Physicochemical stability,pharmacokinetic, and biodistribution evaluation of paclitaxel solid dispersion prepared using supercritical antisolvent process

Aim: To investigate the physicochemical stability, pharmacokinetics (PK), and biodistribution of paclitaxel (PTX) from paclitaxel solid dispersion (PSD) prepared by supercritical antisolvent (SAS) process.

Methods: Physicochemical stability was performed in accelerated (40°C 70?±?5% RH) and stress (60°C) storage conditions for a period of 6 months and 4 weeks, respectively. PK and biodistribution studies were performed in rats following i.v. administration of PTX equivalent to 6 and 12?mg/kg formulations.

Results: Physical stability of PSD showed excellent stability with no recrystallization of the amorphous form. Chemical stability of PSD in terms of % PTX remaining was 98.2?±?0.6% at 6 months and 97.9?±?0.3% at 4 weeks of accelerated and stress conditions, respectively. The PK study showed a nonlinear increase in AUC with increasing dose, that is, 100% increase in dose (from 6 to 12?mg/kg) resulted in 405.90% increase in AUC. Unlike PK study, the organ distribution study of PTX from PSD showed linear relationship with dose escalation. The order of organ distribution of PTX from highest to lowest for both PSD and Taxol^® was liver>kidney>lung>brain.

Conclusions: This study demonstrated excellent physicochemical stability with insight information on the PK and biodistribution of PTX from PSD prepared by SAS process.     

绿原酸磷脂复合物固体分散体的体外溶出和药动学研究

为研究绿原酸磷脂复合物固体分散体(CA-PC-SD)的体外溶出以及体内药动学规律,采用HPLC法考察CA-PC-SD的体外溶出,大鼠灌胃后测定其血药浓度,并采用DAS 2.0软件分析计算药动学参数.结果显示:CA-PC-SD显著改善绿原酸磷脂复合物(CA-PC)的溶出效果,相较于原料药(CA)其相对生物利用度提高2.12倍.表明CA-PC-SD能显著改善CA-PC的体外溶出特性以及CA的口服生物利用率.     

壳聚糖-固态分散体载药微球的制备及性能研究

首先采用不同分子量的壳聚糖通过乳化-化学交联法制备了4种不同的壳聚糖载药微球。通过对微球的粒径、溶胀率、载药率、包封率等指标检测以及缓释性能的研究,发现分子量为240kDa的壳聚糖制备的载药微球缓释效果明显,载药率、包封率均较高,综合性能优于其它分子量壳聚糖制备的微球。利用该分子量壳聚糖包埋固态分散体制备了壳聚糖-固态分散体载药微球,改善了药物的溶解性并具有药物缓释作用。因此,壳聚糖-固态分散体载药微球是一种理想的药物缓释体系,可以用于包埋溶解性差,生物半衰期短,对胃肠刺激性强的药物。     

In vitro and in vivo studies on a novel solid dispersion of repaglinide using polyvinylpyrrolidone as the carrier

In order to improve the dissolution and absorption of the water insoluble drug repaglinide, a solid dispersion was developed by solvent method using polyvinylpyrrolidone K30 (PVP K30) as the hydrophilic carrier for the first time. Studies indicated that both solubility and the dissolution rate of repaglinide were significantly increased in the solid dispersion system compared with that of repaglinide raw material or physical mixtures. The repaglinide solid dispersions with PVP K30 solid state was characterized by polarizing microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). DSC and XRD studies indicated that repaglinide existed in an amorphous form in the solid dispersion. FT-IR analysis demonstrated the presence of intermolecular hydrogen bonding between repaglinide and PVP K30 in the solid dispersion. In the in situ gastrointestinal perfusion experiment, solid dispersion was shown to remarkably enhance the absorption of repaglinide in stomach and all segments of intestine. In vivo pharmacokinetic study in rats showed that immediate and complete release of repaglinide from the solid dispersion resulted in rapid absorption that significantly increased the bioavailability and the maximum plasma concentration over repaglinide raw material. These results demonstrated PVP K30 was an appropriate carrier for solid dispersion of repaglinide, with increased dissolution and oral absorption.     

Preparation,characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA–SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA–PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA–PEG6000 (1:3) SD and NA–suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA–PEG6000 (1:3) SD (C_max?=?0.645?±?0.262?µg/ml, AUC_0–t?=?0.471?±?0.084?µg/ml?h) were higher than that of NA–suspension (C_max?=?0.328?±?0.183?µg/ml, AUC_0–t =?0.361?±?0.093?µg/ml?h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.     

Preparation and characterization of Simvastatin solid dispersion using skimmed milk

Simvastatin has low aqueous solubility resulting in low oral bioavailability (5%) and thus presents a challenge in formulating a suitable dosage form. To improve the aqueous solubility, a solid dispersion formulation of Simvastatin was prepared by lyophilization utilizing skimmed milk as a carrier. Six different formulations were prepared with varying ratios of drug and carrier and the corresponding physical mixtures were also prepared. The improvement of amorphous state through solid dispersion was confirmed by differential scanning calorimetry and X-ray diffraction studies. The optimum drug-to-carrier ratio of 1:9 enhanced solubility nearly 30-fold as compared to pure drug. In-vitro drug release studies exhibited a cumulative release of 86.69% as compared to 25.19% for the pure drug. Additionally, scanning electron microscopy studies suggested the conversion of crystalline Simvastatin to an amorphous form. In a Triton-induced hyperlipidemia model, a 3-fold increase in the lipid lowering potential was obtained with the reformulated drug as compared to pure drug. These results suggest that solid dispersion of Simvastatin using skimmed milk as carrier is a promising approach for oral delivery of Simvastatin.     

Formulation and optimization of spray-dried amlodipine solid dispersion for enhanced oral absorption

Objective: To enhance the oral absorption of photosensitive amlodipine free base, which exhibits a slow dissolution rate and low permeability characteristics, an amorphous solid dispersion system was formulated and characterized.

Material and methods: The solid dispersion was prepared by dispersing the amlodipine free base in excess dextrin (1:10 by weight) using a spray-drying technique in the presence of a minimum amount (0.9% w/w) of SLS as an absorption enhancer. The dextrin-based solid dispersion of amlodipine (Amlo-SD) was evaluated in term of formulation, characterization and in vivo absorption study, as well as the spray-drying process was also optimized.

Results and discussion: The Amlo-SD particles were spherical with a smooth surface and an average particle size of 12.9 μm. Amlodipine was dispersed in an amorphous state and its content remained uniform in the Amlo-SD. The physicochemical stability of the Amlo-SD was maintained at room temperature for 6 months and the photostability was considerably improved. The dissolution of the Amlo-SD was much faster than that of amlodipine at pH 1.2 and 6.8. Amlo-SD produced significantly higher plasma concentrations of amlodipine in rats than amlodipine alone. Amlo-SD with and without SLS provided 2.8- and 2.0-fold increase in AUC, respectively: the difference seems to be attributed to a permeability enhancement effect by SLS.

Conclusion: The Amlo-SD with SLS system is a potential formulation option for amlodipine.     

Cryomilling-induced solid dispersion of poor glass forming/poorly water-soluble mefenamic acid with polyvinylpyrrolidone K12

The effect of mechanical impact on the polymorphic transformation of mefenamic acid (MFA) and the formation of a solid dispersion of mefenamic acid, a poor glass forming/poorly-water soluble compound, with polyvinylpyrrolidone (PVP) K12 was investigated. The implication of solid dispersion formation on solubility enhancement of MFA, prepared by cryomilling, was investigated. Solid state characterization was conducted using powder X-ray diffraction (PXRD) and Fourier-transform infrared (FTIR) spectroscopy combined with crystal structure analysis. Apparent solubility of the mixtures in pH 7.4 buffer was measured. A calculation to compare the powder patterns and FTIR spectra of solid dispersions with the corresponding physical mixtures was conducted. Solid state characterization showed that (1) MFA I transformed to MFA II when pure MFA I was cryogenically milled (CM); and (2) MFA forms a solid dispersion when MFA was cryogenically milled with PVP K12. FTIR spectral analysis showed that hydrogen bonding facilitated by mechanical impact played a major role in forming solid dispersions. The apparent solubility of MFA was significantly improved by making a solid dispersion with PVP K12 via cryomilling. This study highlights the importance of cryomilling with a good hydrogen bond forming excipient as a technique to prepare solid dispersion, especially when a compound shows a poor glass forming ability and therefore, is not easy to form amorphous forms by conventional method.     

Synchronized release of bufadienolides in a stable Lutrol F127 based solid dispersion prepared with spray congealing

Objective: The objective of this study was to design and prepare a novel solid dispersion using spray congealing to achieve fast and synchronous dissolution of bufalin, cinobufagin, and resibufogenin, three therapeutically complementary drugs.

Methods: The solid dispersion was characterized with dissolution, X-ray diffractometry, and fourier transform infrared spectroscopy after preparation and storage for four?weeks at different temperatures and relative humidity.

Results: It was found that all drugs were molecularly dispersed within matrix and had a significant enhancement (～4-fold higher) of dissolution rate. Furthermore, synchronized release of different drugs from a single carrier was achieved due to the highly molecular dispersibility and the excellent solubilization properties of F127. In addition, the solid dispersion was physically stable for at least four?weeks at controlled conditions. But for samples under stress conditions, the results showed that drug-rich phase was formed and storage temperature was the dominant factor in determining stability of the solid dispersion (SD).

Conclusions: These findings highlight the fitness of spray congealing to co-deliver multiple drugs, which open new perspectives for the development of more advanced combination of multiple therapeutic agents, presumably improving the bioavailability and therapeutic efficacy.     

Enhancing the bioavailability of magnolol in rabbits using melting solid dispersion with polyvinylpyrrolidone

Objective: Preparation of magnolol-loaded amorphous solid dispersion was investigated for improving the bioavailability.

Materials and methods: A solid dispersion of magnolol was prepared with polyvinylpyrrolidone K-30 (PVP) by melting method, and the physical properties were characterized by using differential scanning calorimetry, powder X-ray diffractometry, Fourier transformation-infrared spectroscopy and scanning electron microscope. In addition, dissolution test was also performed. Subsequently, the bioavailability of magnolol pure compound, its physical mixture and solid dispersion were compared in rabbits. The blood samples withdrawn via marginal ear vein at specific time points were assayed by HPLC method.

Results: Oral administration of the solid dispersion of magnolol with PVP significantly increased the systemic exposures of magnolol and magnolol sulfates/glucuronides by 80.1% and 142.8%, respectively, compared to those given with magnolol pure compound.

Conclusion: Magnolol-loaded amorphous solid dispersion with PVP has demonstrated enhanced bioavailability of magnolol in rabbits.     

Solubility and dissolution performances of spray-dried solid dispersion of Efavirenz in Soluplus

Abstract

Efavirenz (EFV), a first-line anti-HIV drug largely used as part of antiretroviral therapies, is practically insoluble in water and belongs to BCS class II (low solubility/high permeability). The aim of this study was to improve the solubility and dissolution performances of EFV by formulating an amorphous solid dispersion of the drug in polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus^®) using spray-drying technique. To this purpose, spray-dried dispersions of EFV in Soluplus^® at different mass ratios (1:1.25, 1:7, 1:10) were prepared and characterized using particle size measurements, SEM, XRD, DSC, FTIR and Raman microscopy mapping. Solubility and dissolution were determined in different media. Stability was studied at accelerated conditions (40?°C/75% RH) and ambient conditions for 12 months. DSC and XRD analyses confirmed the EFV amorphous state. FTIR spectroscopy analyses revealed possible drug–polymer molecular interaction. Solubility and dissolution rate of EFV was enhanced remarkably in the developed spray-dried solid dispersions, as a function of the polymer concentration. Spray-drying was concluded to be a proper technique to formulate a physically stable dispersion of amorphous EFV in Soluplus^®, when protected from moisture.     

Improved stability of solid dispersions of manidipine with polyethylene glycol 4000/copovidone blends: application of ternary phase diagram

Context: Manidipine (MDP) is generally used clinically as an antihypertensive agent; however, the bioavailability of orally administered MDP is limited due to their very low water solubility.

Objective: The objectives of this research were, therefore, to increase the solubility of MDP by the formation of ternary solid dispersions (tSD) with polyethylene glycol 4000 (PEG4000) and copovidone and to improve their stability.

Methods: Solid ternary phase diagram was constructed to find homogeneous solid dispersion region after melting and solidifying at low temperature with different quenching substances. The pulverized powder of solid dispersions was then determined, for their physicochemical properties, by differential scanning calorimetry, powder X-ray diffractometry, Fourier transform infrared (FTIR) spectroscopy and hot stage microscopy. The solubility and dissolution of MDP from the tSD were investigated. The physical stability of tSD was also determined under accelerated condition at 40?°C/75% relative humidity (RH) for 6 months.

Results and discussion: The results showed that MDP was molecularly dispersed in PEG4000 and copovidone when the tSD was created from homogeneous region of solid ternary phase diagram. FTIR results confirmed that strong hydrogen bonding was presented between MDP and copovidone, leading to a significant increase in the solubility and dissolution of MDP. After storage at accelerated condition (40?°C/75%RH) for 6 months, the tSD still showed a good appearance and high solubility.

Conclusion: The results of this study suggest that tSD prepared by melting has promising potential for oral administration and may be an efficacious approach for improving the therapeutic potential of MDP.     

On-line dissolution determination of Baicalin in solid dispersion based on near infrared spectroscopy and circulation dissolution system

Drug on-line circulation dissolution system with near infrared spectrophotometer for dissolution determination was reported in this paper and subsequently partial least squares (PLS) calibration model was established for concentration prediction of Baicalin in solid dispersion. When the main factor number in PLS calibration model was 6, the correlation coefficients of PLS calibration samples and prediction ones were all 0.9999 and the relative standard deviations were 0.69% and 1.10%, respectively, which showed good robustness and predictability. Combining drug circulation dissolution system with the PLS calibration model, dissolution of Baicalin in raw material drug and solid dispersion were obtained at different times. The results indicated that the dissolution property of Baicalin in solid dispersion (especially at the early time) had been significantly improved. The accumulated dissolution of Baicalin in the solid dispersion at 45 min reached nearly 40%, increasing by 15% compared with raw material drug (about 25%). The aforementioned PLS model associated with drug circulation dissolution system provided a simple, accurate and on-line support for dissolution determination of drug, especially at the early time of rapid dissolution.     

New metastable form of glibenclamide prepared by redispersion from ternary solid dispersions containing polyvinylpyrrolidone-K30 and sodium lauryl sulfate

Modification of polymorphic forms of poorly water-soluble drugs is one way to achieve the desirable properties. In this study, glibenclamide (GBM) particles with different polymorphic forms, including a new metastable form, were obtained from redispersion of ternary solid dispersion systems. The ternary solid dispersion systems, consisting of GBM, polyvinylpyrrolidone-K30 (PVP-K30) and sodium lauryl sulfate (SLS), were prepared by solvent evaporation method and subsequently redispersed in deionized water. The precipitated drug particles were then collected at a given time period. The drug particles with different polymorphic forms could be achieved depending on the polymer/surfactant ratio. Amorphous drug nanoparticles could be obtained by using a high polymer/surfactant ratio, whereas two different crystalline forms were obtained from the systems containing low polymer/surfactant ratios. Interestingly, a new metastable form IV of GBM with improved dissolution behavior could be obtained from the system of GBM:PVP-K30:SLS with the weight ratio of 2:2:4. This new polymorphic form IV of GBM was confirmed by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffractometry (PXRD) and solid state ¹³C nuclear magnetic resonance (NMR) spectroscopy. The molecular arrangement of the new polymorphic form IV of GBM was proposed. The GBM particles with polymorphic form IV also showed an improved dissolution behavior. In addition, it was found that the formation of the new polymorphic form IV of GBM by this process was reproducible.     

Controlled release of ziprasidone solid dispersion systems from osmotic pump tablets with enhanced bioavailability in the fasted state

Objective: The purpose of this work was to develop a controlled release of ziprasidone with no food effect by the osmotic release strategy.

Methods: The solution of ziprasidone and poloxamer188 (P188) with different weight ratios was spray-dried to form solid dispersion of ziprasidone (SD-ZIP). The SD-ZIP was characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (X-RD) and solubility testing. The SD-ZIP osmotic pump tablets were prepared by wet granulation method. The effect of formulation variables on the release characteristic was investigated. The SD-ZIP osmotic pump tablets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation Zeldox® as a control.

Results: The results of DSC and X-RD indicated that ziprasidone resides in P188 with no crystalline changes. Solubility studies demonstrated that the solubility of SD-ZIP was substantially improved compared to ziprasidone and physical mixtures of ziprasidone and P188. The optimized formulation and drug release profiles of SD-ZIP osmotic pump tablets in different medium were obtained which showed typical osmotically controlled release and could fitted to zero-order kinetics with good linear correlation. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolong actions and no food effect was achieved simultaneously in SD-ZIP osmotic pump tablet compared with Zeldox®.

Conclusion: The SD-ZIP osmotic pump tablet could be able to enhance the bioavailability in the fasted state and showed sustained release with prolonged actions.     

Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier: formulation,characterization, in vitro,and in vivo study

Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD₅₀). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability.     

Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits

Objective: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability.

Methods: Liquid SNEDDS (L-SNEDDS) composed of Capryol? 90 (oil), Cremophor^® RH40 (surfactant), and Transcutol^® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits.

Results: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in t_max, AUC_(0–12), and AUC_(0–∞) at p?<?.05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product.

Conclusions: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.     

Enhanced dissolution and bioavailability of grapefruit flavonoid Naringenin by solid dispersion utilizing fourth generation carrier

Context: Naringenin (NRG), the aglycone flavonoid present in grapefruits, possesses anti-inflammatory, anti-carcinogenic, anti-lipid peroxidation and hepato-protective effects. However, it is poorly soluble in water and exhibits slow dissolution after oral ingestion, thus restricting its therapeutic efficacy.

Objective: With the aim to enhance the dissolution rate and oral bioavailability of NRG, solid dispersion technique has been applied using Soluplus® as carrier.

Methods: Solid dispersions of NRG were prepared by solvent evaporation and kneading methods using various ratios (1:4, 3:7, 2:3 and 1:1) of NRG:Carrier. Characterization of the optimized formulations was performed using Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. The in vivo behavior of the optimized formulations was also investigated in Wistar Albino rats.

Results: NRG solid dispersion showed a significantly higher solubility and drug dissolution rate than pure NRG (p?Conclusion: Based on these results, it was concluded that solid dispersion technique markedly enhances the in vitro drug release and in vivo behavior of the grapefruit flavonoid NRG.     

HPAM/AlCit胶态分散体系成胶性能评价及其对岩石润湿性的影响

以部分水解聚丙烯酰胺、柠檬酸铝为主要材料合成了可用于油藏深部调驱的新型胶态分散体系(HACDS),评价了HPAM浓度、放置时间、HPAM/AlCit质量比对HACDS成胶性能的影响,并利用自吸吸入法研究了HACDS对岩石润湿性的影响.研究表明:随HPAM浓度的增加,HACDS的成胶时间缩短;随放置时间的增加,HACDS的粘度增大;HPAM/AlCit质量比对HACDS成胶时间有一定的影响;HACDS的注入可使岩石的润湿性向亲水方向转化;HACDS的注入量对相对润湿指数有一定的影响.分析认为HACDS在岩心中形成吸附膜是导致岩心润湿性改变的主要原因.