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To investigate the effect of supersaturation induced by micelle formation during dissolution on the bioavailability of itraconazole (ITZ)/Soluplus® solid dispersion.
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... beagle dog studies. It is also worth noting that the Tmax of ITZ tablets was earlier than that of Sporanox ® , mainly due to the rapid and complete dissolution of the tablets in the stomach and the supersaturation state maintained in the intestinal cavity. The permeability of biological membranes is a key deter- minant of drug pharmacokinetics. Fig. 8 shows how micelles can permeate the intestinal membrane. The transportation of a drug across the intestinal membrane is a complex transfer process involving several mechanisms: (1) transcellular per- meation through the epithelial cells that consists of passive transcellular and carrier-mediated permeation; (2) paracellular permeation ...Similar publications
Objectives
Antibiotics are the most commonly administered medications among pediatric patients. However most of the time, accurate dose administration to children becomes a problem due to the extremely bitter taste. Cefpodoxime proxetil (CP) and roxithromycin (ROX) are antibiotics often prescribed to the pediatric population and have a bitter taste...
Citations
... As Soluplus® dissolves in water, polymeric coils may form due to the contraction of the PVAc-co-PVCL lipophilic sidechains caused by a natural reaction to reduce the area of contact with water. Multiple Transmission Electronic Microscopy (TEM) studies have been carried out on Soluplus® molecules within water [15,[17][18][19]. The TEM images show that the Soluplus® molecules exist as spheroids beyond the CMC. ...
... W-Sol-1:5, which contains drug nan d50: 0.26 µm and ~20% amorphous ITZ, generated four times more supersa W-AR-Sol-1:5 (790% vs. 210%), demonstrating the importance of drug p HyNASDs for supersaturation generation. Additionally, crystalline ITZ pa barely solubilized by Sol [56,57]; thus, micellar solubilization of crystalline I not fully account for the observed high supersaturation. However, with Figure 8. Evolution of ITZ release from as-received ITZ and spray-dried powders prepared from ITZ suspension-based (W) feeds with 5:1, 1:3 and 1:5 ITZ:Sol mass ratios. ...
... W-Sol-1:5, which contains drug nanocrystals with d 50 : 0.26 µm and~20% amorphous ITZ, generated four times more supersaturation than W-AR-Sol-1:5 (790% vs. 210%), demonstrating the importance of drug particle size in Hy-NASDs for supersaturation generation. Additionally, crystalline ITZ particles can be barely solubilized by Sol [56,57]; thus, micellar solubilization of crystalline ITZ by Sol cannot fully account for the observed high supersaturation. However, without any prior processing, achieving 210% is also quite impressive, which might be due to the amorphization of AR-Sol-1:5 (~13%) during spray drying through ITZ-Sol interactions and solubilization of ITZ in Sol micelles. ...
We prepared hybrid nanocrystal–amorphous solid dispersions (HyNASDs) to examine their supersaturation capability in the release of a poorly soluble drug, itraconazole (ITZ), a slow crystallizer during dissolution. The HyNASD formulations included a polymer (HPC: hydroxypropyl cellulose, Sol: Soluplus, or VA64: Kollidon-VA64) and a surfactant (SDS: sodium dodecyl sulfate). Additionally, the dissolution performance of the HyNASDs and ASDs was compared. To this end, wet-milled aqueous nanosuspensions containing a 1:5 ITZ:polymer mass ratio with/without SDS as well as solutions of the same ratio without SDS in dichloromethane were spray-dried. XRPD–DSC confirmed that ASDs were formed upon spray drying the solution-based feeds, whereas HyNASDs (~5–30% amorphous) were formed with the nanosuspension-based feeds. SDS aided to stabilize the ITZ nanosuspensions and increase the amorphous content in the spray-dried powders. During dissolution, up to 850% and 790% relative supersaturation values were attained by HyNASDs with and without SDS, respectively. Due to the stronger molecular interaction between ITZ–Sol than ITZ–HPC/VA64 and micellar solubilization by Sol, Sol-based HyNASDs outperformed HPC/VA64-based HyNASDs. While the ASD formulations generated greater supersaturation values (≤1670%) than HyNASDs (≤790%), this extent of supersaturation from a largely nanocrystalline formulation (HyNASD) has not been achieved before. Overall, HyNASDs could boost drug release from nanoparticle-based formulations and may render them competitive to ASDs.
... SLP was previously utilized as a polymeric matrix with various molecules to prepare ASDs, where it demonstrated enhancement in the solubility due to its ability to develop in situ micelles of nano dimensions. [25][26][27][28][29] RTGP/ RTG-SLP thermodynamic miscibility was studied employing Flory Huggins theory and the solubility parameter approach. Further, the solid-state characterization of prepared ASDs was performed using DSC, FTIR PXRD techniques and evaluated the improvement in solubility. ...
... This increase in solubility over the physical mixtures could be attributed to the ability of Soluplus® to present the drug as an amorphous solid dispersion. Further, Soluplus® is also reported to provide and maintain super saturated condition of poorly soluble materials and this has been presented as a reason for increased bioavailability of a drug from solid dispersions in the polymer [22]. Since the 1: 4 ratio of drug: polymer resulted in the highest enhancement at the lower concentration of excipient, which was more than 130 times the native solubility of loratadine in SSF, this product was further characterized and then incorporated into the mouth-dissolving tablets. ...
Objective: The objective of the present work was to develop an orodispersible tablet of loratadine, an orally active, non-sedating anti-histaminic, belonging to BCS Class II. The drug was prepared as a solid dispersion using Soluplus® as carrier and formulated into an optimal tablet using Design of Experiments. Methods: Solid dispersions of loratadine with varying ratios of Soluplus® were prepared by solvent evaporation and subjected to solubility study in simulated salivary fluid. Selected composition was characterized by differential scanning calorimetry and X-ray diffraction and formulated into an orodispersible tablet by direct compression after addition of suitable excipients. DOE based on a full factorial design was used to optimize the product using a trial version of JMP software, so as to obtain a tablet with low friability, rapid disintegration and maximal drug dissolution within 5 min. The optimized tablet was prepared and evaluated for several attributes, including in vivo disintegration and palatability. Results: A solid dispersion prepared with a 1: 4 ratio of loratadine: Soluplus® was found to show a 130-fold increase in drug solubility in the simulated salivary fluid. X-ray diffraction revealed loratadine in amorphous form. The exercise using DOE for optimization of the orodispersible tablet formula served to balance the proportion of crospovidone as super disintegrant and PVP as dry binder and yielded a formulation with good mechanical strength, rapid in vitro disintegration (39 sec) and dissolution of 93.78% of the drug within 5 min. When evaluated in vivo, the tablets were found to disintegrate in about 60 secs and were reported to be palatable. Conclusion: A patient-friendly dosage form containing a highly soluble form of loratadine was prepared and could be of potential benefit in offering quick relief from allergic conditions.
... Te permeability of a drug is an important factor in determining its bioavailability. Although DTG is a BCS class II candidate with high permeability, ASDs are expected to improve dissolution by generating a colloidal system [45][46][47]. It is imperative to study the fux of prepared DSSD and DFSD due to micelle aggregation over a period, as the colloidal system is dynamic in terms of particle size variation. ...
Amorphous salt solid dispersion (ASSD) of Dolutegravir amorphous salt (DSSD) was generated using quench cooling and compared to its Dolutegravir free acid solid dispersion (DFSD) to improve the solubility and bioavailability. Soluplus (SLP) was used as a polymeric carrier in both solid dispersions. The prepared DSSD and DFSD, physical mixtures, and individual compounds were characterized by employing DSC, XRPD, and FTIR to assess the formation of the single homogenous amorphous phase and the existence of intermolecular interactions. Partial crystallinity was observed for DSSD, unlike DFSD, which is completely amorphous. No intermolecular interactions were observed between the Dolutegravir sodium (DS)/Dolutegravir free acid (DF) and SLP from the FTIR spectra of DSSD and DFSD. Both DSSD and DFSD improved the solubility of Dolutegravir (DTG) to 5.7 and 4.54 folds compared to the pure forms. Similarly, drug release from DSSD and DFSD was 2 and 1.5 folds higher than that in the pure form, owing to the rapid dissolution of the drug from the formulations. The permeability of DSSD and DFSD was estimated using the dialysis membrane, which enhanced the DTG permeability. The improvement in in vitro studies was translated into in vivo pharmacokinetic profiles of DSSD and DFSD, where 4.0 and 5.6 folds, respectively, improved the Cmax of DTG.
... The supersaturation state achieved by amorphous systems can directly translate into improved absorption of active substances, as only free, dissolved molecules are capable of penetrating biological barriers. Several studies show that the supersaturated state contributes to achieving higher drug concentrations in the blood [30][31][32][33][34]. Accordingly, it can be expected that the amorphous dispersions obtained would also enable increased absorption of hesperetin and piperine. ...
The low bioaccessibility of hesperetin and piperine hampers their application as therapeutic agents. Piperine has the ability to improve the bioavailability of many compounds when co-administered. The aim of this paper was to prepare and characterize the amorphous dispersions of hesperetin and piperine, which could help to improve solubility and boost the bioavailability of both plant-origin active compounds. The amorphous systems were successfully obtained by means of ball milling, as confirmed by XRPD and DSC studies. What’s more, the FT-IR-ATR study was used to investigate the presence of intermolecular interactions between the systems’ components. Amorphization enhanced the dissolution rate as a supersaturation state was reached, as well as improving the apparent solubility of both compounds by 245-fold and 183-fold, respectively, for hesperetin and piperine. In the in vitro permeability studies simulating gastrointestinal tract and blood-brain barrier permeabilities, these increased by 775-fold and 257-fold for hesperetin, whereas they were 68-fold and 66-fold for piperine in the GIT and BBB PAMPA models, respectively. Enhanced solubility had an advantageous impact on antioxidant as well as anti-butyrylcholinesterase activities—the best system inhibited 90.62 ± 0.58% of DPPH radicals and 87.57 ± 1.02% butyrylcholinesterase activity. To sum up, amorphization considerably improved the dissolution rate, apparent solubility, permeability, and biological activities of hesperetin and piperine.
... The results suggest that PPD-S/T-MM not only enables a shorter period to reach Tmax, which could clearly benefit to the fast management of acute schizophrenia but also enables higher oral bioavailability of PPD, which could reasonably extrapolate that superior PPD levels can be achieved in the brain after oral administration of PPD-S/T/MM over PPD suspension. The superior in vivo performance of PPD-S/T/MM should be attributed to the following reasons: (1) protection of the loaded PPD from crystallization in the gastrointestinal tract, (2) release of the PPD in a controlled manner at the wall of the small intestine [11], (3) prolongation of the residence time of the dissolved PPD in the gut due to the anti-nucleant performance of Soluplus ® [42], and (4) inhibition of efflux pumps by TPGS to improve the drug accumulation [43]. In SGF (Figure 8A), the cumulative release of PPD from PPD-S/T-MM-1.0 and PPD-S/T-MM-2.0 ...
... The results suggest that PPD-S/T-MM not only enables a shorter period to reach T max , which could clearly benefit to the fast management of acute schizophrenia but also enables higher oral bioavailability of PPD, which could reasonably extrapolate that superior PPD levels can be achieved in the brain after oral administration of PPD-S/T/MM over PPD suspension. The superior in vivo performance of PPD-S/T/MM should be attributed to the following reasons: (1) protection of the loaded PPD from crystallization in the gastrointestinal tract, (2) release of the PPD in a controlled manner at the wall of the small intestine [11], (3) prolongation of the residence time of the dissolved PPD in the gut due to the anti-nucleant performance of Soluplus ® [42], and (4) inhibition of efflux pumps by TPGS to improve the drug accumulation [43]. Table 6. ...
The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus®/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. The critical micelle concentration (CMC) of blank S/T-MM was 4.77 × 10-2 mg/mL. PPD presented much higher solubility in PPD-S/T-MM formulation than that in pure water. The particle size of blank or drug loaded S/T-MM was around 60 nm. The polydispersity index (PDI) was less than 0.1. PPD-S/T-MM presented a nearly spherical shape under transmission electron microscopy. The encapsulation efficiency (EE%) of PPD-S/T-MM was higher than 94%. Based on the analysis of XRD and DSC, it was proved that PPD was incorporated in the core of the mixed micelles as amorphous dispersion or solid solution. PPD-S/T-MM were stable when they were undergoing dilution with water and the change of environmental pH. Although PPD-S/T-MM showed lower rates to release PPD than those from PPD raw material in acidic solution, they provided faster release rates in neutral conditions than those from PPD raw material who only showed modest dissolution in the same neutral condition. This proves that PPD-S/T-MM can release PPD in a more controlled manner. After oral administration of PPD-S/T-MM (dose of PPD, 6 mg/kg) in rats, the plasma concentration of PPD increased rapidly: Tmax was 0.83 ± 0.29 h, and Cmax was 844.33 ± 93.73 ng/mL. Oral administration of PPD suspension resulted in longer Tmax and lower Cmax. The relative oral bioavailability was about 158% for PPD-S/T-MM over PPD suspension. These findings confirm that PPD-S/T-MM can provide faster release in neutral conditions and better oral absorption in rats than those from PPD raw material, which should potentially benefit patients with acute schizophrenia.
... Soluplus V R is a poly(ethylene glycol)-polyvinyl acetate-polyvinylcaprolactam-based grafted copolymer that is amphiphilic, containing both hydrophilic and hydrophobic moieties. It has been reported that Soluplus V R plays an important role in stabilizing the micelles and amorphous form of drugs (Thiry et al. 2016;Zhong et al. 2016). As ternary CD complexes, Soluplus V R might reduce the mobility of CD and change the hydration properties of CD molecules, resulting in enhanced solubility of drugs and their complexes (Loftsson and M asson 2004;Alshehri et al. 2020;Vartak et al. 2020). ...
The poor aqueous solubility of irbesartan (IRB) and candesartan cilexetil (CAC) may hamper their bioavailability when orally or topically administered. Among several attempts, the promising nanoaggregate formation by γ-cyclodextrin (γCD) complexation of drugs in aqueous solution with or without water-soluble polymers was investigated. According to phase solubility studies, Soluplus® showed the highest complexation efficiency (CE) of drug/γCD complexes among the polymers tested. The aqueous solubility of IRB and CAC was markedly increased as a function of Soluplus® concentrations. The binary drug/γCD and ternary drug/γCD/Soluplus® complex formations were supported and confirmed by solid state characterizations, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FT-IR) spectroscopy. The true inclusion mode was also proved by proton nuclear magnetic resonance (¹H-NMR) spectroscopy. The nanoaggregate size and morphology of binary and ternary systems were observed using dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques. The size of these nanocarriers depends on the concentration of Soluplus®. The use of Soluplus® could significantly enhance drug solubility and stabilize complex nanoaggregates, which could be a prospective platform for drug delivery systems.
... 24 SOL can also form nanocarriers to keep the drug saturated in gastrointestinal absorption and sustain its release behavior. 25 Due to its versatile features, SOL is usually prepared as a solid dispersion, 26,27 nano-emulsion, 28 nano-micelle, [29][30][31] thermosensitive hydrogel, 32,33 or transparent film 34 to increase the solubility and bioavailability of APIs. Recent reports have demonstrated that SOL can form composites with excipients, such as Pluronic s , Solutol HS15, hyaluronic acid-ceramide (HACE), and D-a-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), thereby helping antitumor drugs to avoid toxic agents, achieve higher intestinal epithelial adsorption and better target cancer sites. ...
Glutaminolysis inhibitors have shown early promise in cancer therapeutics. Specifically, kidney-type glutaminase (KGA) has been a long-standing anti-tumor drug target; KGA allosteric inhibitors have attracted great attention due to their superior enzyme specificity and good drug safety profiles. However, the main issue with allosteric inhibitors-including BPTES, CB-839, and the recently developed KGA allosteric and glutamate dehydrogenase (GDH) dual inhibitor, Hexylselen (CPD-3B)-is their low solubility; it leads to limited in vivo efficacy. To optimize their formulation, various delivery carriers were screened in the present study. Soluplus® (SOL), an amphiphilic graft polymer, showed an interesting structure-solubility/activity relationship with Selen molecules containing different middle chain sizes. Among these molecules, the long chain molecule CPD-3B showed 3000-fold increased solubility with SOL, forming well-dispersed and stable micelles 60-80 nm in size. Moreover, CPD-3B@SOL micelles exhibited good metabolic stability in both blood and liver microsomes. These advantages significantly enhanced the bioavailability and in vivo antitumor efficacy of CPD-3B@SOL micelles in the H22 hepatocarcinoma xenograft mouse model. Thus, the current study provided a practical delivery system for allosteric inhibitors of glutaminase, which is one of the bottlenecks of targeting tumor glutaminolysis.
... Three ml samples were withdrawn from the test medium without volume replenishment at (5, 10, 15, 30, 60, 30, 45, 60)min, 2 hours, 3hours, 4 hours, 5 hours, and 6 hours. Withdrawn samples were filtered through a 0.45 μm filter medium and then analyzed using UV-spectrophotometer for measuring their UV absorbance at 257 nm (8,9) . ...
Objective: This study aimed to prepare soluplus based liquid supersaturable self-emulsifying drug delivery system (S-SEDD) of cilostazol for oral use. Method:The best liquid self-emulsifying drug delivery (liquid SEDD) formula previously prepared in our laboratory containing oleic acid (10%) as oil, tween 80 (45%) as surfactant and transcutol (45%) as co-surfactant (100 μl, 450 μl and 450 μl respectively) was found to consist of high percentage of vehicles (oil, surfactant and co-surfactant) that might be irritant upon oral administration, therefore, this formula was changed into liquid supersaturable self-emulsifying drug delivery system (S-SEDD) using different percent of soluplus as precipitation inhibitor as well as reducing the vehicle content to the minimum required amount and keeping the same dug content (50 mg). The efficiency of soluplus (as precipitation inhibitor) was evaluated by precipitation test using in-vitro dissolution study under non-sink conditions (in 200 ml dissolution medium pH 1.2 for 2 hours and pH 6.8 for 1 hour) in comparison to the liquid SEDD previously prepared in our laboratory. The droplet size of supersaturated emulsion was measured, in addition to characterization of the precipitate by measuring its melting point, IR and DSC spectrum. Result:The result showed that the formula (LS-3) containing 5% w/w soluplus in addition to oleic acid 25 μl(10%), tween 80 112.5 μl (45%) and transcutol 112.5μl (45%) was effectively retarded drug precipitation and maintained>90% of cilostazol in the solubilized form after 3 hours in non-sink conditions similar to the previously prepared liquid SEDD although it contains one forth the volume of content. The droplet size of the supersaturated SEDD was <250 nm. Conclusion:This study succeeded to prepare cilostazol liquid oral dosage form using supersaturated self-emulsification technology utilizing soluplus with minimum vehicle ingredients in comparison to liquid SEDD that improve drug solubility, absorption and reducing bioavailability variation with no vehicle-related side effects that will lead to improving patient compliance.
