Study on solubility improvement of lidocaine by ternary solid dispersion

In the present study, we aimed to probe the possibility of using mixed poloxamers as carriers to prepare ternary solid dispersion (SD) that facilitated solubility and dissolution rate of the poorly water soluble drug and compare with binary SD with single poloxamer. Lidocaine (LIC) was selected as a model drug, and poloxamer 188 (P188) and poloxamer 407 (P407) were utilized as single and mixed carriers. Depending on DSC and the dissolution testing, the appropriate ratio of SD prepared by melting method was optimized. Ternary and binary SD was characterized by DSC, XRD, SEM and FTIR. In vitro dissolution study, phase solubility study and saturated solubility study were performed to clarify solubilization from apparent phenomena and inherent reason. Moreover, stability study under different relative humidity (RH) was investigated. Physical characterizations of binary and ternary SD exhibited the formation of eutectic mixture and the presence of molecular interaction. Compared with the pure LIC, the dissolution rate and solubility of LIC in binary and ternary SDs were enhanced. The phase solubility study revealed an AL-type curve. Furthermore, the stability test indicated that ternary and binary SD was stable. The results of this study demonstrated that SD with mixed poloxamers could improve dissolution rate and solubility of poorly water-soluble drug.     

Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions

This study investigates the potential of poloxamers as solid dispersions (SDs) carriers in improving the dissolution rate of a poorly soluble drug, carbamazepine (CBZ). Solid dispersions were prepared with poloxamer 188 (P188) and poloxamer 407 (P407) by melting method in different drug:carrier ratios (1:1, 1:2 and 1:3). Prepared samples were characterized using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (HSM), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) to investigate drug physical state within the SDs matrix, possible polymorphic transitions and drug-polymer interactions. The interactions between CBZ molecules and polymeric chains were also evaluated using molecular dynamics simulation (MDS) technique. The most thermodynamically stable polymorphic form III of CBZ was present in all SDs, regardless of the type of poloxamer and drug-to-carrier ratio. The absence of drug-polymer interactions was observed by FT-IR analysis and additionally confirmed by MDS. Formation of persistent hydrogen bond between two CBZ molecules, observed by MDS indicate high tendency of CBZ molecules to aggregate and form crystalline phase within dispersion. P188 exhibit higher efficiency in increasing CBZ dissolution rate due to its more pronounced hydrophilic properties, while increasing poloxamers concentration resulted in decreasing drug release rate, as a consequence of their thermoreversible gelation.     

Improved pH-independent dissolution and oral absorption of valsartan via the preparation of solid dispersion

This study aimed to improve the pH-independent solubility and dissolution characteristics of valsartan via the preparation of solid dispersions (SD) with poloxamer 407. SDs was prepared by using the solvent method at various drug-polymer ratios and their dissolution characteristics were examined at different pHs. Oral pharmacokinetics of SDs was also evaluated in rats. Compared to the untreated powder, SDs significantly improved the dissolution rate as well as the extent of drug release at low pH. Particularly, SD having the drug-polymer ratio of 1:5 exhibited pH-independent dissolution of valsartan, resulting in the rapid and complete drug release over the pH range of 1.2 to 6.8. The improved dissolution of valsartan via SD formulation appeared to be well correlated with the enhanced oral exposure of valsartan in rats. SDs increased C_max and AUC_0–24 of valsartan by 2–7 folds in rats, implying that SDs should be effective to improve the bioavailability of valsartan. In conclusion, SDs containing poloxamer 407 appeared to be effective to improve the pH-independent dissolution and oral absorption of valsartan.     

Preparation, Characterization, and In Vitro Evaluation of Ezetimibe Binary Solid Dispersions with Poloxamer 407 and PVP K30

Ezetimibe (EZE), a water insoluble drug, depicts variable bioavailability. The objective of the present investigation was to improve dissolution characteristics of EZE, which might offer improved bioavailability. The solid dispersions were prepared using poloxamer 407 (L 127) and polyvinyl pyrrolidone by melt and solvent method, respectively. Phase solubility studies indicated linear relationship between drug solubility and carrier concentration. In vitro release studies revealed improvement in the dissolution characteristics of EZE in solid dispersions. Solid dispersion with L 127 gave better rate and extent of dissolution. The best fit model indicating the probable mechanism of drug release from solid dispersions was found to be Korsemeyer–Peppas. The results of characterization of solid dispersions by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction revealed reduction in drug crystallinity which might be responsible for improved dissolution properties. The tablets of solid dispersion, containing L 127 prepared by direct compression, exhibited better drug release as compared to marketed formulation.     

Formulation and in vivo hypoglycemic effect of glipizide solid dispersion

The present study was carried out with a view to enhance dissolution rate of poorly water-soluble drug glipizide (GZ) (BCS class II) using polyethylene glycol (PEG) 6000, PEG 8000 and poloxamer (PXM) 188 as carriers. Solid dispersions (SDs) were prepared by melting method using different ratios of glipizide to carriers. Phase solubility study was conducted to evaluate the effect of carrier on aqueous solubility of glipizide. SD was optimized by drug content estimation and in vitro dissolution study and optimised SD was subjected to bulk characterization, Scanning electron microscopy (SEM), Fourier transformation infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction study (XRD). Preclinical study was performed in mice to study the decrease in blood glucose level from prepared SD compared with pure drug. Due to high solubility and drug release, PXM 188 in weight ratio of 1:2 was optimized. Decrease in blood glucose level in mice from SD was significantly higher (p < 0.05) compared to pure glipizide. Thus, solid dispersion technique can be successfully used for the improvement of the dissolution profile of GZ.     

Enhanced dissolution of ibuprofen using solid dispersion with poloxamer 407

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility, and in-vitro ibuprofen release. Loss of individual surface properties during melting and re-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. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. 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. Comparison of the enhanced solubility, dissolution, AUC, and C_max of ibuprofen from different poloxamers suggested that the preparation of ibuprofen SDs using P 407 as a meltable hydrophilic polymer carrier could be a promising approach to improve its solubility, dissolution and absorption rate.     

Evaluation of Selected Micronized Poloxamers as Tablet Lubricants

The primary objective of this study was to compare the lubrication properties of micronized poloxamer 188 (Lμ trol micro 68®) and micronized poloxamer 407 (Lμ trol micro 127®) with certain conventional lubricants such as magnesium stearate and stearic acid. The secondary objective was to use these micronized poloxamers as water-soluble tablet lubricants in preparation of effervecsent tablets. The results showed that these micronized poloxamers have superior lubrication properties compared with stearic acid, with no negative effect on tablet hardness, friability, disintegration, or dissolution. Moreover, lubricant mixing time had no significant effect on tablet properties when poloxamers were used as lubricants. Effervescent tablets also were produced successfully using micronized poloxamers as lubricants. The micronized poloxamers had a better lubrication effect in compariason with that of water-soluble lubricant l-leucine.     

Evaluation of selected micronized poloxamers as tablet lubricants

The primary objective of this study was to compare the lubrication properties of micronized poloxamer 188 (Lμ trol micro 68^®) and micronized poloxamer 407 (Lμ trol micro 127^®) with certain conventional lubricants such as magnesium stearate and stearic acid. The secondary objective was to use these micronized poloxamers as water-soluble tablet lubricants in preparation of effervecsent tablets. The results showed that these micronized poloxamers have superior lubrication properties compared with stearic acid, with no negative effect on tablet hardness, friability, disintegration, or dissolution. Moreover, lubricant mixing time had no significant effect on tablet properties when poloxamers were used as lubricants. Effervescent tablets also were produced successfully using micronized poloxamers as lubricants. The micronized poloxamers had a better lubrication effect in compariason with that of water-soluble lubricant l-leucine.     

Effect of poloxamer on physicochemical properties of tacrolimus solid dispersion improving water solubility and dissolution rate

Tacrolimus (TCR; also FK-506 and trade name prograf^?), an antibiotic of macrolide family and a novel immunosuppressive agent, is a natural product of actinomycete Streptomyces tskubaensis. But TCR is poorly soluble in water (0.012?mg/mL), so its bioavailability is low and irregular. The aim of this study is to characterize physicochemical properties of TCR and investigate the improvement of solubility and dissolution rate of TCR solid dispersion (SD) with poloxamer. TCR SDs, consisting of various grades and ratios of poloxamer were prepared by hot-melting method and were characterized by DSC, PXRD, and FT-IR. The dissolution profile and solubility of TCR from the SDs were evaluated. SD of TCR prepared with poloxamer 188 at the ratio of 1:1 by the hot-melting method resulted in a significant increase in TCR solubility and enhanced dissolution profile over the TCR crystalline powder.     

Improvement of solubility,dissolution and stability profile of artemether solid dispersions and self emulsified solid dispersions by solvent evaporation method

Abstract

The purpose of this study was to investigate changes in the water solubility of artemether; a poorly soluble drug used for the treatment of malaria. Different solid dispersions (SDs) of artemether were prepared using artemether and polyethylene glycol 6000 at ratio 12:88 (Group 1), self-emulsified solid dispersions (SESDs) containing artemether, polyethylene glycol 6000, cremophor-A-25, olive oil, hydroxypropylmethylcellulose and transcutol in the ratio 12:75:5:4:2:2, respectively (Group 2). SESDs were also prepared by substituting cremophor-A-25 in Group 2 with poloxamer 188 (noted as Group 3). Each of these preparations was formulated using physical mixing and the solvent evaporation method. Aqueous solubility of artemether improved 11-, 95- and 102-fold, while dissolution (in simulated gastric fluid) increased 3-, 13- and 14-fold, for formulation groups 1, 2 and 3, respectively. X-ray diffraction patterns of SDs indicated a decrease in peak intensities at 10° implying reduced artemether crystallinity. Scanning electron micrographs invariably revealed embedment of artemether by various excipients and a glassy appearance for solvent evaporated mixtures for all three formulation Groups. Our findings indicate improved hydrophilic interactions for drug particles yield greater solubility and dissolution in the following order for artemether formulating methods: solvent evaporation mixtures?>?physical mixtures?>?pure artemether.     

800 mg Darunavir tablets prepared by hot melt extrusion

Darunavir (TMC 114) is a protease inhibitor used in the therapy of HIV-1. The aim of this study was to formulate 800?mg of Darunavir in a single unit dosage form, with suitable mechanical properties and dissolution behavior, using a corotating twin screw extruder. In preliminary investigations, extrudates of 1?mm diameter were prepared to evaluate the extrusion and dissolution behavior of Darunavir. Two different poloxamers (188 and 407) were used to modify the dissolution properties of Darunavir, and a higher solubilization for poloxamer 188 was observed. Furthermore, a zero order drug release from pure Darunavir extrudates was found which was modulated by the extrudate diameter. Extrudates of 13?mm diameter were cut into tablets containing 800?mg of Darunavir. Due to the lower specific surface area in comparison to the 1?mm extrudates, an addition of solubilizing agent was required to obtain the desired dissolution profiles. Therefore, the influence of Mannitol and poloxamer 188 was investigated in different formulations. The formulations exhibited acceptable extrusion behavior and dissolution properties.     

Improvement in Dissolution Rate of Cefuroxime Axetil by using Poloxamer 188 and Neusilin US2

A combination of fusion and surface adsorption techniques was used to enhance the dissolution rate of cefuroxime axetil. Solid dispersions of cefuroxime axetil were prepared by two methods, namely fusion method using poloxamer 188 alone and combination of poloxamer 188 and Neusilin US2 by fusion and surface adsorption method. Solid dispersions were evaluated for solubility, phase solubility, flowability, compressibility, Kawakita analysis, Fourier transform-infrared spectra, differential scanning calorimetry, powder X-ray diffraction study, in vitro drug release, and stability study. Solubility studies showed 12- and 14-fold increase in solubility for solid dispersions by fusion method, and fusion and surface adsorption method, respectively. Phase solubility studies showed negative ΔG⁰_tr values for poloxamer 188 at various concentrations (0, 0.25, 0.5, 0.75 and 1%) indicating spontaneous nature of solubilisation. Fourier transform-infrared spectra and differential scanning calorimetry spectra showed that drug and excipients are compatible with each other. Powder X-ray diffraction study studies indicated that presence of Neusilin US2 is less likely to promote the reversion of the amorphous cefuroxime axetil to crystalline state. in vitro dissolution studies, T50% and mean dissolution time have shown better dissolution rate for solid dispersions by fusion and surface adsorption method. Cefuroxime axetil release at 15 min (Q15) and DE15 exhibited 23- and 20-fold improvement in dissolution rate. The optimized solid dispersion formulation was stable for 6 months of stability study as per ICH guidelines. The stability was ascertained from drug content, in vitro dissolution, Fourier transform-infrared spectra and differential scanning calorimetry study. Hence, this combined approach of fusion and surface adsorption can be used successfully to improve the dissolution rate of poorly soluble biopharmaceutical classification system class II drug cefuroxime axetil.     

温控型胰岛素液体直肠栓的制备及处方筛选

目的:制备温控型胰岛素液体直肠栓。方法:以胰岛素含量为指标,以泊洛沙姆407-泊洛沙姆188的比例、壳聚糖含量、p H为因素,采用正交设计试验筛选温控型胰岛素液体直肠栓的处方;并采用无膜、动物黏膜溶出法考察所制栓剂的体外释药机制。结果:所制温控型胰岛素液体直肠栓的胰岛素含量为0.35%;泊洛沙姆407-泊洛沙姆188的比例对栓剂中胰岛素含量影响显著(P<0.05);最优处方为泊洛沙姆407-泊洛沙姆188比例为15%∶25%、壳聚糖含量为0.4%、p H为5;使用无膜和牛肠黏膜时是通过溶蚀方式释放,使用羊肠黏膜时是通过扩散与溶蚀相结合的方式释放。结论:成功制得温控型胰岛素液体直肠栓。     

布渣叶总黄酮固体分散体的制备及体外溶出度测定

目的:采用固体分散体技术考察不同载体材料对布渣叶总黄酮提取物溶出度的影响.方法:选择不同种类的聚乙二醇、泊洛沙姆、聚乙烯吡咯烷酮为载体材料,与布渣叶总黄酮提取物按质量比1:4混合均匀,分别用熔融法和溶剂法制备固体分散体,以固体分散体中总黄酮、牡荆苷、异牡荆苷、水仙苷的90 min累积溶出度作为评价指标,比较不同载体制备的固体分散体的释药速率,并采用X射线衍射和红外光谱分析对其物相特征进行研究.结果:与布渣叶总黄酮提取物和物理混合物相比,以PEG和泊洛沙姆所制备的布渣叶提取物固体分散体中总黄酮、牡荆苷、异牡荆苷和水仙苷的体外溶出度与溶出速率均明显增加.其中以泊洛沙姆407为载体材料所制备的固体分散体中总黄酮体外溶出度最佳,90 min累积溶出度达到84%;以PEG 6000为载体材料所制备的固体分散体中牡荆苷、异牡荆苷、水仙苷体外溶出度最佳,90 min累积溶出度均达96%以上.结论:采用固体分散体技术,选择PEG 6000或泊洛沙姆407为载体制备布渣叶总黄酮提取物固体分散体,对提取物中脂溶性成分的溶出有明显改善作用.     

Preparation and Characterization of Poloxamer 407 Solid Dispersions as an Alternative Strategy to Improve Benznidazole Bioperformance

Benznidazole (BZL), the first line drug for Chagas disease treatment, presents a low solubility, limiting the possibilities for its formulation. In this work, solid dispersions' (SDs) technology was exploited to increase BZL kinetic solubility and dissolution rate, seeking for an improvement in its bioperformance. A physical mixture (PM) and an SD using Poloxamer 407 as carrier were prepared and characterized. Dissolution tests were performed, and data were analyzed with the lumped model, which allowed to calculate different parameters of pharmaceutical relevance. A bioactivity assay was also carried out to probe the SD anti-trypanocidal activity. Among the most relevant results, the initial dissolution rate of the BZL SD was near 3, 4 and about 400-fold faster than the PM, a commercial formulation (CF) and an extracted BZL, respectivley. The times needed for an 80% of drug dissolution were 3.6 (SD), 46.4 (PM), and 238.7 min (CF); while the dissolution efficiency values at 30 min were 85.2 (SD), 71.2 (PM), and 65.0% (CF). Survival curves suggested that using Poloxamer 407 as carrier did not alter the anti-trypanocidal activity of BZL. These results allow to conclude that SDs can be an effective platform for immediate release of BZL in an oral administration.     

Surface-active derivative of inulin (Inutec® SP1) is a superior carrier for solid dispersions with a high drug load

The aim of this study was to compare the applicability of inulin, its surface-active derivative (Inutec? SP1), and polyvinylpyrrolidone (PVP) as carriers in high drug load solid dispersions (SDs) for improving the dissolution rate of a range of lipophilic drugs (diazepam, fenofibrate, ritonavir, and efavirenz). The SDs were prepared by spray freeze-drying. Scanning electron microscopy showed that the obtained samples were highly porous spherical particles. Modulated differential scanning calorimetry showed that the drugs incorporated in these carriers were fully or partially amorphous. The solubility of the drugs in solutions of the different carriers was increased in an order: inulin 2.3 kDa < PVP K30 ? Inutec? SP1. The dissolution behavior of SD tablets was evaluated. Inutec? SP1-based SD tablets showed the best performance followed by PVP- and inulin-based SD tablets. The superior dissolution behavior of the drugs from Inutec? SP1-based SDs could be ascribed to its surface-active nature. In addition, Inutec? SP1-based SD tablets gave good physical stability at 20 °C/45% relative humidity (RH) and 40 °C/75% RH for 3 months.     

Improved solubility and in vitro dissolution of Ibuprofen from poloxamer gel using eutectic mixture with menthol

To improve the solubility and in vitro dissolution of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution study of ibuprofen delivered by poloxamer gels composed of poloxamer 188 and menthol were performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6, followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that 4 parts of ibuprofen formed eutectic mixture with 6 parts of menthol. In the presence of poloxamer 188, the solutions with the same ratio of menthol to ibuprofen showed abrupt increase in the solubility of ibuprofen. Furthermore, the solution with ratio of 4:6 showed more than 2.5- and 6-fold increase in the solubility of ibuprofen compared with that without poloxamer and that without menthol, respectively. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/ml. Menthol improved the dissolution rates of ibuprofen from poloxamer gels. Dissolution mechanism showed that the dissolution rate of ibuprofen from the poloxamer gels without menthol was independent of the time, but the drug might be dissolved from the poloxamer gels with menthol by Fickian diffusion. Thus, the poloxamer gels developed using eutectic mixture with menthol, which gave the improved solubility and dissolution of drug, are potential candidates for ibuprofen-loaded transdermal and rectal delivery system.     

Enhancement of solubility and dissolution of Coenzyme Q10 using solid dispersion formulation

This study aimed to develop a stable solid dispersion of Coenzyme Q₁₀ (CoQ₁₀) with high aqueous solubility and dissolution rate. Among various carriers screened, poloxamer 407 was most effective to form a superior solid dispersion of CoQ₁₀ having significantly enhanced solubility. Particularly, solid dispersion of CoQ₁₀ with poloxamer 407 in the weight ratio of 1:5 prepared by melting method enhanced the solubility of CoQ₁₀ to the greatest extent. However, it exhibited poor stability and hence Aerosil^® 200 (colloidal silicon dioxide) was incorporated into the solid dispersion as an adsorbent to inhibit the recrystallization process. The solid dispersion of CoQ₁₀, poloxamer 407 and Aerosil^® 200 in the weight ratio of 1:5:6 exhibited improved stability with no significant change in solubility during the 1-month stability test. Moreover, the solid dispersion formulation containing Aerosil^® 200 significantly enhanced the extent of drug release (approx. 75% release) as well as the dissolution rate of CoQ₁₀. In conclusion, the present study has developed the stable solid dispersion formulation of CoQ₁₀ with poloxamer 407 and Aerosil^® 200 for the enhanced solubility and dissolution of CoQ₁₀, which could also offer some additional advantages including ease of preparation, good flowability and cost-effectiveness.     

氯霉素温敏型眼用原位凝胶的研制

目的制备氯霉素泊洛沙姆眼用原位温敏型凝胶并建立其质量控制方法。方法以泊洛沙姆P407和P188为温敏材料,通过测定溶液-凝胶相转变温度优化处方;采用紫外分光光度法测定氯霉素含量。结果氯霉素温敏型原位凝胶的胶凝温度随P407浓度增大而降低,随P188浓度增加先升高后降低,模拟泪液的稀释可使胶凝温度升高,建立了泪液稀释后相变温度与泊洛沙姆浓度的拟合方程,经Design-Expert软件优化出的氯霉素温敏型原位凝胶最佳处方为25%P407和4.19%P188;优化处方在29.5℃时为自由流动的液体,泪液稀释后在34.6℃能够发生相变形成凝胶。结论该眼用温敏凝胶符合眼部应用要求,体现出良好的应用前景。     

Enhanced dissolution and systemic availability of albendazole formulated as solid dispersions

Solid dispersions (SDs) containing the anthelmintic compound albendazole (ABZ) and either Pluronic 188 (P 188) or polyethylene glycol 6000 (PEG 6000) as hydrophilic carriers were formulated. Drug–polymers interactions in solid state were investigated using different techniques.

Only a 4% of total ABZ was dissolved at 5 min post-incubation, reaching dissolution rates of 32.8% (PEG 6000) and 69.4% (P 188) in SDs. In this way, P 188 was substantially more efficient as ABZ dissolution promoter in comparison to PEG 6000, especially at the initial stages of the dissolution processes (<30 min).

An increased systemic availability (p < 0.001) was obtained when ABZ was administered as ABZ-P 188 SDs, with a 50% enhancement in systemic exposure (AUC values) compared to treatment with an ABZ suspension. Consistently, the Cmax increased 130% (p < 0.001) following treatment with P 188 based SD ABZ formulation. For the ABZ-PEG 6000 SD formulation, the favorable effect on ABZ systemic availability did not reached statistical significance compared to the control group.

The study reported here showed the utility of pharmacokinetic assays performed on mice as a model for preliminary drug formulation screening studies.