Investigation on Correlation of Phase Behavior and Stability of Curcumin Self-nanoemulsion with Different Drug Loading After in Vitro Dispersion / 中国实验方剂学杂志

Objective:To investigate the relationship between phase behavior of curcumin （CUR） from self-nanoemulsion drug delivery system （SNEDDS） and stability of the formed nanoemulsion in artificial gastrointestinal fluid. Method:The growth rate of precipitation after dispersion of CUR-SNEDDS was expressed by the change tendency of CUR supersaturation-time curve. The effect of drug loading on crystal nucleation and growth was investigated by ultraviolet-visible spectrometry and polarized light microscope， respectively. X-ray powder diffraction （XRD） and differential scanning calorimetry （DSC） were used to analyze the precipitation forms of CUR-SNEDDS with different drug loading in artificial gastrointestinal fluid. At the same time， the effect of drug loading on the quality stability of nanoemulsion formed by CUR-SNEDDS in artificial gastrointestinal fluid was investigated. Result:In the artificial gastrointestinal fluid， with the increase of drug loading， the area under the supersaturation-time curve of CUR was increased （100% drug loading≈90% drug loading>75% drug loading）， the crystallization nucleation and growth rate were accelerated （100% drug loading>90% drug loading>75% drug loading）， the amorphous proportion in the precipitation composition decreased， the nanoemulsion droplets adhered and distributed unevenly， the particle size and dispersivity were increased. Conclusion:High drug loading promotes the nucleation and growth of crystals， and increases the proportion of crystal forms in the precipitation composition， which leads to the decrease in the stability of the formed nanoemulsion. Therefore， it is suggested that the drug loading of CUR-SNEDDS needs to be controlled below 90%.

Formulation optimization of andrographolide self-nanoemulsifying drug delivery system and effect of precipitation inhibitor on its phase behavior / 中草药

Objective: To investigate the effect of HPMC, PVP k30 and PEG 4000 on the phase behavior of andrographolide self-nanoemulsifying drug delivery system (AG-SNEDDS) dispersed in Fasted-state simulated intestinal fluid (FaSSIF). Methods: The preparation technology of andrographolide AG-SNEDDS was optimized by central composite design. The effect of three types of precipitation inhibitors (PVP-k30, HPMC, PEG 4000) on the supersaturation behavior of AG-SNEDDS dispersed in FaSSIF was investigated with the degree of supersaturation as an evaluation index. The precipitated phase was evaluated by polarized light microscopy (PLM). Results: The results showed that the best prescription of AG-SNEDDS was Capryol 90-Cremophor EL:Tween-20 (1:1)-Transcutol HP (12.9:40.5:46.6). The self-microemulsion was uniform, the drug loading was (6.93 ± 0.04) mg/g. The emulsification time was (22.33 ± 0.33) s, the average particle size was (14.25 ± 0.65) nm. HPMC and PEG 4000 can maintain the supersaturation of AG-SNEDDS after being dispersed in FaSSIF, and the effect was positively correlated with their concentration. As for PVP k30, it reduced the degree of supersaturation at a low concentration, but can maintain supersaturation at medium and high concentration. Using any of the three precipitation inhibitors can reduce the particle size of the precipitated particles. Conclusion: Precipitation inhibitors can maintain the supersaturation of AG when disperse AG-SNEDDS in FaSSIF. The ability to maintain supersaturation varies with the types and concentration of precipitation inhibitor.

Effect of precipitation inhibitors on pH-induced supersaturated phase behavior of dl-tetrahydropalmatine / 中草药

Objective: To investigate the effect of three types of precipitation inhibitors (PPI) HPMC K4M, HPMC AS MG and Soluplus on the pH-induced supersaturated phase behavior of dl-tetrahydropalmatine (dl-THP) at oral clinical doses. Methods: dl-THP pH solubility phase diagram and desaturation curve during pH-shift were drawn, and the solubility phase diagram was used to support dl-THP phase behavior. Area under the concentration-time curve and supersaturation ratio were used to analyze the effect of PPI on the phase behavior of dl-THP; Polarized light microscope and differential scanning calorimetry were used to analyze the precipitation properties. Results: Under the clinical dosage, the maximum supersaturation of dl-THP during the pH-shift was 3.93, and the supersaturation was lost over time; HPMC K4M, HPMC AS MG, and Soluplus could all maintain the supersaturation within 180 minutes during the pH-shift dissolution. HPMC K4M, HPMC AS MG, and Soluplus maintained supersaturation levels of 1.19, 1.89 and 1.36 respectively at a concentration of 5%, 1.30, 2.35 and 1.86 at a concentration of 20%, and 1.30, 2.60 and 2.07 at a concentration of 50%. Polarized light microscopy and differential scanning calorimetry results showed that crystalline precipitation occurred. Conclusion: All precipitation inhibitors can improve the pH-induced supersaturated phase behavior of tetrahydropalmatine, and this improvement behavior varies with the type and concentration of precipitation inhibitors. HPMC AS MG has the best effect.

Preparation and in vitro quality evaluation of curcumin supersaturated self-nanoemulsion / 中国中药杂志

In order to improve the supersaturation and maintenance time of drug dispersion in curcumin self-nanoemulsion(CUR-SNEDDS), precipitation inhibitors(PPIs) were introduced to prepare curcumin supersaturated self-emulsion(CUR-SSNEDDS). The composition of CUR-SNEDDS prescriptions was selected through the solubility test, the compatibility of oil phase and surfactant, the investigation of the emulsifying ability of the surfactant and the drawing of the pseudo-ternary phase diagram. Analytic hierarchy process was used in combination with central composite design-response surface method to optimize the prescription. The type and dosage of precipitation inhibitors(PPIs) were selected to maintain the supersaturated concentration and duration of CUR in artificial gastrointestinal fluids. At the same time, polarizing microscope was used to evaluate the crystallization inhibition effect and the quality and in vitro release behavior of CUR-SSNEDDS. The prepared CUR-SSNEDDS prescription was capryol 90-kolliphor RH40-transcutol HP-Soluplus(7.93∶66.71∶25.36∶5), with the drug loading of(65.12±1.25) mg·g~(-1). CUR-SSNEDDS was transparent yellow, and the nanoemulsion droplets were spherical with uniform distribution. The emulsification time was(21.02±0.13) s, the average particle size was(57.03±0.35) nm, the polydispersity index(PDI) was(0.23 ± 0.01), and the Zeta potential was(-18.10±1.30) mV. CUR-SSNEDDS significantly inhibited the generation and growth of crystals after in vitro dilution. The supersaturation could be maintained above 10 within 2 h, and the dissolution rate and degree of CUR in artificial gastrointestinal fluid were significantly increased. Soluplus could effectively maintain the supersaturated state of CUR and enhance CUR dissolution in vitro.

Crosslinked hydrogels-a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs

Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

Evaluation of Biochemical Risk Factors and Relative Supersaturation in Patients with Recurrent Nephrolithiasis / 대한신장학회잡지

PURPOSE: We examined a 24-h urine to evaluate the important biochemical risk factors and relative supersaturation in patients with recurrent nephrolithiasis. METHODS: A total of 17 patients with recurrent nephrolithiasis were analyzed for urinary biochernical stone risk factors and relative supersaturation. They were evaluated using a single 24-h urine specimen with StoneRisk(R) Diagnostic Profile on a random diet. Urinary stone risk factors are calcium, oxalate, citrate, magnesium, uric acid, pH, 24-h urine volume, sodium, phosphorous. Relative supersaturation with respect to stone-forming salts such as calcium oxalate, brushite, monosodium urate and uric acid were calculated. These factors were classified one or more etiologic categories in each patient. RESULTS: Of 17 patients 16 patients (94.2%) had abnormal urinary biochemistry that placed them into one or more of 15 etiologic categories. A single abnormality was documented in only one patient. One patient had no diagnostic abnormality. High urinary sodium encountered in 13 (76.5%) of the patients. Hypercalciuria and hyperuricosuria accounted for 9 (52.9%) and 7(41.1%) of the patients, respectively. The acquired problem of low urine volume (< 2L/d) was found in 8 (47.1%) of the patients and hypoci-traturia affected in 4 (23.5%). But hypomagnesiuria was not detected. The relative supersaturation with respect to monosodium urate was highest and increased in 70.6Yo of patients. CONCLUSION: The StoneRisk(R) Diagnostic Profile using a single 24-h urine specimen is a very useful tool not only in detecting metabolic, environmental and physicochemical abnormalities but also in providing specific therapeutic or preventive guidelines of patients with recurrent nephrolithiasis. In our study the most important biochemical risk factor of recurrent stone former is a high urinary sodium. Furthermore, there is a distinct evidence of high relative supersaturation with respect to monosodium urate. High sodium intake is probably the most important risk factor in patient who develop recurrent stone formation. Therefore, dietary sodium restriction would reduce probability of recurrent nephrolithiasis.

Interpretative Reporting System of the Analysis of Urine Stone Risk / 대한임상병리학회지

BACKGROUNDS: Metabolic and environmental evaluation can provide a powerful tool for management of patients with urolithiasis. We developed the interpretative reporting system of the analysis of urine stone risk and evaluated the clinical usefulness of this system. METHODS: The analysis of urine stone risk with thirty five cases were performed at Samsung Medical Center from January 1 to June 30, 1999. They were studied using a protocol based on 24 hour urine tests including volume, pH, sodium, potassium, chloride, calcium, phosphate, uric acid, magnesium, citrate, oxalate, ammonium and creatinine. Nitroprusside-cyanide spot test, routine urine analysis, urine culture, and several serum tests including electrolytes, calcium, phosphate, uric acid, creatinine, alkaline phosphatase, parathyroid hormone were also included. The results of physical and chemical analysis of urine stone were considered together. Relative supersaturations were estimated using software program EQUIL. We provided comprehensive interpretation about the specific causes and risks of stone formation in each patient. RESULTS: Hyperoxaluria (57.1%), hypercalciuria (57.1%), natriuresis (51.4%) and hypocitraturia (34.3%) were commonly found at the urine of patients with urolithiasis. The results of urine stone risk analysis based on relative supersaturation and related laboratory findings correlated well with the results of urine stone analysis. Mixed form of calcium oxalate stone was most commonly encounterd. Increased supersaturation with respect to calcium oxalate stone was noted in 23 cases (65.7%), which were frequently accompanied by hyperuricosuria or increased supersaturation with uric acid stone. The pH of urine was generally increased in struvite stones and decreased in uric acid stones. CONCLUSIONS: Analysis of urine composition and determination of urine stone risk were very useful for evaluation of patients with urolithiasis. And the interpretative reporting system of the analysis of urine stone risk can provide meaningful information in the treament and prevention of stone disease.

Preparation and evaluation of silymarin supersaturation self-emulsifying drug delivery system / 中草药

Objective To prepare the supersaturation self-emulsifying drug delivery system(S-SEDDS) containing silymarin and to evaluate its basic properties.Methods With the time of self-emulsifying,the consequence of color visual examination and particle size as parameters,the optimum formulations of silymarin SSEDDS were screened by solubility test,compatibility tests and pseudo ternary phase diagrams.The silymarin concentration was determined by HPLC.The in vitro dissolution characteristics of silymarin S-SEDDS were investigated with silymarin SEDDS as control.Results The optimum silymarin S-SEDDS was composed of medium chain triglycerides(MCT) 40%,Cremophor RH40(ethoxylated hydrogenatedcastor oil) 48%,Labrasol 12%.The time of self-emulsifying was less than 3 min,the average particle diameter was 49.6 nm,the adding amount of hydroxypropyl methylcellulose(HPMC) was 50 mg/g,and the average content of silymarin was 39.3 mg/g.The in vitro dissolution test of silymarin S-SEDDS showed that the presence of a small amount of cellulosic polymer effectively sustained a metastable supersaturated state by retarding precipitation kinetics.Conclusion The designed formulation of silymarin S-SEDDS is reasonable and provides a strong foundation for further development of new preparations.