Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity.

The purpose of this work is to develop a bio-relevant dissolution method for formulation screening in order to select an enhanced bioavailable formulation for a poorly water-soluble drug. The methods used included a modified rotating disk apparatus for measuring intrinsic dissolution rate of the new chemical entity (NCE) and the USP dissolution method II for evaluating dissolution profiles of the drug in three different dosage forms. The in vitro dissolution results were compared with the in vivo bioavailability for selecting a bio-relevant medium. The results showed that the solubility of the NCE was proportional to the concentration of sodium lauryl sulfate (SLS) in the media. The apparent intrinsic dissolution rate of the NCE was linear to the rotational speed of the disk, which indicated that the dissolution of the drug is a diffusion-controlled mechanism. The apparent intrinsic dissolution rate was also linear to the surfactant concentration in the media, which was interpreted using the Noyes and Whitney Empirical Theory. Three formulations were studied in three different SLS media using the bulk drug as a reference. The dissolution results were compared with the corresponding bioavailability results in dogs. In the 1% SLS--sink conditions--the drug release from all the formulations was complete and the dissolution results were discriminative for the difference in particle size of the drug in the formulations. However, the data showed poor IVIV correlation. In the 0.5% SLS medium--non-sink conditions--the dissolution results showed the same rank order among the tested formulations as the bioavailability. The best IVIV correlation was obtained from the dissolution in 0.25% SLS medium, an over-saturated condition. The conclusions are: a surfactant medium increases the apparent intrinsic dissolution rate of the NCE linearly due to an increase in solubility. A low concentration of surfactant in the medium (0.25%) is more bio-relevant than higher concentrations of surfactant in the media for the poorly water-soluble drug. Creating sink conditions (based on bulk drug solubilities) by using a high concentration of a surfactant in the dissolution medium may not be a proper approach in developing a bio-relevant dissolution method for a poorly water-soluble drug.     

Preparation,characterization, dissolution,and permeation of flibanserin − 2-HP-β-cyclodextrin inclusion complexes

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-β-CD–FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8).Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K_1:1) was 372.54 M⁻¹. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-β-CD–FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-β-CD–FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-β-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.     

Enhanced Drug Dissolution and Bulk Properties of Solid Dispersions Granulated with a Surface Adsorbent

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug–Gelucire 50/13–Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40°C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.     

Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent.

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug-Gelucire 50/13-Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40 degrees C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.     

Preparation,characterization, dissolution,and permeation of flibanserin − 2-HP-β-cyclodextrin inclusion complexes

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-β-CD–FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8).Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K_1:1) was 372.54 M⁻¹. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-β-CD–FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-β-CD–FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-β-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.     

Dynamic Dissolution Testing To Establish <Emphasis Type="BoldItalic">In Vitro</Emphasis>/<Emphasis Type="BoldItalic">In Vivo</Emphasis> Correlations for Montelukast Sodium,a Poorly Soluble Drug

Purpose  The objectives of the study was to develop a dissolution test method that can be used to predict the oral absorption of montelukast sodium, and to establish an in vitro/in vivo correlation (IVIVC) using computer simulations. Methods  Drug solubility was measured in different media. The dissolution behaviour of montelukast sodium 10 mg film coated tablets was studied using the flow-through cell dissolution method following a dynamic pH change protocol, as well as in the USP Apparatus 2. Computer simulations were performed using GastroPlus™. Biorelevant dissolution media (BDM) prepared using bile salts and lecithin in buffers was used as the dissolution media, as well as the USP simulated intestinal fluid (SIF) pH 6.8 and blank FaSSIF pH 6.5. Dissolution tests in the USP Apparatus 2 were performed under a constant pH condition, while the pH range used in the flow through cells was pH 2.0 to 7.5. The in vitro data were used as input functions into GastroPlus™ to simulate the in vivo profiles of the drug. Results  The solubility of montelukast sodium was low at low pH, but increased as the pH was increased. There was no significant difference in solubility in the pH range of 5.0 to 7.5 in blank buffers, but the drug solubility was higher in biorelevant media compared with the corresponding blank buffers at the same pH. Using the flow through cells, the dissolution rate was fast in simulated gastric fluid containing 0.1% SLS. The dissolution rate slowed down when the medium was changed to FaSSIF pH 6.5 and increased when the medium was changed to FaSSIF medium at pH 7.5. In the USP Apparatus 2, better dissolution was observed in FaSSIF compared with the USP buffers and blank FaSSIF with similar pH values. Dissolution was incomplete with less than 10% of the drug dissolved in the USP-SIF, and was practically non existent in blank FaSSIF pH 6.5. The in vitro results of the dynamic dissolution test were able to predict the clinical data from a bioavailability study best. Conclusions  Dynamic dissolution testing using the flow through cell seems to be a powerful tool to establish in vitro/in vivo correlations for poorly soluble drugs as input function into GastroPlus.     

Effect of hexacosanol on the characteristics of novel sustained-release allopurinol solid lipospheres (SLS): factorial design application and product evaluation

This investigation involved the evaluation of the effect of hexacosanol (HC, ceryl alcohol), a new hydrophobic wax modifier (WM) in comparison with conventional modifiers, on the development of sustained-release allopurinol (AP) solid lipospheres (SLS) intended for use in a suspension formulation and other oral dosage forms. Various beeswax (BW)/WM blends (composition ratio 1:1) were thus used to prepare SLS by a modified oil-in-water emulsion meltable disperse-phase (MDP) encapsulation method without using organic solvents and the influence of these blends on the drug encapsulation efficiency (EE), size distribution and the time for 50% of the drug to be released (t50%) was investigated. Results indicated that incorporation of HC in wall matrix of SLS provided the means to enhance the EE of AP and to modulate the rate of drug release into dissolution media (simulated gastric fluid (S.G.F.: pH 1.2) and simulated intestinal fluid (S.I.F.: pH 7.4). The effects of the process variables; HC concentration, dispersant (pluronic F-68: PF-68) concentration and drug:wax ratio were also studied on the properties of AP-loaded SLS by a 2(3) factorial design. The EE values were in the range of 80.8-92.67%. The only significant parameter affecting (P<0.01) the size and size distribution of the SLS formulations was the amount of the PF-68, whereas the factor with the biggest influence (P<0.05) on the drug EE was the initial loading of AP (in terms of the drug:wax ratio). The amount of HC blended with wax and the initial drug loading significantly (P<0.01) affected the t50% values of all of the formulations. The release of AP was more extended (t50% values (S.I.F.; pH 7.4)=9.91-25.36 h, depending on the drug:wax ratio) and surface morphology of SLS was improved with higher HC content (15%, w/w) formulations. The release patterns fitted the Baker-Lonsdale dissolution kinetics for spherical matrices. A significant decrease of plasma uric acid levels (P<0.05) and hepatic impairment in male rats was observed after oral administration of a SLS (mean size: 120 microm) suspensions of the optimum formulation, compared to suspensions of pure AP.     

羟基喜树碱纳米脂质载体的制备及体外释放

采用“熔融乳化-高压均质法”制备以PEG40硬脂酸酯、PEG100硬脂酸酯修饰的纳米脂质载体PEG40-NLC和PEG100-NLC，并考察释放装置、NLC中脂质材料用量及释放介质流速对体外释放的影响。结果表明，PEG40-NLC和PEG100-NLC在桨-反向动态透析法和流通池-动态透析法中的释放曲线相似，而在转篮-动态透析法中的释放曲线与前二种装置的释放曲线均有显著性差异。随着NLC脂质材料用量增大，释放过程中药物扩散作用增强。对流通池法，释放介质流速增大，药物的释放加快。     

Application of spray granulation for conversion of a nanosuspension into a dry powder form

The in vivo effect of particle agglomeration after drying of nanoparticles has not been extensively studied till date based on current literature review. The purpose of this research was to evaluate the feasibility of spray granulation as a processing method to convert a nanosuspension of a poorly water soluble drug into a solid dosage form and to evaluate the effect of the transformation into a solid powder on the in vivo exposure in beagle dogs. Formulation variables like the level of stabilizer in the nanosuspension formulation, granulation substrate and drug loading in the granulation were evaluated. The granules were characterized for moisture content, drug content, particle size, crystallinity and in vitro dissolution rate. Granulations with 10% drug loading showed dissolution profiles comparable to the nanosuspension, slightly slower dissolution profiles were observed at 20% drug loading. This can be attributed to an increase in the surface hydrophobicity at a higher drug loading and the formation of agglomerates that were harder to disintegrate, thereby compromising the dissolution rate. An in vivo PK study in beagle dogs showed an 8-fold increase and a 6-fold increase in the AUC(0-48) from the nanosuspension and dried nanosuspension formulations respectively compared to the coarse suspension. Also, the nanosuspension and dried nanosuspension formulations showed a 12-fold and 8-fold increase in the C(max) respectively compared to the coarse suspension. This shows the feasibility of using spray granulation as a processing method to convert a nanosuspension into a solid dosage form with improved in vivo exposure compared to the coarse suspension formulation.     

Combined Study of Biphasic and Zero-Order Release Formulations with Dissolution Tests and ATR–FTIR Spectroscopic Imaging

In this study of multi-layer tablets, the dissolution of biphasic and zero-order release formulations has been studied primarily using attenuated total reflection–Fourier transform infrared (ATR–FTIR) spectroscopic imaging as well as UV–Vis detection of dissolved drug in the effluent stream and USP dissolution testing. Bilayer tablets, containing the excipients microcrystalline cellulose (MCC) and glucose, were used for biphasic release with nicotinamide and buflomedil as model drugs. ATR–FTIR spectroscopic imaging showed the changing component distributions during dissolution. Further experiments studied monolithic and barrier-layered tablets containing hydroxypropyl methylcellulose, MCC and buflomedil dissolving in a USP I apparatus. These data were compared with UV–Vis dissolution profiles obtained online with the ATR flow-through cell. ATR–FTIR imaging data of the biphasic formulations demonstrated that the drug release was affected by excipient ratios and effects such as interference between tablet sections. Tablets placed in the ATR–FTIR flow-through cell exhibited zero-order UV–Vis dissolution profile data at high flow rates, similar to barrier-layered formulations studied using the USP I apparatus. ATR–FTIR spectroscopic imaging provided information regarding the dissolution mechanisms in multi-layer tablets which could assist formulation development. The ability to relate data from USP dissolution tests with that from the ATR–FTIR flow-through cell could help spectroscopic imaging complement dissolution methods used in the industry.     

Formulation development and evaluation of pioglitazone hydrochloride self-emulsifying drug delivery systems

As a widely prescribed anti diabetic drug, pioglitazone belongs to class IΙ under BCS and exhibits low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited, and its solubility and dissolutionrate need to be enhanced in order to increase its oral bioavailability. In the present study, we aimed to screen various oils, surfactantsand cosolvents. The highest solubility was observed in Labrafac, Tween-80 and propylene glycol. Then the feasibility of formulatingpioglitazone SEDDS was evaluated, and the effect of dilution on the dissolution rate and dissolution efficiency of pioglitazone was also analyzed. A comparative evaluation of pioglitazone from SEDDS was made in SGF and 1% SLS. Dissolution of pioglitazone from SEDDS was rapid and higher compared with pure drug. The rate and extent of release of pioglitazone hydrochloride from stable SEDDS (F1) were higher in 1% SLS compared with SGF. The FTIR spectra proved that there was on chemical interaction between excipients and drug. SEM studies confirmed that the size was small and spherical.     

The influence of surfactants and additives on drug release from a cationic eudragit coated multiparticulate diltiazem formulation

A cationic polymethacrylate coated multiparticulate diltiazem formulation exhibited sigmoidal drug release. Lag time prior to drug release was influenced by dissolution media, coat thickness, and by the nature of additives included in the formulation. Incorporation of up to 5% w/w sodium lauryl sulfate (SLS) in the coating membrane resulted in substantial increases in lag times in acidic and neutral media. The extent of drug release in acid was 100%, whereas in phosphate buffer, the extent of release was dependent on the level of SLS. Substituting SLS for various compounds was used to assess the functionality of the SLS molecule responsible for these behaviors. The ability to ion-pair with the polymer and the presence of a hydrophobic moiety were both important functionalities.     

The Influence of Surfactants and Additives on Drug Release from a Cationic Eudragit Coated Multiparticulate Diltiazem Formulation

A cationic polymethacrylate coated multiparticulate diltiazem formulation exhibited sigmoidal drug release. Lag time prior to drug release was influenced by dissolution media, coat thickness, and by the nature of additives included in the formulation. Incorporation of up to 5% w/w sodium lauryl sulfate (SLS) in the coating membrane resulted in substantial increases in lag times in acidic and neutral media. The extent of drug release in acid was 100%, whereas in phosphate buffer, the extent of release was dependent on the level of SLS. Substituting SLS for various compounds was used to assess the functionality of the SLS molecule responsible for these behaviors. The ability to ion-pair with the polymer and the presence of a hydrophobic moiety were both important functionalities.     

Probing the Mechanisms of Drug Release from Hydroxypropylmethyl Cellulose Matrices

The transient dynamic swelling and dissolution behavior during drug release from hydroxypropylmethyl cellulose (HPMC) matrices was investigated using fluorescein as a model drug. A new flow-through cell capable of providing a well-defined hydrodynamic condition and a non-destructive mode of operation was designed for this purpose to assess the associated moving front kinetics. The results obtained show a continuous increase in transient gel layer thickness irrespective of the polymer viscosity grade or drug loading. This is attributed to the faster rate of swelling solvent penetration than that of polymer dissolution under the present experimental condition. On the other hand, the observed shrinkage of sample diameter over a longer time period demonstrates that polymer dissolution does indeed occur in HPMC matrices. Further, both the rates of polymer swelling and dissolution as well as the corresponding rate of drug release increase with either higher levels of drug loading or lower viscosity grades of HPMC. For water-soluble drugs, the present results suggest that the effect of HPMC dissolution on drug release is insignificant and the release kinetics are mostly regulated by a swelling-controlled diffusional process, particularly for higher viscosity grades of HPMC.     

Once-a-day controlled-release dosage form of divalproex sodium II: development of a predictive in vitro drug release method

During formulation design of a once-daily controlled release matrix system of divalproex sodium, the in vitro dissolution test (USP II, 100 rpm, pH 6.8 buffer) was found to result in release rates that were slower than in vivo absorption. The test method also did not sufficiently discriminate formulations with different in vivo absorption rates. To develop an in vitro method that is directly correlated with in vivo absorption, statistically designed studies were carried out to investigate the effects of various in vitro testing variables on drug release using USP dissolution apparatuses. The variables studied included agitation intensity, apparatus, pH, surfactant and ionic strength of the dissolution medium. Experimental data were analyzed using ANOVA. In vitro/in vivo correlation was tested based on the hypothesis that the same linear regression equation holds for three formulations with different release rates. A mixed effects model was used in which the dependence among observations from the same subject was taken into account. Factorial studies indicated that higher pH, addition of sodium lauryl sulphate (SLS) to the dissolution medium, and higher agitation intensity increased the release rate from the matrix tablet. Use of SLS not only lead to increased release rates that are more comparable to in vivo absorption rates, but also improved differentiation among formulations with varying release rates. Furthermore, drug release was also affected by interactions among the variables studied. Statistical analysis indicated that a combination of higher SLS concentration and lower pH provided enhanced differentiation between release profiles of the fast and slow releasing formulations. Based on the above findings, a new set of testing conditions was identified and demonstrated to be predictive of in vivo drug absorption for various controlled release formulations of divalproex sodium. The new method uses USP Apparatus II operating at 100 rpm in 500 mL of 0.1 N HCl for 45 min followed by 900 mL of 0.05 M phosphate buffer containing 75 mM SLS, pH 5.5, 37 +/- 0.5 degrees C. In conclusion, adjusting dissolution testing conditions to match the behavior of the formulations in vitro with that in vivo is a useful approach in identifying a predictive method in development of in vitro-in vivo correlation.     

Dependence of area under the curve on proquazone particle size and in vitro dissolution rate

The in vitro dissolution and GI absorption of various sieve fractions of proquazone were studied (particle-size ranges of 45-74, 160-300, and 500-1000 micrometer). The dissolution rates of preparations F45, F160, and F500 were determined in vitro in a flow-through assembly in artificial gastric juice at 37 degrees. The time required for 63% of the maximum amount of soluble drug to pass into solution was characterized by the dissolution variable tau D. The in vitro dissolution rates for the preparations differed significantly in the order tau D, F45 less than tau D, F160 less than tau D, F500. After oral administration of 300 mg of the fractions to each of eight rhesus monkeys, the area under the plasma level-time curve (AUC) differed significantly in the order AUC F45 greater than AUC F160 greater than AUC F500. The dissolution rate increased with decreasing particle size. The AUC increased with decreasing particle size and with increasing dissolution rate. These results indicate that the dissolution rate probably determines the extent of absorption when dissolution is rate limiting.     

Effect of Peptide Loading and Surfactant Concentration on the Characteristics of Physically Crosslinked Hydrogel

The purpose of this study was to investigate the effect of varying drug load and concentration of a surfactant (sodium lauryl sulfate [SLS]) on the release characteristics of a model peptide (bovine serum albumin [BSA]), and study the net effects of the swelling properties of the hydrogel matrix [poly(vinyl alcohol) (PVA)]. The PVA hydrogel was prepared by a freeze-thaw process in the absence of a chemical crosslinking agent. The effect of protein loading on drug release was examined at three levels (0.65, 1.3, and 2%), whereas the effect of SLS was studied at four levels (0, 0.07, 0.13, and 0.26%). The baseline time for reaching equilibrium swelling was 48 hr for the hydrogel containing 0.65% BSA, and the equilibrium swelling time decreased significantly as the protein load was increased to 2%. The net effect of increased BSA concentrations resulted in faster BSA dissolution from the hydrogel matrix. The equilibrium-swelling ratio decreased from 21 to 10% when SLS was added to the PVA solution, which resulted in a reduction in the extent of equilibrium swelling; however, the time to reach equilibrium swelling was increased. The investigation provided a mechanistic basis toward the development of a hydrogel formulation by altering the concentration of two fundamental components, i.e., drug and surfactant, within the delivery system.     

Effect of peptide loading and surfactant concentration on the characteristics of physically crosslinked hydrogel

The purpose of this study was to investigate the effect of varying drug load and concentration of a surfactant (sodium lauryl sulfate [SLS]) on the release characteristics of a model peptide (bovine serum albumin [BSA]), and study the net effects of the swelling properties of the hydrogel matrix [poly(vinyl alcohol) (PVA)]. The PVA hydrogel was prepared by a freeze-thaw process in the absence of a chemical crosslinking agent. The effect of protein loading on drug release was examined at three levels (0.65, 1.3, and 2%), whereas the effect of SLS was studied at four levels (0, 0.07, 0.13, and 0.26%). The baseline time for reaching equilibrium swelling was 48 hr for the hydrogel containing 0.65% BSA, and the equilibrium swelling time decreased significantly as the protein load was increased to 2%. The net effect of increased BSA concentrations resulted in faster BSA dissolution from the hydrogel matrix. The equilibrium-swelling ratio decreased from 21 to 10% when SLS was added to the PVA solution, which resulted in a reduction in the extent of equilibrium swelling; however, the time to reach equilibrium swelling was increased. The investigation provided a mechanistic basis toward the development of a hydrogel formulation by altering the concentration of two fundamental components, i.e., drug and surfactant, within the delivery system.     

Bioavailability of cyclosporin A dispersed in sodium lauryl sulfate-dextrin based solid microspheres

The purpose of this work was to develop a solid dispersion system containing cyclosporin A (CsA) in order to improve the bioavailability of poorly water-soluble CsA. Solid dispersion systems that are spherical in shape (CsA-microspheres) were prepared with varying ratios of CsA/sodium lauryl sulfate/dextrin using a spray-drying technique. The effects of sodium lauryl sulfate (SLS) and dextrin on the dissolution of CsA dispersed in SLS-dextrin based solid microspheres were investigated. The bioavailability of CsA-microspheres was compared with CsA powder alone and commercial Sandimmun in dogs. SLS significantly enhanced the dissolution of CsA from microspheres, while dextrin did not affect this. The CsA-microspheres at the CsA/SLS/dextrin ratio of 1/3/1, which gave the highest dissolution rate of CsA among the formula treated, was selected as an optimal formula for oral delivery. This formula gave significantly higher blood levels, area under the drug concentration-time curve (AUC) and maximum blood concentration of drug (Cmax) of CsA in dogs compared with the CsA powder alone. The AUC, Cmax and time to reach maximum blood concentration (Tmax) of CsA with CsA-microspheres was not significantly different from those after oral administration of Sandimmun, suggesting the similar bioavailability to Sandimmun in dogs. Our study demonstrates that the CsA-microspheres prepared with SLS and dextrin, with improved bioavailability of CsA, would be useful to deliver a poorly water-soluble CsA and could be applicable to other poorly water-soluble drugs.     

紫杉醇多孔硅微球的制备及提高渗透性考察

目的：制备载有紫杉醇（paclitaxel ,PTX）的多孔硅微球（mesoporous silicon microparticle ,MSM ）,并考察MSM对PTX溶出速率以及在人结直肠腺癌细胞（Caco-2）和人结肠癌细胞（HT-29）共培养单层细胞模型中渗透性的影响。方法以“Top-down”的电化学阳极氧化法制备MSM ,用动态光散射法测定粒径,然后采用浸入法装载 PTX以制备紫杉醇多孔硅微球（PTX-MSM）;采用高效液相色谱法测定PTX-MSM的载药量,用透析法测定药物释放度,并用粉末X射线衍射对装载的PTX进行固态分析;考察MSM对PTX的体外释放度及透过Caco-2和 HT-29单层细胞模型能力的影响。结果制备的 MSM 的粒径为1.3～7.1μm ;载药量约为17．46％±1．19％,吸附在MSM的PTX多为无定形态;PTX载入MSM 后体外释放明显加快;MSM使得PTX透过Caco-2和 HT-29共培养单层细胞模型速度显著提高。结论 MSM作为药物载体,可显著提高难溶性药物的释放速率和吸收速度。