Exploring the utility of the Chasing Principle: influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension

Jørgensen, Scheyla Daniela Siqueira; Rades, Thomas; Mu, Huiling; Gräeser, Kirsten; Müllertz, Anette

doi:10.1016/j.apsb.2018.07.004

Cited by 15 publications

(8 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The basic drug CIN is, among the three model APIs, the most lipophilic compound with a logP of 5.8 [ 47 ]. It is, therefore, reasonable to expect lower affinity between the drug and the hydrophilic carrier Gelucire.…”

Section: Resultsmentioning

confidence: 99%

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances

2020

View full text Add to dashboard Cite

Delivery of poorly water soluble active pharmaceutical ingredients (APIs) by semi-crystalline solid dispersions prepared by spray congealing in form of microparticles (MPs) is an emerging method to increase their oral bioavailability. In this study, solid dispersions based on hydrophilic Gelucires® (Gelucire® 50/13 and Gelucire® 48/16 in different ratio) of three BCS class II model compounds (carbamazepine, CBZ, tolbutamide, TBM, and cinnarizine, CIN) having different physicochemical properties (logP, pKa, Tm) were produced by spray congealing process. The obtained MPs were investigated in terms of morphology, particles size, drug content, solid state properties, drug-carrier interactions, solubility, and dissolution performances. The solid-state characterization showed that the properties of the incorporated drug had a profound influence on the structure of the obtained solid dispersion: CBZ recrystallized in a different polymorphic form, TBM crystallinity was significantly reduced as a result of specific interactions with the carrier, while smaller crystals were observed in case of CIN. The in vitro tests suggested that the drug solubility was mainly influenced by carrier composition, while the drug dissolution behavior was affected by the API solid state in the MPs after the spray congealing process. Among the tested APIs, TBM-Gelucire dispersions showed the highest enhancement in drug dissolution as a result of the reduced drug crystallinity.

show abstract

Section: Resultsmentioning

confidence: 99%

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances

2020

View full text Add to dashboard Cite

show abstract

“…[27] In another in vitro study, the solubility of carvedilol in simulated intestinal fluid with extreme BS concentration (50 mM) was ~ 0.7 mg/ml, and further increased in the presence of digested LBF to ~ 0.8 mg/ml. [28] Taken together, in vitro the presence of FFAs is the essential component for increased drug solubilisation of the weak base carvedilol, while in vivo the effect is mediated by both FFA and triggered BS secretion.…”

Section: Discussionmentioning

confidence: 99%

Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?

Alskär

Parrow

Keemink

et al. 2019

Journal of Controlled Release

View full text Add to dashboard Cite

Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly watersoluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipid-based drug formulation containing the predissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acid) and bile salt. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acid and bile salt in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in solid form, e.g. due to chemical instability in the lipid vehicle. Finally, the in vitro lipolysispermeation used herein established IVIVC for carvedilol in the presence of LBFs.

show abstract

“…Maisine CC is winterized oil composed of long-chain mono-, di-, and triglycerides for lipid-based formulations and is commonly applied not only to solubilize poorly water-soluble lipophilic APIs but to increase their oral bioavailabilities at the same time. 57 , 58 This property enhances chyle particle production as well as lymphatic transport of drug and avoids drug degradation by first-pass hepatic metabolism, by which reasons the bioavailability of the drug can be improved. 47 , 59 Hence, for the purposes of achieving optimum drug loading, forming the smallest particle sizes and improving lymphatic transport of GKA, Maisine CC was selected as the oil phase in GKA-SNEDDS.…”

Section: Discussionmentioning

confidence: 99%

Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

Yin¹,

Yin²,

Ouyang³

et al. 2021

DDDT

View full text Add to dashboard Cite

Purpose The aim of the present study was to develop an optimized Genkwanin (GKA)-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation to enhance the solubility, intestinal permeability, oral bioavailability and anti-colitis-associated colorectal cancer (CAC) activity of GKA. Methods We designed a SNEDDS comprised oil phase, surfactants and co-surfactants for oral administration of GKA, the best of which were selected by investigating the saturation solubility, constructing pseudo-ternary phase diagrams, followed by optimizing thermodynamic stability, emulsification efficacy, self-nanoemulsification time, droplet size, transmission electron microscopy (TEM), drug release and intestinal permeability. In addition, the physicochemical properties and pharmacokinetics of GKA-SNEDDS were characterized, and its anti-colitis-associated colorectal cancer (CAC) activity and potential mechanisms were evaluated in AOM/DSS-induced C57BL/6J mice model. Results The optimized nanoemulsion formula (OF) consists of Maisine CC, Labrasol ALF and Transcutol HP in a weight ratio of 20:60:20 (w/w/w), in which ratio the OF shows multiple improvements, specifically small mean droplet size, excellent stability, fast release properties as well as enhanced solubility and permeability. Pharmacokinetic studies demonstrated that compared with GKA suspension, the relative bioavailability of GKA-SNEDDS was increased by 353.28%. Moreover, GKA-SNEDDS not only significantly prevents weight loss and improves disease activity index (DAI) but also reduces the histological scores of inflammatory cytokine levels as well as inhibiting the formation of colon tumors via inducing tumor cell apoptosis in the AOM/DSS-induced CAC mice model. Conclusion Our results show that the developed GKA-SNEDDS exhibited enhanced oral bioavailability and excellent anti-CAC efficacy. In summary, GKA-SNEDDS, using lipid nanoparticles as the drug delivery carrier, can be applied as a potential drug delivery system for improving the clinical application of GKA.

show abstract

Exploring the utility of the Chasing Principle: influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension

Cited by 15 publications

References 38 publications

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances

Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?

Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

Contact Info

Product

Resources

About