Screening of Ketoprofen-Poloxamer and Ketoprofen-Eudragit solid dispersions for improved physicochemical characteristics and dissolution profile

The aim of the present study was to enhance the dissolution rate of an NSAID drug Ketoprofen by formulating it into solid dispersions with water soluble carrier Poloxamer 188 and Eudragit S 100. The solid dispersions of Ketoprofen with Poloxamer 188 were prepared at 1:1, 1:1.5 and 1:2 (Ketoprofen: Poloxamer 188) ratio by Solvent evaporation methods. The same concentration ratio was used for the preparation of solid dispersion with Eudragit S 100 by melting/fusion technique. Further, solid dispersions were investigated by solubility, ATR-FTIR, XRD, DSC, surface morphology, in-vitro dissolution and accelerated stability study. Results demonstrated that both Poloxamer 188 and Eudragit S 100 improve solubility of drugs by 8­10 folds. The result of ATR-FTIR study showed the slight shifting/broadening of principle peaks. In vitro dissolution studies showed that in the solid dispersion system containing Ketoprofen: Poloxamer 188 batch P2 (1:1.5) gives faster dissolution rate of Ketoprofen than the physical mixtures. The solid dispersion with Eudragit S 100, batch E1 (1:1) gives faster dissolution rate of Ketoprofen than the physical mixtures. In phase solubility study with Poloxamer 188 showed concentration dependent solubilization of drug but Eudragit S 100 produced opposite result. The effect of pH on solubility of Eudragit S 100 was carried out which showed solubility at pH 7.4. The dissolution profile of solid dispersion with Eudragit S 100 at pH 7.4 gives excellent result. The Accelerated stability of solid dispersions & its physical mixtures were studied at 400±2 °C/75 ± 5% RH for a period of 1 month. In these studies, Solid Dispersion batches produced an unstable formulation. The Ketoprofen solid dispersions with Poloxamer 188 and Eudragit S 100 could be introduced as a suitable form with improved solubility

Determination of ethylene glycol, diethylene glycol and triethylene glycol in poloxamer 188 by gas chromatography / 中国药科大学学报

@#The gas chromatography method was developed for the determination of ethylene glycol, diethylene glycol and triethylene glycol in poloxamer 188 to provide scientific basis for the quality control. The samples was separated on column VF-17ms(30 m×0. 53 mm, 1. 0 μm)with temperature programming, inlet temperature was 270 °C, detector temperature was 290 °C and the split ratio was 10 ∶1. The method showed great linearity over the range of 6-15 μg/mL(r≥0. 999). The injection precision(n=8)of the three residual impurities were 3. 3%, 3. 0%, 2. 3% and the average recoveries were 99. 05%(RSD=2. 9%, n=9), 102. 20%(RSD=4. 0%, n=9), 101. 91%(RSD=3. 1%, n=9), respectively. The analytical method is specific, accurate and sensitive, which is suitable for the determination of ethylene glycol, diethylene glycol and triethylene glycol in poloxamer 188, providing reference and guidance for the production and quality control of poloxamer 188.

In Vitro Evaluation of Poloxamer 188 Modified Polyethyleneimine as Gene Vectors / 医药导报

Objective To modify polyethyleneimine (PEI) by using Poloxamer 188 (P188) , and evaluate its related feature as carriers of genes in vitro. Methods PEI was modified through conjugating one hydroxyl group of P188 to the amino group of PEI by carbonate method. Structural analysis of synthesized polymer was performed by using 1H-NMR. The particle size and Zeta potential of synthesized polymer /DNA complexes were measured. The cytotoxicity of the complexes was evaluated using MTT method in MCF-7 cells, HeLa cells and HepG2 cells. The pGL3-lus was used as a reporter gene, and the transfection efficiency of complexesat HeLa cells was evalutated by measuring activity of luciferase. Results The result of 1H-NMR showed the purity of these synthesized polymers was high. The particle size of complexes were decreased with the increment of N /P ratios. The Zeta potential of complexes increased with the increment of N /P ratios. The cytotoxicity of the complexes increased with the increment of N /P ratios. The synthesized polymers showed lower cytotoxicity than unmodified PEI. The new synthesized polymers had maintained the high transfection efficiency at high N /P ratios. In particular, the optimal transfection efficiency of (P188) 1- PEI (N /P = 24) was significantly higher than that of PEI (N /P = 6) . Conclusion The P188 modifed PEI can serve as a effective non-viral gene carriers to transfect Hela cells.

Preparation of annonaceous acetogenins nanosuspensions using poloxamer 188 as a stabilizer and their in vitro and in vivo investigation / 药学学报

Annonaceous acetogenins (ACGs) are effective part extracted and separated from Annona squamosa seeds, they have good antitumor activity against a variety of tumor cells. However, the solubility of ACGs is poor with serious toxic and side effects, which greatly limits their application in clinical practice. In this study poloxamer 188 (P188) was selected as a drug carrier or a stabilizer to prepare ACGs nanosuspensions (ACGs-NSps) using anti-solvent precipitation. The nanosuspensions were examined via dynamic light scattering (DLS) method to examine size of the nanosuspensions. Transmission electron microscopy was used to observe their morphology. HPLC assay was used to measure their drug loading content and the in vitro drug release. The stability of ACGs-NSps at room temperature, in various physiological media and plasma, and the hemolytic test and lyophilization were all investigated. MTT assay was performed to study the cytotoxocity of ACGs-NSps against four tumor cell lines. 4T1 bearing tumor model was used to assess their in vivo antitumor therapeutic efficacy. The obtained ACGs-NSps were spherical, the average particle size was 169.4±1.25 nm, the polydispersity index (PDI) value was 0.130±0.020, the zeta potential was -19.8 mV and the drug loading content was 48.18%. ACGs-NSps were stable at room temperature for at least 15 days. They could be lyophilized in the presence of 0.5% glucose and 2.0% P188. ACGs-NSps showed sustained in vitro drug release, and the cumulative drug release reached 80.82% within 144 hours. ACGs-NSps maintained their particle size in various physiological media, and plasma with no hemolysis and then met demands of both oral and intravenous administration. In contrast to free ACGs, ACGs-NSps displayed significantly higher cytotoxicity against 4T1 (IC50, 0.892±0.124 μg·mL-1 vs 2.495±0.108 μg·mL-1, P 50, 0.747±0.051 μg·mL-1 vs 2.204±0.064 μg·mL-1, P 50, 2.265±0.081 μg·mL-1 vs 4.159±0.071 μg·mL-1, P 50, 0.473±0.024 μg·mL-1 vs 1.196±0.022 μg·mL-1, P in vivo study demonstrated that the daily oral administration of ACGs-NSps (3 mg·kg-1) resulted in higher tumor inhibition rate compared to ACGs/oil solution (67.23% vs 53.11%), comparable to the intravenous injection of 0.5 mg·kg-1 ACGs-NSps every other day (70.34%). Nanosuspensions effectively solved the problem of ACGs insolubility and difficulty in drug delivery. Using P188, a pharmaceutic adjuvant approved by FDA for iv injection, the resultant ACGs-NSps appear promising as an anti-tumor drug that can be used in clinic.

Preparation and characterization of cefuroxime axetil solid dispersions using poloxamer 188

The main objective of the present work was to enhance the solubility and dissolution rate of poorly water-soluble drug cefuroxime axetil (CA) by formulating it into solid dispersions (SDs) with water soluble carrier poloxamer 188. Different methods were employed to prepare the dispersion, such as: Solvent method (SM), Kneading method (KM), Melt evaporation method (MEM) and Physical mixture (PM) in different drug: carrier ratios 1:1, 1:2 and 1:3 (cefuroxime axetil: poloxamer 188). The physical mixture(s) and solid dispersion(s) were characterized for drug carrier interaction, drug content, solubility, dissolution rate, differential scanning calorimetry (DSC) and FT-IR study. The dissolution rate of the prepared solid dispersion systems was determined in phosphate buffer (pH 6.8) for 1 h. The solubility of drug from different systems was also determined in water. All SD formulations were found to have a higher dissolution rate comparatively to pure CA. The dissolution rate was enhanced in the following order SM > MEM > KM. The enhancement of dissolution rate may be caused by increase wettability, dispersibillity reduction in particle size or the formation of CA ß crystalline. The FT-IR study probability revealed that there was no chemical interaction between drug and poloxamer 188

Preparation and in Vitro Properties of Paeonol Thermo Sensitive Gel / 世界科学技术-中医药现代化

This study aimed at preparing paeonol thermosensitive gel and preliminary exploring its properties in vitro.Tube inversion method was adopted to investigate the effects of concentrations of poloxamer 407 and poloxamer 188 on gelation temperature.Then,viscosity of the gel was detected by rotary viscometer,and in vitro erosion and drug release characteristics of the gel by no film stripping method.As a result,the gelation temperature of poloxamer 407 decreased with the increase of its concentration,while gelation temperature of poloxamer 407 increased with the accelerating concentration of poloxamer 188.The cumulative drug release of paeonol thermo sensitive gel was up to 70％ in 320 rin.Gel dissolution and drug release were simultaneously performed without burst release phenomenon.It was concluded that the preparation process of paeonol thermo sensitive gel was simple and easy to use with the overt effect of sustained-release.

retention of poloxamer-basedhydrogels for vaginal application in mouse and rat models

The purpose of this study is to evaluate theretention capabilities of poloxamer-basedhydrogels for vaginal application with nonoxinol-9 as the model drug. Twohydrogel formulations, which contained 18% poloxamer 407 plus 1% poloxamer 188 (GEL1, relative hydrophobic) or 6% poloxamer 188 (GEL2, relative hydrophilic), were compared with respect to the rheological properties,hydrogel erosion and drug release. The vaginal retention capabilities of these hydrogel formulations were further determined in two small animal models, including drug quantitation of vaginal rinsing fluid in mice and isotope tracing withTc in rats. The two formulations exhibited similar phase transition temperatures ranging from 27 to 32 °C. Increasing the content of poloxamer 188 resulted in higher rheological moduli under body temperature, but slightly accelerated hydrogel erosion and drug release. When compared, GEL1 was eliminated significantly slower in rat vagina than GEL2, while the vaginal retention of these two hydrogel formulations behaved similarly in mice. In conclusion, increases in the hydrophilic content of formulations led to faster hydrogel erosion, drug release and intravaginal elimination. Rats appear to be a better animal model than mice to evaluate thehydrogel for vaginal application.

Study on Preparation and Dissolution Rate of Icaritin-Poloxamer 188 Solid Dispersion / 中国药房

OBJECTIVE:To prepare icaritin-poloxamer 188 solid dispersions in order to increase the dissolution rate of icaritin. METHODS:With poloxamer 188 as the carrier,melting method was used to prepare solid dispersions. By comparing the in vitro dissolution rates,the effects of the content of poloxamer 188(the ratios of icaritin to poloxamer 188 were 5∶1,3∶1,2∶1,1∶1,1∶3,1∶5,1∶7,1∶9,1∶11,1∶13,1∶15,1∶17,1∶19,1∶27 and 1∶31),melting temperature(60,70 and 80 ℃)and cooling tem-perature(-20,0 and 20 ℃)on the dissolution rate of icaritin in the solid dispersions were investigated,and the in vitro dissolu-tion rates of icaritin in its active pharmaceutical ingredient,physical mixture and solid dispersions were compared to confirm the for-mation of the solid dispersions. RESULTS:The dissolution rate of icaritin in the prepared solid dispersions increased to some extent as the proportion of the carrier increased. When the ratio of icaritin to the carrier was 1∶17-1∶27,the dissolution rate of icaritin at 120 min was above 90%. Where melting temperature and cooling temperature were respectively determined as 60 ℃ and 0 ℃ after comprehensive comparison,the dissolution rate of icaritin in the solid dispersions was 1.5 times as much as that in the physical mix-ture at 30 min. CONCLUSIONS:The prepared solid dispersion has a significantly higher dissolution rate of icaritin.

Preparation and Properties of Resveratrol-poloxamer 188-solid Dispersion / 中国药房

OBJECTIVE:To prepare Resveratrol-poloxamer 188-solid dispersion(RES-P188-SD)and study its dissolving char-acteristic in vitro and antibacterial activity. METHODS:With P188 as the carrier, solvent method was used to prepare RES-P188-SD. With the mass ratio of drug to carrier,melting temperature and mesh number as the observed factors,and solubility and yield of RES as the observed indexes,L9(34)orthogonal test was designed to optimize the preparation technology,and compre-hensive score of observed indexes were analyzed. The verification test was carried out. After RES-P188-SD was prepared by the op-timal technology,basket method was used to determine its dissolution rate and then its accumulative dissolution rate was calculat-ed,scanning electron microscopy to analyze phase characterization and cylinder-plate method to determine antibacterial activity. RE-SULTS:The optimal technology was as follows as the mass ratio of drug to carrier of 1∶10,melting temperature of 70 ℃ and mesh number of 80. For the sample prepared by the optimal technology,average solubility was 0.51 mg/ml (RSD=1.96%,n=3),average yield was 91%(RSD=0.64%,n=3),average 15 min accumulative dissolution rate was up to 83%(RSD=0.69%, n=3);the drug in amorphous form was homogenously distributed in the carrier;RES-P188-SD could inhibit Staphylococcus aure-us and Escherichia coli. CONCLUSIONS:The optimal technology is stable and feasible,by which RES-P188-SD has been pre-pared successfully,providing reference for increasing the solubility,dissolution rate and antibacterial activity of RES.

Preparation of luteolin-loaded mixed micelles and their anti-tumor activity / 中国药学杂志

OBJECTIVE: To prepare luteolin-loaded Solutol hsl5/Poloxamerl88 mixed micelles, evaluate their pharmaceutical property and study their anti-tumor activity. METHODS: The luteolin-loaded mixed micelles were prepared by thin-film hydration method. The particle size was measured by laser granulometry, and the morphology was observed under transmission electron microscope (TEM). The in vitro release behavior was determined by the dialysis method. Cell toxicity and uptake assays were employed to evaluate the anti-tumor activity. The targeting effect was studied by fluorescence labeling. RESULTS: The prepared luteolin-loaded mixed micelles showed spherical and regular shape with an average particle size of 66.43 nm and its entrapment efficiency was more than 80%. The 12 h-accumulated release ratio in vitro was up to 97.42%. The cytotoxicity of luteolin-loaded mixed micelles on human lung adenocarcinoma cell line A549 was significantly stronger than that of free luteolin and the uptake rate was improved. After injecting DiR-loaded mixed micelles into nude mouse, the drug begun to accumulate in tumors after 2 h and reached the highest concentration at 6 h which was significantly higher than that in other tissues. There remained strong drug distribution in the tumors after 12 h. CONCLUSION: The Solutol hs15/Poloxamer188 mixed micelles have small particle size and high entrapment efficiency and can enhance cell toxicity and uptake with certain passive targeting effect. It is a promising delivery system for anti-tumor drug.

Preparation, Characterization and Optimization of Poloxamer Solid Dispersions of a Poorly Water Soluble Drug Aprepitant.

Aim: The aim of the present investigation was to enhance the dissolution rate of a poorly water soluble drug, aprepitant, by preparation of solid dispersion with hydrophilic carrier, poloxamer 188, using solvent evaporation method. Place and Duration of Study: Department of Pharmaceutical Sciences and Department of Emerging Life Sciences, Guru Nanak Dev University, Amritsar, Punjab, between August 2012 and July 2013. Study Design: Designs of experiments were carried out with two input variables, drug to carrier ratio (X1) and amount of solvent (X2). A total of 7 experiments were performed (4 factorial runs and 3 centre points) as per full factorial design. Percent dissolution efficiency at 60 min (DE60) was selected as the response variable. Pareto chart along with half probability plot were studied for determining the most significant process variables, which were modelled using ANOVA. Methodology: Solid dispersions of aprepitant with poloxamer 188 were prepared using the solvent evaporation method and studied systematically using an optimization technique. A 22 full factorial design approach was used for the optimization of process variables on dissolution characteristics. The optimized solid dispersion was characterized by dissolution studies, Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry, X-ray powder Diffraction studies and Scanning Electron Microscopy. Results: The results of the experimental study confirm that the factors like drug to carrier ratio and solvent amount significantly influence the dependent variable DE60. A high level of drug to carrier ratio and low level of solvent amount were found to be suitable for maximum DE60. The use of factorial design approach helped in the optimization of the solid dispersion. The characterization of optimized solid dispersion (F5) demonstrated that the decrease in crystallinity of aprepitant and poloxamer 188 might be responsible for the enhanced dissolution rate. Analysis of dissolution data indicated the best fitting with firstorder model. Conclusion: Dissolution enhancement of aprepitant was successfully obtained by preparing its solid dispersion with poloxamer 188 using solid evaporation method.

Application of membrane sealing materials in repair of the spinal cord injury / 国际生物医学工程杂志

The integrity of the neuronal membrane is important for its specific physiological function.Spinal cord injury (SCI) can result in immediate disruption of neuronal membranes.Now,a novel treatment method for SCI is sealing the compromised membranes at the early stage of SCI.In this article,recent development of membrane repair agents in treating SCI is discussed,including polyethylene glycol(PEG),poloxamer 188(P188),chitosan and some nanomaterials.At the same time,problems remained in recent researches are reviewed and the prospect is discussed.

Preparation and characterization of polymeric micelles with chemical conjugation of doxorubicin (DOX-P) / 中国药学杂志

OBJECTIVE: Poloxamer-doxorubicin polymer (DOX-P) was prepared through covalent binding mode via an amide bond, DOX-P can be self-assemble to form nanoscale Characterization and anti-tumor activity of chemical conjugation of doxorubicin (DOX) in polymeric micelles were investigated. METHODS: Succinic anhydride activated Poloxamer188 was first synthesized and the primary amine group in doxorubicin was conjugated to the terminal carboxyl of Poloxamerl88 via a amide. The resulting polymeric micelles in aqueous solution were characterized by measurement of size, ℰ-potential, drug loading and critical micelle concentration. RESULTS: DOX-P micelles had superiorities over physically-loaded DOX micelles in loading efficiency, diameter and CMC value. From drug release experiment in vitro, DOX-P micelles reached a sustained release profile for DOX with 10 d while physically-loaded DOX only 2 d. CONCLUSION: With low CMC value, high loading efficiency, nanometer diameter and controlled release behaviour, DOX-P micelles might be developed as a new cancer targeted delivery system.

Formulation and evaluation of sustained release ondansetron poloxamer based solid suppositories.

The present investigation studies the effect of water swellable polymer hydroxylpropylmethyl cellulose (HPMC K4M, Methocel) on in vitro release of ondansetron from suppositories. Suppositories were prepared by using mixture of Poloxamer 407 and Poloxamer 188 hydrophilic bases. Suppositories containing 16 mg of ondansetron were prepared by fusion method. Weight variation, content uniformity, breaking (hardness), disintegration time, melting point and liquefaction time of the formulations were determined. In vitro release test was carried out according to USP XXII basket method. In vitro release data demonstrates ondansetron release from suppositories up to 12hrs and follows the zero order kinetics from poloxamer mixture based suppositories.

Preparation, dissolution and bioavailability of lycopene-Poloxamer 188 solid dispersion / 中国药科大学学报

Aim: To improve the solubility, dissolution and bioavailability of lycopene by preparing lycopene solid dispersion. Methods: Lycopene solid dispersion was prepared by the solvent method using Poloxamer 188 as car-rier. The physicochemical characteristics of the dispersion were determined by DSC, ultraviolet-visible spectra and the Dissolution Apparatus Ⅱ( Paddle). The oral bioavailability of lycopene was estimated in rat after oral dosing of lycopene solid dispersion or oil preparation. The plasma concentrations of lycopene in rats were determined by HPLC. The pharmacokinetic parameters were estimated by Kinetica software package. Results: In vitro dissolution of lycopene solid dispersion was greater than those of lycopene (raw material), and the physical mixture of lyco-pene and Poloxamer 188, partly due to the existing molecular state of lycopene in the dispersion. It was also found that the relative bioavailability of lycopene solid dispersion to lycopene oil preparation was (312. 2±96. 9) % . The optimal ratio of lycopene to carrier in the dispersion was about 1: 5. Conclusion: Lycopene-Poloxamer 188 solid dispersion could be prepared by the proposed simple, low-costly procedure resulting in improved bioavail-ability of lycopene, which is worthy of further development.

Preparation of Diclofenac Sodium Microemulsion with Poloxamer 188 as Coemulsifier / 中国药房

OBJECTIVE: To investigate the effect of poloxamer 188 as co-emulsifier on the pharmaceutical property of emulsion.METHODS: Diclofenac sodium was used as model drug and poloxamer 188 as co-emulsifier,the emulsion was prepared by high pressure homogen-colostrum pH adjusting method,with its entrapment efficiency,particle size,?-electric potential etc determined.RESULTS: The emulsion which was added with poloxamer 188 showed decreased entrapment efficiency and ?-electric potential but increased particle size as comapred with the one without poloxamer 188.CONCLUSION: The pharmaceutical property of emulsion wouldn't necessarily be enhanced by adding poloxamer 188 as co-emulsifier.

Preparation of Berberine Hydrochloride Poloxamer 188 Solid Dispersion / 中国药房

OBJECTIVE: To prepare solid dispersion of berberine hydrochloride poloxamer 188. METHODS: Melting method was adopted to prepare solid dispersion. The influences of the ratio of the drug to poloxamer 188, melting temperature and cooling temperature on the dissolution of drugs were investigated. The difference of the dissolution between solid dispersion and physical mixture were explored. RESULTS: When the ratio of the drug to poloxamer 188 rose to 1 ∶ 1, the amount of the carrier was enough to distribute the drug evenly. Melting temperature had little influence on the dissolution of drugs while cooling temperature had strong influence on the dissolution of drugs. The fastest dissolution rate was achieved emerged when the cooling tempreture was 0℃. As compared with physical mixture, the dissolution rate of berberine hydroclride was nearly increased one time. CONCLUSION: Berberine hydrocloride poloxamer 188 solid dispersion improves the in vitro dissolution rate of berberine hydrocloride.

Preparation and evaluation of silibinin solid dispersions in vitro / 第二军医大学学报

Objective: To prepare silibinin solid dispersion and measure its dissolution in vitro .Methods: Silibinin solid dispersions were obtained with urea, PVP and poloxamer188 as carriers by melting and coevaporation methods. Differential thermal analysis and powder X ray diffraction were used to determine the status of drug in carriers, and the dissolution characteristics in vitro were studied in simulated gastric juice. Results: In PVP silibinin solid dispersions drug was amorphous; in poloxamer188 silibinin solid dispersions, drug existed as fine crystal, while in urea silibinin solid dispersions most of silibinin existed as crystal, only a little as molecule. Poloxamer188 was the better carrier in improving the solution and dissolution rate of the drug. Conclusion: Poloxamer188 is a very useful carrier in improving the solubility and dissolution of silibinin. [