尼索地平纳米混悬液的制备及其体外溶出度

目的制备、优化尼索地平纳米混悬液,检测研磨介质残留,评价尼索地平纳米混悬液的体外溶出度。方法采用介质研磨法制备尼索地平纳米混悬液,以粒径为指标筛选、优化处方,利用电感耦合等离子体质谱仪测定研磨介质的残留,采用浆法评价尼索地平纳米混悬液的体外溶出。结果最优处方为尼索地平与PVP-K30质量比4∶1,其平均粒径为(445.5±2.8)nm,zeta电位为(0.294±1.00)m V,20 min时纳米混悬液累积溶出(87.0±4.5)%,在4℃和20℃条件下,该纳米混悬液30 d内物理稳定性良好。结论采用介质研磨法制备的纳米混悬液可以提高尼索地平的体外溶出度。     

Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension

The purpose of this article was to compare the in vitro and in vivo profiles of itraconazole (ITZ) extrudates and nanosuspension separately prepared by two different methods. And it was proved truly to form nanocrystalline and amorphous ITZ characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrum (FTIR), transmission electron microscope (TEM), and scanning electron microscope (SEM). The release of ITZ/Soluplus solid dispersions with amorphous ITZ was almost complete while only 40% release was obtained with ITZ nanocrystals. The amorphous state need not to cross over the crystal lattice energy upon dissolution while the crystalline need to overcome it. In the in vivo assay, the AUC(0–t) and C_max of ITZ/Soluplus were 6.9- and 11.6-time higher than those of pure ITZ. The formulation of the extrudate had an AUC(0–t) and C_max similar to those of ITZ and also OH-ITZ compared with the commercial capsule (Sporanox®). The relative bioavailability values with their 95% confidence limit were calculated to be 98.3% (92.5–104.1%) and 101.3% (97.9–104.1%), respectively. The results of this study showed increased dissolution and bioavailability of the solid dispersion of Soluplus-based carrier loading ITZ prepared by HME compared with the ITZ nanosuspension prepared by wet milling.     

Mixing-tank model for predicting dissolution rate control or oral absorption

A mixing-tank model is used to simulate GI absorption of nonionized drugs. The model is useful for predicting circumstances under which dissolution rate dominates membrane transport and transit rate, thus limiting the extent of absorption. The model is developed from mass balance considerations in which the nonsink dissolution term is a function of the remaining surface area and the concentration gradient across the boundary layer. Other dissolution parameters include initial particle radius, dose, diffusivity, density, and boundary-layer thickness. Readily calculable estimators for the general solution of the model are derived and their ranges of usefulness are discussed. Drug examples chosen for simulation are griseofulvin and digoxin. The model correctly predicts bioavailability as a function of particle size for both of these poorly soluble drugs.     

Benoxaprofen, a new anti-inflammatory agent: particle-size effect on dissolution rate and oral absorption in humans.

The particle-size effect of benoxaprofen, a new nonsteroidal anti-inflammatory agent, on the in vitro dissolution rate and oral absorption in humans was evaluated. Ten normal subjects participated in a randomized crossover-designed absorption study with two sieved particle-size formulations: one with crystals larger than 60 mesh (mean equivalent spherical diameter = 640 micron) and the other with crystals smaller than 100 mesh (mean equivalent spherical diameter = 67 micron). Plasma drug concentrations and urinary drug excretion were used to determine the relative absorption of the two formulations. The standard USP procedure was used for the dissolution study. Particle size had a dramatic effect on both the in vitro drug dissolution and its oral absorption in humans. In vitro, the smaller crystals dissolved more rapidly and more efficiently than the larger crystals. In vivo, the smaller crystals produced higher plasma concentrations, more rapid peak concentration attainment, and more drug excreted in the urine.     

伐昔洛韦缓释片体外释放速率与人体内吸收速率的相关性

目的:研究伐昔洛韦缓释片体外释放速率与人体内吸收速率的相关性。方法:以水为释放介质,测定伐昔洛韦缓释片的体外释放速率;采用Wagner-Nelson法计算单剂量口服缓释片后体内吸收分数,考察吸收相体内吸收与体外释放的相关性。结果:伐昔洛韦缓释片体内吸收分数(f_a)与体外释放速率(f_r)的关系为:f_a=2.11f_r -20.12,r=0.994 0(n=5)。结论:伐昔洛韦缓释片人体内外相关性良好(P<0.001)。     

In vitro dissolution and in vivo oral absorption of methylphenidate from a bimodal release formulation in healthy volunteers

PURPOSE: The objective of this study was to evaluate the in vitro dissolution and in vivo absorption of D,L-threo-methylphenidate (MPH) from a novel bimodal release formulation (Ritalin LA capsule) compared with an immediate-release formulation (Ritalin IR tablet) in healthy volunteers. METHODS: The bimodal release formulation contains 50% of the dose in the immediate-release (IR) beads and 50% in polymethacrylate-coated, delayed-release (DR) beads. To better understand the impact of dissolution from the DR beads on oral absorption of MPH, three Ritalin LA formulations with different dissolution profiles for the DR beads (referred to as slow-, medium and fast-release formulations) were prepared, and tested together with the immediate-release formulation in 18 healthy male and female volunteers after a single oral dose under fasted conditions. The rate and extent of oral absorption of MPH were evaluated based on the overall Cmax, tmax and AUC values, as well as the Cmax, tmax and AUC values for each individual peak of the bimodal plasma concentration-time profile. The in vivo absorption-time profile was also examined by deconvolution. RESULTS: All three Ritalin LA formulations demonstrated similar bimodal plasma concentration-time profiles with two peak concentrations observed at approximately 2 and approximately 6 h post dose, mimicking that of Ritalin IR tablets given 4 h apart. Deconvolution results showed that the absorption of MPH was biphasic, with a rapid absorption phase between 0 to approximately 2 h, and a somewhat slower second absorption between approximately 3-6 h, consistent with the in vitro bimodal release characteristics of Ritalin LA formulation. The three Ritalin LA formulations were bioequivalent to one another based on the overall Cmax and AUC values and the corresponding values describing the first and second peaks, although their in vitro dissolution profiles for the DR beads were different. Compared with Ritalin IR, the Ritalin LA formulation demonstrated a similar rate of absorption for the first peak, a lower second Cmax and a higher trough concentration between peaks, as well as similar overall plasma AUC. CONCLUSIONS: Following a single oral drug administration, Ritalin LA demonstrated a two-peak plasma concentration-time profile, similar to that of the IR formulation given 4 h apart, but with less fluctuation in the plasma concentration-time profile. The in vivo biphasic absorption of MPH appeared to be well correlated with the bimodal dissolution characteristics of this new Ritalin LA formulation, and some changes in the dissolution profiles for the DR beads appeared not to affect the overall bioavailability of MPH in humans.     

Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats

Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (T_g) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated.FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a T_g of 101.2 °C, whereas the T_g for the amorphous free acid was found to be 61.8 °C. The amorphous free acid was physically stable for 4 days at 22 °C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 °C and 75% RH both forms converted to crystalline forms after 2 days.The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively.The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster T_max compared to the solution and amorphous and crystalline free acid. C_max for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster T_max compared to the amorphous and crystalline free acid.     

非洛地平缓释片体外释药因素分析及释放度比较

目的 考察影响非洛地平缓释片体外释药的因素,比较自制与市售进口非洛地平缓释片的释放度.方法 通过相似因子法(f2)考察溶出装置,转速,释放介质的pH值及介质中表面活性剂浓度对药物释放速率的影响,并全面比较市售片和自制片在不同释放介质中的释放度.结果 药物的释放速率受转速和介质中表面活性剂的浓度影响较大,溶出装置和介质的...     

Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles

The slow dissolution rate exhibited by poorly water-soluble drugs is a major challenge in the drug development process. Following oral administration, drugs with slow dissolution rates generally show erratic and incomplete absorption which may lead to therapeutic failure. The aim of this study was to improve the dissolution rate and subsequently the oral absorption and bioavailability of a model poorly water-soluble drug. Microparticles containing the model drug (griseofulvin) were produced by spray drying the drug in the absence/presence of a hydrophilic surfactant. Poloxamer 407 was chosen as the hydrophilic surfactant to improve the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried griseofulvin/Poloxamer 407 particles were significantly increased compared to the control. Although spray drying griseofulvin alone increased the drug's in vitro dissolution rate, no significant improvement was seen in the absolute oral bioavailability when compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.     

Itraconazole nanosuspension for oral delivery: Formulation, characterization and in vitro comparison with marketed formulation

Background and the purpose of the study

Itraconazole is a poorly water soluble drug which results in its insufficient bioavailability. The purpose of the present study was to formulate Itraconazole in a nanosuspension to increase the aqueous solubility and to improve its formulation related parameters, dissolution and hence oral bioavailability.

Methods

Itraconazole nanosuspension was prepared by pearl milling technique using zirconium oxide beads as a milling media, Poloxamer 407 as a stabilizer and glycerol as a wetting agent. Effects of various process parameters like, stirring time and the ratio of the beads were optimized by keeping drug:surfactant:milling media (1:3.0:50) as a constant initially and then optimized process parameters were used to optimize formulation parameters by 32 factorial designs. The optimized nanosuspension was lyophilized using mannitol (1:1 ratio) as a cryoprotectant. Nanosuspension was characterized by particle size and size distribution, drug content, scanning electron microscopy, differential scanning colorimetry and X-ray diffraction techniques.

Results

Optimized nanosuspension showed spherical shape with surface oriented surfactant molecules and a mean particle diameter of 294 nm. There was no significant change in crystalline nature after formulation and it was found to be chemically stable with high drug content.

Conclusion

The in vitro dissolution profile of the optimized formulation compared to the pure drug and marketed formulation (Canditral Capsule) by using 0.1N Hydrochloric acid as release medium showed higher drug release.     

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.     

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.     

The use of an in vitro dissolution and absorption system to evaluate oral absorption of two weak bases in pH-independent controlled-release formulations.

The aim of this study was to compare the oral absorption of two weak bases including their pH-independent controlled-release preparations using an in vitro evaluation system. This system is able to simulate dissolution of drugs, pH change and permeation of drugs through the epithelial cell membrane in the gastrointestinal tract. Albendazole-polymers solid dispersion and pH-independent sustained-release granules of dipyridamole were prepared by using a solvent method. Elution profiles and predicted absorption of these preparations in gastric pH conditions similar to those in healthy subjects and patients with achlorhydria were compared with those of a physical mixture and commercial tablets. When a physical mixture or commercial tablets were used, the elution profile and predicted absorption of both albendazole and dipyridamole were extremely pH-dependent. On the other hand, when a solid dispersion and granules were used, elution and predicted absorption were not affected by changes in pH of the flowing solution in a drug-dissolving vessel. These results are in agreement with the results of our previous in vivo study using gastric acidity-controlled rabbits. Our results suggest that this in vitro system is useful for the evaluation of oral absorption of pH-independent controlled-release preparations.     

Estimating in vitro glass fiber dissolution rate from composition

A method is presented for calculating the dissolution rate constant of a borosilicate glass fiber in the lung, as measured in vitro, from the oxide composition in weight percent. It is based upon expressing the logarithm of the dissolution rate as a linear function of the composition. It was found that the calculated dissolution rate constant agreed with the measured value within the variation of the measured data in a set of compositions in which the dissolution rate constant ranged over a factor of 100. The method was shown to provide a reasonable estimate of dissolution over a considerably wider range of composition than what was used to determine the parameters, such as a set of data in which the dissolution rate constant varied over a factor of 100,000. The dissolution rate constant may be used to estimate whether disease would ensue following animal inhalation or intraperitoneal studies.     

卡马西平片体外溶出度与体内吸收相关性

目的：考察卡马西平（ＣＢＺ）片溶出度与体内吸收的相关性。方法：应用ＺＲＳ－４溶出度仪测定卡马西平片的溶出度。４名男性健康志愿性ｐｏ单剂量２００ｍｇＣＢＺ用ＴＤｘ分析仪测定血药浓度，并按照Ｗａｇｎｅｒ－Ｎｅｌｓｏｎ公式计算药物吸收分数。结果：体外溶出度与体内药物吸收分数的相关系数ｒ＝０．９２６１，体外溶出度与体内药物吸收分数的相关系数ｒ＝０．９９７７。结论：ＣＢＺ片体外溶出度与体内吸收有较好的相关性     

Correlations between in vitro dissolution rate and bioavailability of alaproclate tablets

In two different absorption studies, quantitative correlations between the in vitro dissolution rate and the bioavailability have been shown after single administration of various tablet compositions of alaproclate hydrochloride to healthy subjects. Both statistical moment analysis and the use of empirical single value parameters were tested. For conventional tablets a linear relationship was obtained between mean dissolution time in vitro and in vivo. A similar relationship was obtained between the mean dissolution time in vitro and the mean residence time for controlled release tablets of the matrix type. It was also possible to establish an in vitro--in vivo correlation for these latter tablets by using the single point estimate of maximum plasma concentration as in vivo parameter. When comparing the mean dissolution time in vitro to the total area under the plasma drug concentration-time curve attained after different types of tablets, it is obvious that the extent of bioavailability of alaproclate will not fall below 80% of the value found for an aqueous solution until the mean dissolution time in vitro exceeds approximately 3 hr. Statistical moment analysis seems to have a broader applicability than the use of empirical point estimates, and it seems to be useful both for conventionally dissolving tablets and controlled release tablets.