Preparation of ibuprofen-loaded liquid suppository using eutectic mixture system with menthol

To prepare an ibuprofen-loaded liquid suppository using eutectic mixture with menthol, the effects of menthol and poloxamer 188 (P 188) on the aqueous solubility of ibuprofen were investigated. The physicochemical properties such as gelation temperature, gel strength and bioadhesive force of various formulations composed of ibuprofen, menthol and P 188 were investigated. Then, the pharmacokinetic study of ibuprofen delivered by the liquid suppositories composed of P 188 and menthol were then performed. In the absence of P 188, 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 four parts of ibuprofen formed eutectic mixture with six parts of menthol. In the presence of P 188, the solutions with the same ratio 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 additives 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, 1.2mg/ml. Ibuprofen increased the gelation temperature and weakened the gel strength and bioadhesive force of liquid suppositories. However, menthol did the opposite due to forming the eutectic mixture with ibuprofen. The ibuprofen-loaded liquid suppository [P 188/menthol/ibuprofen (15/0.25/2.5%)] with the maximum ibuprofen solubility of 1.2mg/ml was administered easily to the anus and to remain at the administered site without leakage after the dose. Furthermore, it gave significantly higher initial plasma concentrations, Cmax and AUC of ibuprofen than did solid suppository, indicating that the drug from poloxamer gel could be more absorbed than that from solid one in rats. Thus, the liquid suppository system with P 188 and menthol, a more convenient and effective rectal dosage form for ibuprofen will be expected to enhance the rectal bioavailability of ibuprofen.     

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.     

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.     

Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol

Piroxicam is a nonsteroidal anti-inflammatory drug that is characterized by low solubility-high permeability. The present study was designed to improve the dissolution rate of piroxicam at the physiological pH's through its increased solubility by preparing semi-solid dispersions of drug using Gelucires and Labrasol. These excipients are essentially characterized by their melting points and HLB (hydrophilic-lipophilic balance) values. The dissolution tests of the preparations were performed in the media with different pH's. Differential scanning calorimetry (DSC), were used to examine the interaction between piroxicam and excipients. Gelucire 44/14 and Labrasol at the concentration of 15% w/v in water provided 20- and 50-fold increase in the solubility of piroxicam, respectively. The semi-solid dispersion containing 1/20 of drug/excipient mixture (20% Gelucire 44/14 and 80% Labrasol in w/w) produced the dissolution not less than 85% of piroxicam within 30 min in each dissolution media (simulated gastric fluid (SGF), pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). DSC analysis of this semi-solid dispersion indicated that there was no chemical reaction between the drug and excipients, and that a solid-state solution of piroxicam with excipient formed.     

布洛伪麻胶囊溶出度测定方法研究

目的:建立测定布洛伪麻胶囊溶出度的高效液相色谱方法.方法:以磷酸盐缓冲液(pH7.2)为溶出介质,转速为120r·min-1,取样时间为45 min,采用桨法测定布洛伪麻胶囊的溶出度.结果:布洛芬和盐酸伪麻黄碱检测浓度的线性范围分别为0.08～0.4 mg·ml-1(R=0.9999)和0.012～0.06 mg·ml-1(R=0.9999);平均回收率为99.73%(RSD=1.23%)、99.56%(RSD=1.42%),3批样品45 min平均溶出度均在90%以上.结论:本方法操作简便,结果准确可靠.     

Release of flurbiprofen from poloxamer 407 gel

Release rates of flurbiprofen from transdemal gels made of poloxamer 407 were evaluated using a membraneless diffusion cell in order to study the effects of formulation variables on flurbiprofen release such as poloxamer 407 (17.5–25%), drug (0.1–1.0%), ethanol (10–20%), PG or PEG 300 (5–15%) concentrations and gel pH (3–7). Isopropyl myristate was employed as a receptor medium for the drug released from the gel. The diffusion coefficient of flurbiprofen decreased linearly as the amount of poloxamer 407 and the drug in the gel increased. The release rate of flurbiprofen was gel pH-dependent and the diffusion coefficient of the drug in the gel increased as the pH of the gel increased. The addition of more ethanol in the gel increased the drug release, resulting from the increase of the thermodynamic activity of the drug in the aqueous phase of the gel. However, the concentration effects of PG and PEG 300 on the release rate of flurbiprofen were negligible over the concentration range used.     

不同厂家布洛芬混悬液的溶出度对比研究

摘 要 目的：比较国产布洛芬混悬液和进口制剂的溶出曲线相似性,为全面评价布洛芬混悬液的质量提供依据。方法: 分别考察各厂家布洛芬混悬液在pH 7.2磷酸盐缓冲液中的溶出度,并比较国内3个厂家布洛芬混悬液与进口制剂分别在pH 1.2盐酸溶液、pH 4.5醋酸盐缓冲液、pH 6.8磷酸盐缓冲液、pH 7.2磷酸盐缓冲液和水5种溶出介质中溶出行为相似性。结果: 各厂家布洛芬混悬液在pH 7.2磷酸盐缓冲液60 min时溶出度均达到80%以上;3个厂家的布洛芬混悬液溶出曲线与进口制剂溶出曲线相比较,有两个厂家的制剂与进口制剂相似性达到要求。结论:不同厂家生产的布洛芬混悬液,其溶出行为有明显差异。     

复方布洛芬软胶囊中2组分溶出度的测定方法研究

目的 :建立同时测定复方布洛芬软胶囊中布洛芬和对乙酰氨基酚2组分溶出度的方法。方法 :以磷酸盐缓冲液 (pH=7 2)为溶剂 ,转速为75r/min ,取样时间为45min ,采用反相高效液相色谱法测定布洛芬和对乙酰氨基酚的溶出度 ,其中色谱柱为氰基柱 ,流动相为磷酸盐缓冲液 (pH=6 6) -甲醇 (60∶40) ,流速为1 0ml/min ,检测波长为223nm ,柱温为30℃。结果 :对乙酰氨基酚与布洛芬检测浓度线性范围分别为0 17～100 14μg/ml(r=0 9999 ,n=9)、0 21～124 86μg/ml(r=0 9999 ,n=9) ;平均回收率分别为99 62 %(RSD=0 36 %)、99 79 %(RSD=0 49 %)。结论 :本方法简便、快速、准确、可靠 ,能同时测定复方布洛芬软胶囊中2组分的溶出量。     

Preparation,characterization, and in vitro/vivo evaluation of polymer-assisting formulation of atorvastatin calcium based on solid dispersion technique

 Due to low solubility and bioavailability, atorvastatin calcium is confronted with challenge in conceiving appropriate formulation. Solid dispersion of atorvastatin calcium was prepared through the solvent evaporation method, with Poloxamer 188 as hydrophilic carriers. This formulation was then characterized by scanning electron microscopy, differential scanning calorimetry,powder X-ray diffraction and fourier transform infrared spectroscopy. Moreover, all these studies suggested the conversion of crystalline atorvastatin calcium. In addition, the drug solubility studies as well as dissolution rates compared with bulk drug and market tablets Lipitor were also examined. Furthermore, the study investigated the pharmacokinetics after oral administration of Lipitor and solid dispersion. And the AUC0–8 h and Cmax increased after taking ATC-P188 solid dispersion orally compared with that of Lipitor. All these could be demonstrated that ATC-P188 solid dispersions would be prospective means for enhancing higher oral bioavailability of ATC.     

复方布洛芬苯海拉明软胶囊溶出度测定方法

建立了同时测定布洛芬和苯海拉明的含量反相高效液相法,确定以C18柱,流动相为乙腈-磷酸盐缓冲盐-甲醇为3∶2∶5,流速为1.0 mL.min-1,检测波长为210 nm的色谱条件;通过对溶出转速、介质和溶出曲线等条件考察,建立了本软胶囊溶出度的测定方法。结果:布洛芬在55.1～551μg.mL-1浓度范围内呈良好的线性关系,苯海拉明在6.9～69μg.mL-1浓度范围内呈良好的线性关系,布洛芬和盐酸苯海拉明的平均回收率分别100.8%±0.7%和101.4%±0.6%,溶出度测定结果限度为30 min大于标示量的80%。     

Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000

The aim of this study was to prepare and characterize solid dispersions of water insoluble non-steroidal anti-inflammatory drug, indomethacin (IND), with polyethylene glycol 4000 (PEG4000) and Gelucire 50/13 (Gelu.) for enhancing the dissolution rate of the drug. The solid dispersions (SDs) were prepared by hot melting method at 1:1, 1:2 and 1:4 drug to polymer ratios. Scanning electron microscopy (SEM), X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to examine the physical state of the drug. Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The data from the XRD showed that the drug was still detectable in its solid state in all SDs of IND–Gelu. and disappeared in case of higher ratio of IND–PEG4000. DSC thermograms showed the significant change in melting peak of the IND when prepared as SDs suggesting the change in crystallinity of IND. The highest ratio of the polymer (1:4) enhanced the drug solubility about 4-folds or 3.5-folds in case of SDs of IND–PEG or IND–Gelu., respectively. An increased dissolution rate of IND at pH 1.2 and 7.4 was observed when the drug was dispersed in these carriers in form of physical mixtures (PMs) or SDs. IND released faster from the SDs than from the pure crystalline drug or the PMs. The dissolution rate of IND from its PMs or SDs increased with an increasing amount of polymer.     

Pharmaceutical characterisation and evaluation of cocrystals: Importance of in vitro dissolution conditions and type of coformer

The objectives of this study were to demonstrate the importance of experimental set-up and type of coformer for the enhanced dissolution properties of cocrystals. Carbamazepine–saccharin and carbamazepine–nicotinamide cocrystals were prepared by the sonic slurry method and characterised with SEM, DSC, XRPD and particle size analysis. Solubility and dissolution testing (closed and open system) were performed in compendial media and media with a physiologically relevant amount of surfactant. Carbamazepine cocrystals (1:1 molar ratio) did not show a difference in the equilibrium solubility compared to the carbamazepine in compendial media but a substantial difference was observed in modified media. In compendial media, a faster dissolution rate was obtained only from the carbamazepine–saccharin cocrystal, whereas in modified media both cocrystals had a substantial higher dissolution compared to carbamazepine. With the selected method a clear difference in the dissolution profiles of each cocrystal is shown, driven by the characteristics of the coformer used. This study demonstrated that improved dissolution of carbamazepine from the cocrystal forms can be revealed only by appropriate selection of in vitro conditions. The characteristics of the coformer define a critical variable for dissolution of pharmaceutical cocrystals with important implications for their in vivo performance.     

Gene transfer mediated by sphingosine/ dioleoylphosphatidylethanolamine liposomes in the presence of poloxamer 188

A cationic liposome system consisting of sphingosine (SP) and dioleoylphosphatidylethanolamine (DOPE) was developed for in vitro and in vivo gene transfer. A nonionic surface active agent of poloxamer 188 was incorporated in the formulations to stabilize the DNA/liposome complex. Comparison of the results obtained from systems with and without the effect of poloxamer 188 was made to investigate the efficiency of gene expression. In vitro transfection study of the DNA/liposome complex showed that with the effect of poloxamer 188, gene transfer into some cell lines was enhanced. In vivo systemic delivery of the DNA/liposome complex with poloxamer 188 demonstrated gene expression with improved luciferase activity in all major organs including lung, spleen, heart, liver, and kidney. High level transgene activity was found in lung and spleen with prolonged gene expression. This was attributed to poloxamer 188 that stabilized the liposome system and produced homogeneous DNA/liposome complex for enhancement of gene delivery.     

Design,optimization and evaluation of glipizide solid self-nanoemulsifying drug delivery for enhanced solubility and dissolution

A solid self-nanoemulsifying drug-delivery system (solid SNEDDS) has been explored to improve the solubility and dissolution profile of glipizide. SNEDDS preconcentrate was systematically optimized using a circumscribed central composite design by varying Captex 355 (Oil), Solutol HS15 (Surfactant) and Imwitor 988 (Co-surfactant). The optimized SNEDDS preconcentrate consisted of Captex 355 (30% w/w), Solutol HS15 (45% w/w) and Imwitor 988 (25% w/w). The saturation solubility (SS) of glipizide in optimized SNEDDS preconcentrate was found to be 45.12 ± 1.36 mg/ml, indicating an improvement (1367 times) of glipizide solubility as compared to its aqueous solubility (0.033 ± 0.0021 mg/ml). At 90% SS, glipizide was loaded to the optimized SNEDDS. In-vitro dilution of liquid SNEDDS resulted in a nanoemulsion with a mean droplet size of 29.4 nm. TEM studies of diluted liquid SNEDDS confirmed the uniform shape and size of the globules. The liquid SNEDDS was adsorbed onto calcium carbonate and talc to form solid SNEDDS. PXRD, DSC, and SEM results indicated that, the presence of glipizide as an amorphous and as a molecular dispersion state within solid SNEDDS. Glipizide dissolution improved significantly (p < 0.001) from the solid SNEDDS (∼100% in 15 min) as compared to the pure drug (18.37%) and commercial product (65.82) respectively.Abbreviations: solid SNEDDS, solid self-nanoemulsifying drug delivery system; SS, saturation solubility; DR_15min, percentage drug release in 15 minutes; LCT, long chain triglycerides; MCT, medium chain triglycerides     

Retarded dissolution of ibuprofen in gelatin microcapsule by cross-linking with glutaradehyde

Ibuprofen-loaded gelatin microcapsule, a solid form of microcapsules simultaneously containing ethanol and ibuprofen in water-soluble gelatin shell was previously reported to improve the dissolution of drug. In this study, to retard the initial high dissolution of ibuprofen from gelatin microcapsule, the ibuprofen-loaded cross-linked gelatin microcapsule was prepared by treating an ibuprofen-loaded gelatin microcapsule with glutaraldehyde and its dissolution was evaluated compared to ibuprofen powder and gelatin microcapsule. The ibuprofen-loaded cross-linked microcapsule treated with glutaraldehyde for 10 and 60 sec gave significantly higher dissolution rates than did ibuprofen powder. Furthermore, the dissolution rate of ibuprofen from the cross-linked microcapsule treated for 10 sec was similar to that from gelatin microcapsule. However, the dissolution rate of ibuprofen from the cross-linked microcapsule treated for 60 sec decreased significantly compared to gelatin microcapsule, suggesting that the treatment of gelatin microcapsule with glutaraldehyde for 60 sec could cross-link the gelatin microcapsule. Furthermore, the cross-linking of gelatin microcapsule markedly retarded the release rate of ibuprofen in pH 1.2 simulated gastric fluid compared to gelatin microcapsule. However, the cross-linking of gelatin microcapsule with glutaraldehyde hardly changed the size of gelatin microcapsules, ethanol and ibuprofen contents encapsulated in gelatin microcapsule. Thus, the ibuprofen-loaded cross-linked gelatin microcapsule could retard the initial high dissolution of poorly water-soluble ibuprofen.     

几种适合于眼药中使用的非离子表面活性剂对薄荷脑增溶能力的比较

目的研究三种适合于在眼用剂型中使用的非离子表面活性剂在水中对薄荷脑增溶的能力,找出以水为溶剂时适合增溶薄荷脑的非离子表面活性剂,以便在眼用剂型中使用薄荷脑。方法直接在已知浓度的表面活性剂中加入不同量增溶质至平衡(产生浑浊或沉淀),找出以水为溶剂时,对薄荷脑增溶能力最大的非离子表面活性剂。结果及结论几种非离子表面活性剂中,CremophorRH40对薄荷脑的增溶能力最强。     

Pharmaceutical particle technologies: An approach to improve drug solubility,dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.     

布洛芬颗粒的溶出度测定及评价

目的：创建一种测定布洛芬颗粒溶出度的方法。方法：采用桨法,pH值7.2磷酸盐缓冲液500ml为溶出介质,转速50r/min,采用高效液相法测定含量及溶出曲线,并用f2相似因子法进行比较分析。结果：布洛芬颗粒的进样量在0.04～0.6（mg/ml）（r=0.9999）的范围内线性关系良好,平均回收率99.7%,RSD=0.52%。结论：本法准确、可行性强,可作为布洛芬颗粒的质量标准中控制项目之一。     

Enhancement of solubility and dissolution rate of poorly water-soluble naproxen by complexation with 2-hydroxypropyl-β-cyclodextrin

The solubility and dissolution rate of naproxen (NPX) complexed with 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) using coprecipitation, evaporation, freeze-drying and kneading method were investigated. Solubility of NPX linearly increased (correlation coefficient, 0.995) as 2-HP-βCD concentration increased, resulting in A_L type phase solubility curve. Inclusion complexes prepared by four different methods were compared by differential scanning calorimetry (DSC). The NPX showed sharp endothermic peak around 156°C but inclusion complexes by evaporation, freeze-drying and kneading method showed very broad peak without distinct phase transition temperature. In contrast, inclusion complex prepared by coprecipitation method resulted in detectable peak around 156°C which is similar to NPX, suggesting incomplete formation of inclusion complex. Dissolution rate of inclusion complexes prepared by evaporation, freeze-drying and kneading except coprecipitation method was largely enhanced in the simulated gastric and intestinal fluid when compared to NPX powder and commercial NAXEN^® tablet. However, about 65% of NPX in gastric fluid still remained unreleased but most of NPX dissolved within 5 min in intestinal fluid. In case of inclusion complex prepared by coprecipitation method, formation of inclusion complex appeared to be incomplete, resulting in no marked enhancement of dissolution rate. From these findings, inclusion complexes of poorly water-soluble NPX with 2-HPβCD were useful to increase solubility and dissolution rate, resulting in enhancement of bioavailability and minimization of gastrointestinal toxicity of drug upon oral administration of inclusion complex.     

Enhancement of water solubility of indomethacin by complexation with protein hydrolysate

Complex formation between indomethacin (Indo) and casein hydrolysate was developed as a novel technique for enhancing the water solubility of Indo. The complex (Indo-Pep) was prepared by mixing an ethanol solution of Indo and an aqueous solution of peptide mixture, followed by lyophilization. The water solubility of Indo-Pep under weakly acidic and neutral conditions is much higher than that of Indo alone. The water solubility of Indo increased with increasing quantity of peptide. Characterization of Indo-Pep using scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction showed that Indo was incorporated in Indo-Pep in an amorphous state. The fluorescence quenching of Indo-Pep also suggested complexation between Indo and the peptides. An aqueous solution of Indo-Pep was fractioned by centrifugation followed by filtration using membrane filters and ultrafilters. Analysis of the fractions by dynamic light scattering and ultraviolet–visible spectroscopy showed that Indo-Pep consisted of small particles and was not a hydrocolloidal material.