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.     

Application of scCO2 technology for preparing CoQ10 solid dispersion and SFC-MS/MS for analyzing in vivo bioavailability

Objective: In this study, solid dispersion (SD) for oral delivery of a poorly water-soluble drug, coenzyme Q10 was developed by supercritical fluid technology and characterized in vitro and in vivo.

Methods: Dissolution was used to optimize the formulations of CoQ10-SD. The physicochemical properties of SD were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The supercritical fluid chromatography–electrospray ionization tandem mass spectrometry (SFC–ESI-MS/MS) was used for the in vivo study.

Results: The results of DSC and PXRD indicated that the drug in SD was in amorphous state. In vitro drug release, the dissolution of coenzyme Q10 in solid dispersion improved to 78.8% compared with commercial tablets of 0.16%. The area under c–t curve (AUC_0–72h) and mean maximum concentrations (C_max) of CoQ10-SD were 2.43-fold and 3.0-fold, respectively higher than that of commercial tablets in rats, confirming improved bioavailability.

Conclusion: Supercritical fluid technology was successfully used for the preparation and analysis of CoQ10-SD for the first time and significantly improved the dissolution and bioavailability of coenzyme Q10.     

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.     

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20?min. Finally, the PK profile of SDG-T and a reference formulation Oraxol? (oral solution formulation used in Phase I clinical study) at a dose of 60?mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10?mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol? solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol? solution was 132.25% at a dose of 60?mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10–150?ng/mL for a period of 24?h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.     

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.     

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.     

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.     

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.     

Study of a novel disintegrable oleanolic acid-polyvinylpolypyrrolidone solid dispersion

Novel solid dispersions of oleanolic acid-polyvinylpolypyrrolidone (OLA-PVPP SDs) were designed and prepared to improve the apparent solubility of drug, as well as to improve the stability, fluidity and compressibility of SDs. Disintegrable OLA-PVPP SDs were then evaluated both in vitro and in vivo. DSC, XRD, IR and SEM analysis proved the formation of OLA-PVPP SD and its amorphous state. The results of fluidity study, moisture absorption test and stability test showed that OLA-PVPP SD with good fluidity and qualified stability was successfully obtained. Meanwhile excellent dissolution rate was achieved for in vitro studies; dissolution test showed that ～50–75% of OLA was dissolved from SDs within the first 10?min, which is about 10–15 times of free OLA. In vivo study indicated that the formation of solid dispersion could largely improve the absorption of OLA, resulting in a much shorter T_max (p?C_max (p?0→∞ of OLA-PVPP SDs (1:6) were 155.4?±?37.24?h·ng/mL compared to the 103.11?±?26.69?h·ng/mL and 94.92?±?13.05?h·ng/mL of OLA-PVPP physical mixture (1:6) and free OLA, respectively. These proved PVPP could be a promising carrier of solid dispersions and was industrially feasible alternative carrier in the manufacture of solid dispersions.     

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.     

The improved dissolution performance of a post processing treated spray-dried crystalline solid dispersion of poorly soluble drugs

Context: Solution-mediated transformation has been cited as one of the main problems that deteriorate dissolution performances of solid dispersion (SD). This is mainly attributed by the recrystallization tendency of poorly soluble drug. Eventually, it will lead to extensive agglomeration which is a key process in reducing the dissolution performance of SD and offsets the true benefit of SD system. Here, a post-processing treatment is suggested in order to reduce the recrystallization tendency and hence bring forth the dissolution advantage of SD system.

Objectives: The current study investigates the effect of a post processing treatment on dissolution performance of SD in comparison to their performances upon production.

Methods: Two poorly soluble drugs were spray dried into SD using polyvinyl alcohol (PVA) as hydrophilic carrier. The obtained samples were post processing treated by exposure to high humidity, i.e. 75% RH at room temperature. The physical properties and release rate of the SD system were characterized upon production and after the post-processing treatment.

Results and discussion: XRPD, Infrared and DSC results showed partial crystallinity of the fresh SD systems. Crystallinity of these products was further increased after the post-processing treatment at 75% RH. This may be attributed to the high moisture absorption of the SD system that promotes recrystallization process of the drug. However, dissolution efficiencies of the post-treated systems were higher and more consistent than the fresh SD. The unexpected dissolution trend was further supported by the results intrinsic dissolution and solubility studies.

Conclusions: An increase of crystallinity in a post humidity treated SD did not exert detrimental effect to their dissolution profiles. A more stabilized system with a preferable enhanced dissolution rate was obtained by exposing the SD to a post processing humidity treatment.     

The incorporation of low-substituted hydroxypropyl cellulose into solid dispersion systems

While the use of amorphous solid dispersions to improve aqueous solubility is well documented, little consideration has traditionally been given to the finished dosage form. The objective of this study was to evaluate the dissolution performance of amorphous solid dispersions containing a dispersed superdisintegrant with binding properties. KinetiSol® dispersing was used to thermally process hypromellose acetate succinate-based compositions containing the drug substance nifedipine (NIF) and a highly compressible grade of low-substituted hydroxypropyl cellulose (New Binder Disintegrants; NBD-grade). Solid-state analysis demonstrated that compositions were rendered amorphous during processing. Tablets containing intra-dispersion NBD were found to exhibit non-sink dissolution performance similar to milled intermediate, demonstrating excellent disintegration characteristics. Conversely, tablets without intra-dispersion NBD were found to release significantly less NIF during dissolution analysis due to particle agglomeration. It was determined that compressibility and particle wetting increased as the level of intra-dispersion NBD increased.     

Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies

Objective: A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug’s low solubility in water and to conduct proof-of-concept clinical studies.

Significance: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug’s suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride.

Methods: Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15–25?°C, +2–8?°C and ?20?°C.

Results: The ASD powder was composed of freeze dried elacridar hydrochloride–povidone K30–sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25?mg elacridar hydrochloride and were stable for at least 12 months at –20?°C.

Conclusions: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.     

Formulation optimization and the absorption mechanisms of nanoemulsion in improving baicalin oral exposure

Objective: The aim of this study was to optimize baicalin nanoemulsion, clarify the absorption mechanisms of nanoemulsion improving the exposure of baicalin, and assess the potential of employing nanoemulsion as nanosystem for insoluble drugs.

Significance: A novel nanoemulsion formulation was successfully prepared to enhance oral exposure of baicalin.

Methods: Pseudo-ternary phase diagrams were utilized to evaluate nanoemulsion area. Physicochemical properties of optimal nanoemulsion formulation were investigated. The exposure of baicalin from the nanoemulsion was compared with baicalin suspension. The in situ single-pass intestine perfusion (SPIP) method and chylomicron-blocked rat model were used to study the absorption mechanisms of nanoemulsion.

Results: Baicalin nanoemulsion was nearly spherical in shape with the average droplet size of 58.43?nm, and the zeta potential was –8.18?±?1.2?mV. The stability test showed that baicalin nanoemulsion was very stable. Pharmacokinetic study indicated that baicalin nanoemulsion showed 14.56-fold improvement in exposure in comparison to baicalin suspension. The results of SPIP and chylomicron flow blocking study showed that intestinal absorption and lymphatic transport process contributed to its systemic exposure.

Conclusions: Based on the results, optimal nanoemulsion might be promising nanosystems for oral delivery of baicalin to satisfy clinical requirements.     

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.     

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。     

Effects of solid dispersion and self-emulsifying formulations on the solubility,dissolution, permeability and pharmacokinetics of isorhamnetin,quercetin and kaempferol in total flavones of Hippophae rhamnoides L.

The aim of this study was to investigate the effects of solid dispersions (SD) and self-emulsifying (SE) formulations on the solubility and absorption properties of active components in total flavones of Hippophae rhamnoides L. (TFH). The solubility, dissolution rate, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in TFH SD/SE formulations and TFH were compared. The results showed that the solubility and dissolution rate of isorhamnetin, quercetin and kaempferol in SD/SE formulations were significantly enhanced compared to those in TFH, however, their intestinal permeability was comparable. The bioavailability of isorhamnetin, quercetin and kaempferol in rats remarkably increased after oral administration of TFH SD formulations compared to TFH, but there was no significant increase after oral administration of TFH SE formulations. The results of this study indicated the SD formulations on the improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH were much better than those of SE formulations. The improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH by SD formulations was probably ascribed to the enhancement of the solubility and dissolution of the three components, but was not relevant to the intestinal permeability. Therefore, as for herb extracts containing multiple components, especially for their major components with poor water solubility, solid dispersion formulations might have the better potential to enhance their bioavailability.     

In vitro and in vivo effects of morin on the intestinal absorption and pharmacokinetics of olmesartan medoxomil solid dispersions

Abstract

Purpose: In-situ evaluation to corroborate morin effects on the intestinal absorption and pharmacokinetic behavior of freeze-dried OLM-loaded solid dispersions with Caco-2 and in-vivo studies

Methods: Intestinal transport and absorption studies were examined by Caco-2 permeability, in-situ single pass perfusion and closed-loop models along with in-vivo pharmacokinetic studies to evaluate and confirm the effect of P-gp-mediated activity of morin. We evaluated the intestinal membrane damage in the presence of morin by measuring the release of protein and lactate dehydrogenase (LDH) followed by using qualitative and quantitative morphometric analysis to describe the surface characteristics of intestinal epithelium.

Results: Morin showed the highest P_eff value 13.8?±?0.34?×?10^?6?cm/s in jejunum than ileum (p?<?.01) at 100?µM with absorption enhancement of 1.31-fold together with enhanced (p?<?.01) secretory transport of 6.27?±?0.27?×?10?^?6?cm/s in Caco-2 monolayer cells. Our findings noticed 2.37 (in-situ); 2.39 (in-vivo) and 1.43 (in-situ); 1.36 (in-vivo) fold increase in AUC_0–t with elevated C_max and shortened T_max for freeze-dried solid dispersion in the presence of morin as compared to pure OLM and freeze-dried solid dispersions without morin, respectively.

Conclusions: Our study demonstrated that increased solubilization through freeze-dried OLM-loaded solid dispersion together with efflux inhibition improved intestinal permeability to one system that might lead to novel solubilization and efflux pump inhibition as a novel alternative potential to increase oral absorption and bioavailability of OLM.     

Preparation and evaluation of bicyclol microemulsions for enhanced oral bioavailability

Context: Bicyclol is a novel anti-hepatitis drug used for the treatment of chronic hepatitis B. Bicyclol is insoluble in water and poorly absorbed after oral administration. To date, formulation development studies to improve the in vitro dissolution profiles of bicyclol and the in vivo oral absorption characteristics have not been performed.

Objective: To overcome problems associated with the poor solubility and low oral bioavailability of bicyclol, a microemulsion system was prepared and evaluated in vitro and in vivo.

Methods: The solubility of bicyclol in various cosurfactants was determined. The optimized premicroemulsion concentrate consisted of transcutol, Tween 20, Cremophor RH 40, propylene glycol monocaprylate and bicyclol (ratio, 50:150:100:150:3). The in vitro solubility and dissolution profiles were determined, and the in vivo oral absorption pharmacokinetics were evaluated in rats (dose, equivalent to 25?mg/kg of bicyclol) in comparison with bicyclol suspended in 0.5% calcium-carboxymethylcellulose (Ca-CMC).

Results and conclusion: Of various cosurfactants tested, transcutol provided the most significantly increased solubility of bicyclol (>20?mg/ml). Bicyclol was rapidly dissolved from the premicroemulsion concentrate (approximately 80% within 10?min). Consistent with the improved in vitro profiles, the oral absorption of bicyclol was significantly increased for the premicroemulsion concentrate, i.e. AUC and C_max were increased by 7.7- and 7.2-fold, respectively, over control values. These findings demonstrate that the microemulsion may be a useful drug delivery system to improve the oral bioavailability of bicyclol.