. The melt-in procedure resulted generally in a homogeneous distribution of Lu-X in the agglomerates. The compounds in the agglomerates were found primarily to be crystalline, and the dissolution profiles were unchanged after 12 weeks storage at 25 degrees C at 50% RH.